CN100586421C - Ligustrazine microcosmic salt liposome medicine and preparing method - Google Patents
Ligustrazine microcosmic salt liposome medicine and preparing method Download PDFInfo
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- CN100586421C CN100586421C CN200610138601A CN200610138601A CN100586421C CN 100586421 C CN100586421 C CN 100586421C CN 200610138601 A CN200610138601 A CN 200610138601A CN 200610138601 A CN200610138601 A CN 200610138601A CN 100586421 C CN100586421 C CN 100586421C
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- 239000003814 drug Substances 0.000 title claims abstract description 73
- 239000002502 liposome Substances 0.000 title claims abstract description 36
- FINHMKGKINIASC-UHFFFAOYSA-N Tetramethylpyrazine Chemical compound CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 title claims description 53
- CUXQLKLUPGTTKL-UHFFFAOYSA-M microcosmic salt Chemical compound [NH4+].[Na+].OP([O-])([O-])=O CUXQLKLUPGTTKL-UHFFFAOYSA-M 0.000 title claims description 24
- 238000000034 method Methods 0.000 title description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 71
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 48
- 238000002360 preparation method Methods 0.000 claims abstract description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000000203 mixture Substances 0.000 claims abstract description 33
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 32
- 235000010445 lecithin Nutrition 0.000 claims abstract description 32
- 239000000787 lecithin Substances 0.000 claims abstract description 32
- 229940067606 lecithin Drugs 0.000 claims abstract description 32
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims abstract description 17
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims abstract description 16
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims abstract description 16
- BTEISVKTSQLKST-UHFFFAOYSA-N Haliclonasterol Natural products CC(C=CC(C)C(C)(C)C)C1CCC2C3=CC=C4CC(O)CCC4(C)C3CCC12C BTEISVKTSQLKST-UHFFFAOYSA-N 0.000 claims abstract description 16
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229960003180 glutathione Drugs 0.000 claims abstract description 16
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 claims abstract description 16
- 229940032091 stigmasterol Drugs 0.000 claims abstract description 16
- 235000016831 stigmasterol Nutrition 0.000 claims abstract description 16
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000004698 Polyethylene Substances 0.000 claims abstract description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 15
- -1 polyethylene Polymers 0.000 claims abstract description 15
- 229920000573 polyethylene Polymers 0.000 claims abstract description 15
- SGNBVLSWZMBQTH-FGAXOLDCSA-N Campesterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 SGNBVLSWZMBQTH-FGAXOLDCSA-N 0.000 claims description 15
- 102000002322 Egg Proteins Human genes 0.000 claims description 15
- 108010000912 Egg Proteins Proteins 0.000 claims description 15
- 241000287828 Gallus gallus Species 0.000 claims description 15
- SGNBVLSWZMBQTH-PODYLUTMSA-N campesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](C)C(C)C)[C@@]1(C)CC2 SGNBVLSWZMBQTH-PODYLUTMSA-N 0.000 claims description 15
- 235000000431 campesterol Nutrition 0.000 claims description 15
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 15
- 235000003969 glutathione Nutrition 0.000 claims description 15
- 210000004681 ovum Anatomy 0.000 claims description 15
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 15
- 229920000053 polysorbate 80 Polymers 0.000 claims description 15
- 239000006185 dispersion Substances 0.000 claims description 14
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 14
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 14
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 14
- 239000008363 phosphate buffer Substances 0.000 claims description 12
- 229960004756 ethanol Drugs 0.000 claims description 8
- 230000001804 emulsifying effect Effects 0.000 claims description 7
- 239000000706 filtrate Substances 0.000 claims description 7
- 238000013467 fragmentation Methods 0.000 claims description 7
- 238000006062 fragmentation reaction Methods 0.000 claims description 7
- 238000005374 membrane filtration Methods 0.000 claims description 7
- 230000010355 oscillation Effects 0.000 claims description 7
- 230000001954 sterilising effect Effects 0.000 claims description 7
- 238000004659 sterilization and disinfection Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 229940079593 drug Drugs 0.000 abstract description 40
- KWWLGXNRLABSMP-UHFFFAOYSA-N phosphoric acid;2,3,5,6-tetramethylpyrazine Chemical compound OP(O)(O)=O.CC1=NC(C)=C(C)N=C1C KWWLGXNRLABSMP-UHFFFAOYSA-N 0.000 abstract description 7
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 abstract 1
- 108010024636 Glutathione Proteins 0.000 abstract 1
- 241001494479 Pecora Species 0.000 abstract 1
- 230000002490 cerebral effect Effects 0.000 abstract 1
- 229920000136 polysorbate Polymers 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 24
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 20
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 15
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 15
- 238000002651 drug therapy Methods 0.000 description 15
- 238000002347 injection Methods 0.000 description 15
- 239000007924 injection Substances 0.000 description 15
- 241001597008 Nomeidae Species 0.000 description 10
- 108090000190 Thrombin Proteins 0.000 description 10
- 230000004520 agglutination Effects 0.000 description 10
- 238000004220 aggregation Methods 0.000 description 10
- 230000002776 aggregation Effects 0.000 description 10
- 229940114079 arachidonic acid Drugs 0.000 description 10
- 235000021342 arachidonic acid Nutrition 0.000 description 10
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 229960004072 thrombin Drugs 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- 238000013096 assay test Methods 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000001939 inductive effect Effects 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- 230000003285 pharmacodynamic effect Effects 0.000 description 5
- 238000003825 pressing Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 4
- 210000002249 digestive system Anatomy 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 241000125183 Crithmum maritimum Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000011981 development test Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
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- 230000008685 targeting Effects 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention relates to a tetramethylpyrazine phosphate liposome drug and a preparation method; wherein, the drug is characterized in that: the effective efficacy components and weight accounts of the liposome drug are as following: a mixture 200 to330 with a weight ratio 4 to 1 of egg yolk lecithin and sheep cerebral lecithin, a mixture 170 to 280 with a weight ratio 3 to 1of stigmasterol and campestrol, reduction glutathione 2.5 to 10, tetramethylpyrazine phosphate 15 to 25, a mixture 720 to 1200 with a weight ratio 1 : 0.01 to 0.05 : 0.02 to 0.07 of tert-butyl alcohol, ethanol, acetone, amixture 140 to 160 with a weight ratio 4:05 to 1 of polyethylene glycol-2000 and tween 801, and hydroxyl propyl methyl cellulose 100 to 120. The invention also provides the preparation method for theliposome drugs. The invention has the advantages of adopting the provided drugs, enabling to decrease the drug dosage by two third and once a day, and improving the efficacy above fifteen percent.
Description
Technical field
The present invention relates to a kind of ligustrazine microcosmic salt liposome medicine and preparation method.
Background technology
Ligustrazine is the extraction monomer component of samphire Rhizoma Chuanxiong, now can be by synthetic.Ligustrazine microcosmic salt character is more stable than ligustrazine, ligustrazine salt hydrochlorate, and is difficult for distillation.Make medicine with ligustrazine microcosmic salt, can treat and prevent and treat cardiovascular and cerebrovascular disease, and have instant effect, good effect, the little advantage of side effect.
But in the prior art, still there is side effect in the ligustrazine microcosmic salt medicine, and especially the digestive system side effect is obvious, and every day, administration number of times was many simultaneously, even intravenous drip, still need twice every day, needs 3-4 hour at every turn.All make troubles elapsed time for patient and doctor.Simultaneously, stability of drug is still not high, and especially antibody external oxidation and body endoperoxides is indifferent.
Summary of the invention
In order to overcome the above-mentioned defective of existing ligustrazine microcosmic salt medicine, the invention provides a kind of ligustrazine microcosmic salt liposome medicine, the present invention also provides the preparation method of described liposome medicament.
Technical scheme of the present invention is as follows:
The invention provides a kind of ligustrazine microcosmic salt liposome medicine, it is characterized in that, the effective active ingredient and the parts by weight thereof of described liposome medicament are as follows:
Ovum Gallus domesticus Flavus lecithin, 4: 1 weight ratio mixture of Medulla caprae seuovis lecithin 200-330;
3: 1 mixture 170-280 of stigmasterol and campesterol weight ratio;
Reduced glutathion 2.5-10;
Ligustrazine microcosmic salt 15-25;
The tert-butyl alcohol, dehydrated alcohol, acetone weight ratio 1: 0.01-0.05: 0.02-0.07 mixture 720-1200;
Polyethylene Glycol-2000, Tween 80 weight ratio 4: 0.5-1 mixture 140-160;
Hydroxypropyl methylcellulose 100-120.
The present invention also provides the preparation method of above-mentioned liposome medicament, it is characterized in that, described preparation method comprises the steps:
(1) Ovum Gallus domesticus Flavus lecithin, Medulla caprae seuovis lecithin, stigmasterol, the campesterol of described amount is dissolved in the tert-butyl alcohol, dehydrated alcohol and the acetone mixed liquor of described amount, fully dissolving fully;
(2) reduced glutathion, ligustrazine microcosmic salt, Polyethylene Glycol-2000, Tween 80, the hydroxypropyl methylcellulose of described amount joined in the phosphate buffer of 0.01M, pH3.0-7.5 of 1700-2800 weight portion fully dissolving;
(3) mixed liquor with step (1) and step (2) preparation mixes, and makes uniform dispersion solution;
(4) the dispersion solution with step (3) preparation carries out fragmentation by nanometer high pressure homogenizer (Langfang, Hebei machinery plant), disperse, emulsifying, and carry out cold sterilization, and pressure is 100MPa-300MPa, the jet flow velocity is 480 meter per seconds, the higher-order of oscillation takes place, repeat to be nanoscale until forming liposome, and to be dispersed into equally distributed mean diameter for several times less than the 100nm liposome solutions;
(5) with the liposome solutions of step (4) preparation with 0.22 μ m membrane filtration, get filtrate, carry out lyophilizing by receivable dosage on the pharmaceutics, remove the tert-butyl alcohol, ethanol and acetone, make the water residual quantity less than 1.5%, add on the pharmaceutics acceptable auxiliary then and make acceptable forms on the pharmaceutics.
The technique effect that the present invention realized is as follows:
1. medicine provided by the present invention can reduce drug dose 2/3rds, and medication every day number of times is only for once, and curative effect improves more than 15%.
2. owing to make lipidosome drug carrier, digestive system distributes seldom in vivo, adds that dosage and medication number of times reduce, so medicine of the present invention is almost eliminated the side effect of digestive system.
3. added reduced glutathion in the medicine of the present invention, so resist external oxidation of medicine and body endoperoxides and medicine itself anaphylaxis effectively to liver.
4. in the medicine of the present invention, owing to added Polyethylene Glycol and Tween 80, make and realized long circulation in the lipidosome drug carrier blood system in vivo, initiatively targeting is in heart, vascular system, and treatment is better than general ordinary preparation and general Liposomal formulation greatly for cardiovascular and cerebrovascular vessel.
5. prove through development test of the present invention, Ovum Gallus domesticus Flavus lecithin, Medulla caprae seuovis lecithin weight proportion by the invention prescription, reach stigmasterol and campesterol weight proportion by the present invention's prescription, making lipidosome drug carrier is the single chamber nanometer grade liposome, envelop rate reaches more than 96%, and shutoff is solid does not leak, and burst effect is very little in vivo, discharges evenly.
6. medicine of the present invention forms uniform nanoscale unilamelar liposome, and can not assemble after aquation again.
7. medicine of the present invention adopts animal lecithin identical with the human body cell material, so, no antigen reaction in human body.
8. in the medicine of the present invention, add formula ratio ethanol, acetone in the t-butanol solvent, when making the freezing distillation.Dehydrated alcohol, acetone are got through the distillation passage of the tert-butyl alcohol and moisture on the ice cube top layer, distillation is accelerated.
The specific embodiment
Embodiment 1:
The prescription that present embodiment adopted following (consumption unit: restrain):
Ovum Gallus domesticus Flavus lecithin, 4: 1 weight ratio mixture 200 of Medulla caprae seuovis lecithin;
3: 1 mixture 170 of stigmasterol and campesterol weight ratio;
Reduced glutathion 2.5;
Ligustrazine microcosmic salt 15;
The tert-butyl alcohol, dehydrated alcohol, 1: 0.01: 0.02 mixture 720 of acetone weight ratio;
Polyethylene Glycol-2000,4: 0.5 mixture 140 of Tween 80 weight ratio;
Hydroxypropyl methylcellulose 100.
Present embodiment adopts phosphate buffer 1 700 grams of 0.01M, pH3.0-7.5.
The preparation method of present embodiment is as follows:
(1) Ovum Gallus domesticus Flavus lecithin, Medulla caprae seuovis lecithin, stigmasterol, the campesterol of described amount is dissolved in the tert-butyl alcohol, dehydrated alcohol and the acetone mixed liquor of described amount, fully dissolving fully;
(2) reduced glutathion, ligustrazine microcosmic salt, Polyethylene Glycol-2000, Tween 80, the hydroxypropyl methylcellulose of described amount joined in the phosphate buffer of 0.01M, pH3.0-7.5 of 1700-2800 weight portion fully dissolving;
(3) mixed liquor with step (1) and step (2) preparation mixes, and makes uniform dispersion solution;
(4) the dispersion solution with step (3) preparation carries out fragmentation by the nanometer high pressure homogenizer, disperse, emulsifying, and carry out cold sterilization, and pressure is 100MPa-300MPa, the jet flow velocity is 480 meter per seconds, the higher-order of oscillation takes place, repeat to be nanoscale until forming liposome, and to be dispersed into equally distributed particle diameter for several times less than the 100nm liposome solutions;
(5) with the liposome solutions of step (4) preparation with 0.22 μ m membrane filtration, get filtrate, carry out lyophilizing by receivable dosage on the pharmaceutics, remove the tert-butyl alcohol, ethanol and acetone, make the water residual quantity less than 1.5%, add on the pharmaceutics acceptable auxiliary then and make acceptable forms on the pharmaceutics.
The pharmacodynamics checking is as follows:
Test model:
1.1 platelet function assay test: vivo medicine-feeding, select rat for use, the selective aggregation derivant: adenosine diphosphate (ADP) (ADP), thrombin, arachidonic acid (AA), observe maximum agglutination rate.The derivant maximum agglutination rate should be effective more than 50%.Press down platelet aggregation rate (on average pressing down platelet aggregation rate) to statistics after control drug and the Drug therapy medication of the present invention.
1.2 1.2 platelet dependency thrombotests: vivo medicine-feeding, select mice for use, select intravenous injection, the aggregation inducing agent is a thrombin.To control drug and Drug therapy of the present invention, observe the statistics mouse death rate.
2. control drug is selected the ligustrazine phosphate injection for use, and dosage is 5mg/kg.
3. medicine of the present invention is selected lyophilized injection for use, and dosage is 2.5mg/kg.
4. medication and time: once a day, lumbar injection, one week of medication.
Above matched group and be 30 one group with medicine group of the present invention.
5. result of the test is as follows:
Embodiment 2:
The prescription that present embodiment adopted following (consumption unit: restrain):
Ovum Gallus domesticus Flavus lecithin, 4: 1 weight ratio mixture 260 of Medulla caprae seuovis lecithin;
3: 1 mixture 200 of stigmasterol and campesterol weight ratio;
Reduced glutathion 6;
Ligustrazine microcosmic salt 20;
The tert-butyl alcohol, dehydrated alcohol, 1: 0.01: 0.07 mixture 1000 of acetone weight ratio;
Polyethylene Glycol-2000,4: 1 mixture 150 of Tween 80 weight ratio;
Hydroxypropyl methylcellulose 110.
Present embodiment adopts phosphate buffer 2500 grams of 0.01M, pH3.0-7.5.
The preparation method of present embodiment is as follows:
(1) Ovum Gallus domesticus Flavus lecithin, Medulla caprae seuovis lecithin, stigmasterol, the campesterol of described amount is dissolved in the tert-butyl alcohol, dehydrated alcohol and the acetone mixed liquor of described amount, fully dissolving fully;
(2) reduced glutathion, ligustrazine microcosmic salt, Polyethylene Glycol-2000, Tween 80, the hydroxypropyl methylcellulose of described amount joined in the phosphate buffer of 0.01M, pH3.0-7.5 of 1700-2800 weight portion fully dissolving;
(3) mixed liquor with step (1) and step (2) preparation mixes, and makes uniform dispersion solution;
(4) the dispersion solution with step (3) preparation carries out fragmentation by the nanometer high pressure homogenizer, disperse, emulsifying, and carry out cold sterilization, and pressure is 100MPa-300MPa, the jet flow velocity is 480 meter per seconds, the higher-order of oscillation takes place, repeat to be nanoscale until forming liposome, and to be dispersed into equally distributed mean diameter for several times less than the 100nm liposome solutions;
(5) with the liposome solutions of step (4) preparation with 0.22 μ m membrane filtration, get filtrate, carry out lyophilizing by receivable dosage on the pharmaceutics, remove the tert-butyl alcohol, ethanol and acetone, make the water residual quantity less than 1.5%, add on the pharmaceutics acceptable auxiliary then and make acceptable forms on the pharmaceutics.
The pharmacodynamics checking is as follows:
Test model:
1.3 platelet function assay test: vivo medicine-feeding, select rat for use, the selective aggregation derivant: adenosine diphosphate (ADP) (ADP), thrombin, arachidonic acid (AA), observe maximum agglutination rate.The derivant maximum agglutination rate should be effective more than 50%.Press down platelet aggregation rate (on average pressing down platelet aggregation rate) to statistics after control drug and the Drug therapy medication of the present invention.
1.4 1.2 platelet dependency thrombotests: vivo medicine-feeding, select mice for use, select intravenous injection, the aggregation inducing agent is a thrombin.To control drug and Drug therapy of the present invention, observe the statistics mouse death rate.
2. control drug is selected the ligustrazine phosphate injection for use, and dosage is 5mg/kg.
3. medicine of the present invention is selected lyophilized injection for use, and dosage is 2.5mg/kg.
4. medication and time: once a day, lumbar injection, one week of medication.
Above matched group and be 30 one group with medicine group of the present invention.
5. result of the test is as follows:
Embodiment 3:
The prescription that present embodiment adopted following (consumption unit: restrain):
Ovum Gallus domesticus Flavus lecithin, 4: 1 weight ratio mixture 330 of Medulla caprae seuovis lecithin;
3: 1 mixture 280 of stigmasterol and campesterol weight ratio;
Reduced glutathion 10;
Ligustrazine microcosmic salt 25;
The tert-butyl alcohol, dehydrated alcohol, 1: 0.05: 0.027 mixture 1200 of acetone weight ratio;
Polyethylene Glycol-2000,4: 1 mixture 160 of Tween 80 weight ratio;
Hydroxypropyl methylcellulose 120.
Present embodiment adopts phosphate buffer 2800 grams of 0.01M, pH3.0-7.5.
The preparation method of present embodiment is as follows:
(1) Ovum Gallus domesticus Flavus lecithin, Medulla caprae seuovis lecithin, stigmasterol, the campesterol of described amount is dissolved in the tert-butyl alcohol, dehydrated alcohol and the acetone mixed liquor of described amount, fully dissolving fully;
(2) reduced glutathion, ligustrazine microcosmic salt, Polyethylene Glycol-2000, Tween 80, the hydroxypropyl methylcellulose of described amount joined in the phosphate buffer of 0.01M, pH3.0-7.5 of 1700-2800 weight portion fully dissolving;
(3) mixed liquor with step (1) and step (2) preparation mixes, and makes uniform dispersion solution;
(4) the dispersion solution with step (3) preparation carries out fragmentation by the nanometer high pressure homogenizer, disperse, emulsifying, and carry out cold sterilization, and pressure is 100MPa-300MPa, the jet flow velocity is 480 meter per seconds, the higher-order of oscillation takes place, repeat to be nanoscale until forming liposome, and to be dispersed into equally distributed particle diameter for several times less than the 100nm liposome solutions;
(5) with the liposome solutions of step (4) preparation with 0.22 μ m membrane filtration, get filtrate, carry out lyophilizing by receivable dosage on the pharmaceutics, remove the tert-butyl alcohol, ethanol and acetone, make the water residual quantity less than 1.5%, add on the pharmaceutics acceptable auxiliary then and make acceptable forms on the pharmaceutics.
The pharmacodynamics checking is as follows:
Test model:
1.5 platelet function assay test; Vivo medicine-feeding is selected rat for use, the selective aggregation derivant: adenosine diphosphate (ADP) (ADP), thrombin, arachidonic acid (AA), observe maximum agglutination rate.The derivant maximum agglutination rate should be effective more than 50%.Press down platelet aggregation rate (on average pressing down platelet aggregation rate) to statistics after control drug and the Drug therapy medication of the present invention.
1.6 1.2 platelet dependency thrombotests: vivo medicine-feeding, select mice for use, select intravenous injection, the aggregation inducing agent is a thrombin.To control drug and Drug therapy of the present invention, observe the statistics mouse death rate.
2. control drug is selected the ligustrazine phosphate injection for use, and dosage is 5mg/kg.
3. medicine of the present invention is selected lyophilized injection for use, and dosage is 2.5mg/kg.
4. medication and time: once a day, lumbar injection, one week of medication.
Above matched group and be 30 one group with medicine group of the present invention.
5. result of the test is as follows:
Embodiment 4:
The prescription that present embodiment adopted following (consumption unit: restrain):
Ovum Gallus domesticus Flavus lecithin, 4: 1 weight ratio mixture 200 of Medulla caprae seuovis lecithin;
3: 1 mixture 280 of stigmasterol and campesterol weight ratio;
Reduced glutathion 2.5;
Ligustrazine microcosmic salt 25;
The tert-butyl alcohol, dehydrated alcohol, 1: 0.05: 0.07 mixture 720 of acetone weight ratio;
Polyethylene Glycol-2000,4: 0.8 mixture 160 of Tween 80 weight ratio;
Hydroxypropyl methylcellulose 100.
Present embodiment adopts phosphate buffer 2700 grams of 0.01M, pH3.0-7.5.
The preparation method of present embodiment is as follows:
(1) Ovum Gallus domesticus Flavus lecithin, Medulla caprae seuovis lecithin, stigmasterol, the campesterol of described amount is dissolved in the tert-butyl alcohol, dehydrated alcohol and the acetone mixed liquor of described amount, fully dissolving fully;
(2) reduced glutathion, ligustrazine microcosmic salt, Polyethylene Glycol-2000, Tween 80, the hydroxypropyl methylcellulose of described amount joined in the phosphate buffer of 0.01M, pH3.0-7.5 of 1700-2800 weight portion fully dissolving;
(3) mixed liquor with step (1) and step (2) preparation mixes, and makes uniform dispersion solution;
(4) the dispersion solution with step (3) preparation carries out fragmentation by the nanometer high pressure homogenizer, disperse, emulsifying, and carry out cold sterilization, and pressure is 100MPa-300MPa, the jet flow velocity is 480 meter per seconds, the higher-order of oscillation takes place, repeat to be nanoscale until forming liposome, and to be dispersed into equally distributed particle diameter for several times less than the 100nm liposome solutions;
(5) with the liposome solutions of step (4) preparation with 0.22 μ m membrane filtration, get filtrate, carry out lyophilizing by receivable dosage on the pharmaceutics, remove the tert-butyl alcohol, ethanol and acetone, make the water residual quantity less than 1.5%, add on the pharmaceutics acceptable auxiliary then and make acceptable forms on the pharmaceutics.
The pharmacodynamics checking is as follows:
Test model:
1.7 platelet function assay test: vivo medicine-feeding, select rat for use, the selective aggregation derivant: adenosine diphosphate (ADP) (ADP), thrombin, arachidonic acid (AA), observe maximum agglutination rate.The derivant maximum agglutination rate should be effective more than 50%.Press down platelet aggregation rate (on average pressing down platelet aggregation rate) to statistics after control drug and the Drug therapy medication of the present invention.
1.8 1.2 platelet dependency thrombotests: vivo medicine-feeding, select mice for use, select intravenous injection, the aggregation inducing agent is a thrombin.To control drug and Drug therapy of the present invention, observe the statistics mouse death rate.
2. control drug is selected the ligustrazine phosphate injection for use, and dosage is 5mg/kg.
3. medicine of the present invention is selected lyophilized injection for use, and dosage is 2.5mg/kg.
4. medication and time: once a day, lumbar injection, one week of medication.
Above matched group and be 30 one group with medicine group of the present invention.
5. result of the test is as follows:
Embodiment 5:
The prescription that present embodiment adopted following (consumption unit: restrain):
Ovum Gallus domesticus Flavus lecithin, 4: 1 weight ratio mixture 330 of Medulla caprae seuovis lecithin;
3: 1 mixture 170 of stigmasterol and campesterol weight ratio;
Reduced glutathion 10;
Ligustrazine microcosmic salt 15;
The tert-butyl alcohol, dehydrated alcohol, 1: 0.01: 0.02 mixture 1200 of acetone weight ratio;
Polyethylene Glycol-2000,4: 0.5 mixture 140 of Tween 80 weight ratio;
Hydroxypropyl methylcellulose 120.
Present embodiment adopts phosphate buffer 2000 grams of 0.01M, pH3.0-7.5.
The preparation method of present embodiment is as follows:
(6) Ovum Gallus domesticus Flavus lecithin, Medulla caprae seuovis lecithin, stigmasterol, the campesterol of described amount is dissolved in the tert-butyl alcohol, dehydrated alcohol and the acetone mixed liquor of described amount, fully dissolving fully;
(7) reduced glutathion, ligustrazine microcosmic salt, Polyethylene Glycol-2000, Tween 80, the hydroxypropyl methylcellulose of described amount joined in the phosphate buffer of 0.01M, pH3.0-7.5 of 1700-2800 weight portion fully dissolving;
(8) mixed liquor with step (1) and step (2) preparation mixes, and makes uniform dispersion solution;
(9) the dispersion solution with step (3) preparation carries out fragmentation by the nanometer high pressure homogenizer, disperse, emulsifying, and carry out cold sterilization, and pressure is 100MPa-300MPa, the jet flow velocity is 480 meter per seconds, the higher-order of oscillation takes place, repeat to be nanoscale until forming liposome, and to be dispersed into equally distributed 100nm liposome solutions for several times;
(10) with the liposome solutions of step (4) preparation with 0.22 μ m membrane filtration, get filtrate, carry out lyophilizing by receivable dosage on the pharmaceutics, remove the tert-butyl alcohol, ethanol and acetone, make the water residual quantity less than 1.5%, add on the pharmaceutics acceptable auxiliary then and make acceptable forms on the pharmaceutics.
The pharmacodynamics checking is as follows:
Test model:
1.9 platelet function assay test: vivo medicine-feeding, select rat for use, the selective aggregation derivant: adenosine diphosphate (ADP) (ADP), thrombin, arachidonic acid (AA), observe maximum agglutination rate.The derivant maximum agglutination rate should be effective more than 50%.Press down platelet aggregation rate (on average pressing down platelet aggregation rate) to statistics after control drug and the Drug therapy medication of the present invention.
1.10 1.2 platelet dependency thrombotests: vivo medicine-feeding, select mice for use, select intravenous injection, the aggregation inducing agent is a thrombin.To control drug and Drug therapy of the present invention, observe the statistics mouse death rate.
2. control drug is selected the ligustrazine phosphate injection for use, and dosage is 5mg/kg.
3. medicine of the present invention is selected lyophilized injection for use, and dosage is 2.5mg/kg.
4. medication and time: once a day, lumbar injection, one week of medication.
Above matched group and be 30 one group with medicine group of the present invention.
5. result of the test is as follows:
Claims (2)
1. a ligustrazine microcosmic salt liposome medicine is characterized in that, being made by following compositions in portion by weight of described liposome medicament:
Ovum Gallus domesticus Flavus lecithin, 4: 1 weight ratio mixture of Medulla caprae seuovis lecithin 200-330;
3: 1 mixture 170-280 of stigmasterol and campesterol weight ratio;
Reduced glutathion 2.5-10;
Ligustrazine microcosmic salt 15-25;
The tert-butyl alcohol, dehydrated alcohol, acetone weight ratio 1: 0.01-0.05: 0.02-0.07 mixture 720-1200;
Polyethylene Glycol-2000, Tween 80 weight ratio 4: 0.5-1 mixture 140-160;
Hydroxypropyl methylcellulose 100-120.
2. the preparation method of the described liposome medicament of claim 1 is characterized in that, described preparation method is as follows:
(1) Ovum Gallus domesticus Flavus lecithin, Medulla caprae seuovis lecithin, stigmasterol, the campesterol of described amount is dissolved in the tert-butyl alcohol, dehydrated alcohol and the acetone mixed liquor of described amount, fully dissolving fully;
(2) reduced glutathion, ligustrazine microcosmic salt, Polyethylene Glycol-2000, Tween 80, the hydroxypropyl methylcellulose of described amount joined in the phosphate buffer of 0.01M, pH3.0-7.5 of 1700-2800 weight portion fully dissolving;
(3) mixed liquor with step (1) and step (2) preparation mixes, and makes uniform dispersion solution;
(4) the dispersion solution with step (3) preparation carries out fragmentation by the nanometer high pressure homogenizer, disperse, emulsifying, and carry out cold sterilization, and pressure is 100MPa-300MPa, the jet flow velocity is 480 meter per seconds, the higher-order of oscillation takes place, repeat to be nanoscale until forming liposome, and to be dispersed into equally distributed mean diameter for several times less than the 100nm liposome solutions;
(5) with the liposome solutions of step (4) preparation with 0.22 μ m membrane filtration, get filtrate, carry out lyophilizing by receivable dosage on the pharmaceutics, remove the tert-butyl alcohol, ethanol and acetone, make the water residual quantity less than 1.5%, add on the pharmaceutics acceptable auxiliary then and make acceptable forms on the pharmaceutics.
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| CN101785782B (en) * | 2010-03-04 | 2011-10-19 | 西安力邦制药有限公司 | Long-circulating ligustrazine composite injection and preparation method thereof |
| CN101912363A (en) * | 2010-07-29 | 2010-12-15 | 蔡海德 | Dissolving ultrafiltration-spray drying-molecule dispersion coating-hydration palletizing-freeze drying method for preparing liposome combination medicine |
| CN107080748B (en) * | 2017-04-15 | 2019-12-03 | 长沙医学院 | A kind of tetramethylpyrazine ferulate solid lipid nano granule and the preparation method and application thereof |
| CN108030088B (en) * | 2017-10-26 | 2021-05-28 | 武汉轻工大学 | Preparation method of protein-modified phytosterol liposome powder |
| CN109966251A (en) * | 2019-04-11 | 2019-07-05 | 成都大学 | The drug and preparation method and the drug effect method of inspection of inhibition choroidal neovascularization |
| CN113967192A (en) * | 2021-11-09 | 2022-01-25 | 陕西海斯夫生物工程有限公司 | Pharmaceutical composition for accelerating wound healing, preparation method and application thereof |
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