CN100486585C - Antitumor ginsenoside Rh2 injection and its preparation process - Google Patents
Antitumor ginsenoside Rh2 injection and its preparation process Download PDFInfo
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- CN100486585C CN100486585C CNB2004100021080A CN200410002108A CN100486585C CN 100486585 C CN100486585 C CN 100486585C CN B2004100021080 A CNB2004100021080 A CN B2004100021080A CN 200410002108 A CN200410002108 A CN 200410002108A CN 100486585 C CN100486585 C CN 100486585C
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- Prior art keywords
- injection
- ginsenoside
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- present
- preparation
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- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000002398 materia medica Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Abstract
The present invention discloses one kind of antitumor ginsenoside Rh2 injection and its preparation process. The injection contains rare ginsenoside, injection solventg and assistant, and has high curative effect, high bioavailability and stable quality.
Description
Technical field
The present invention relates to a kind of antineoplastic rare ginsenoside injection and preparation method thereof, further relate to the ginsenoside Rh
2Injection, lyophilized powder, infusion preparation.
Background technology
The early existing report of the antitumor action that Radix Ginseng has along with the further investigation to Radix Ginseng, to gradually clear and definite of constituent of ginseng, finds that some ginsenosides have extraordinary antitumor action.Radix Ginseng total saponins Rh
1And Rh
2Energy and surface of cell membrane combination, it is synthetic to suppress DNA during high concentration, Rh
2Can suppress the propagation of reactive antibody (HRA) cell told in the ovary cystoma patient ascites and growth (Byun.B.Helal.PlantaMedica, 1997,63 (5): 389) of mouse black-in tumor cell.Contain anticancer active constituent 20 (R)-ginsenoside-Rh in the Herba Herminii
2(Zhao Yuqing waits CHINA JOURNAL OF CHINESE MATERIA MEDICA, and 1991,16 (11): 78).The ginsenoside Rh
2Belong to glycol saponins, it can suppress the propagation and the growth of tumor cell by inducing differentiation or apoptosis, but very low (Xu Jing reaches Changbai Mountain Chinese medicine research and development, 1996,5 (5): 48) to normal tissue toxicity.Li Shi discovers the ginsenoside Rh
2To C
6Glioma cell has tangible propagation to suppress and apoptosis-induced effect, and this effect has period specific.He thinks Rh
2Be the active skull cap components of Radix Ginseng, toxicity is low, and molecular weight is little, and is fat-soluble, by blood brain barrier, is a kind of potential chemotherapeutic easily.Use as merging with other cycle-specific agent, can improve cerebral glioma chemotherapy effect (Li Dianyou waits Norman Bethune Medical University's journal, 2000,26 (4): 342).
The ginsenoside Rh
2Preparation both can be used as the direct killing cancerous cell clinically, but also combined with chemotherapy, radiotherapy kills and wounds the effect of cancerous cell with raising, and alleviated its detrimental effect to body.The ginsenoside also is used for the recovery of tumor post-operation body, is used for the patient with advanced cancer mitigation symptoms, improves patient's general state and the effect that prolongs life.
At present, clinical practice antineoplastic rare ginsenoside all mostly is oral Preparation, as Rg
3Deng, because the content of rare ginsenoside in Radix Ginseng is lower, and the rare ginsenoside that has prepares by existing ginsenoside is advanced manual method, and the oral administration bioavailability is very low, causes the great wasting of resources; Disclosed the injection of some rare ginsenosides in the existing patent documentation, as, CN1182433, ginsenoside's saponins by human intestinal bacteria metabolite and anticancer preparation thereof, but there is not one piece of document specifically to disclose the technical scheme of its used for intravenous injection preparation.
The injection of rare ginsenoside is intravenous formulations especially, medicinal liquid directly injects tissue or blood vessel, have absorb fast, onset rapidly, reliable effect, the characteristics that bioavailability is high, and the ginsenoside is along with the reduction of sugared aglucon number, and ginsenoside's water solublity worse and worse; Because the unusual indissoluble of rare ginsenoside, and unstable in solution, therefore rare ginsenoside is made injection, intravenous injection especially, its slightly solubility has become the technology barrier that is difficult to cross over.
Summary of the invention
The present invention is directed to above-mentioned technological deficiency a kind of antineoplastic ginsenoside-Rh is provided
2Intravenous injection.
Radix Ginseng saponin-Rh of the present invention
2Injection contains ginsenoside-Rh
2, injection solvent and additives, wherein ginsenoside-Rh among the present invention
2Can also can be synthetic, as chemical synthesis, bacterial metabolism method etc. for what from panax ginseng plant, extract by manual method; Radix Ginseng saponin-Rh of the present invention
2Can be 20 (R)-ginsenoside-Rh
2, 20 (S)-ginsenoside-Rh
2Or 20 (R, S)-ginsenoside-Rh
2Radix Ginseng saponin-Rh of the present invention
2At injection content is 0.1-50% (w/v), and its preferred content is 0.2-20% (w/v), and wherein the preferred rare ginsenoside monomer of the present invention can adopt extracting method or synthetic and the acquisition of bacterial metabolism method that the prior art document discloses.
Injection solvent is a kind of, two or more the combination in water for injection, ethanol, propylene glycol, glycerol, isopropyl alcohol, isobutanol and the Polyethylene Glycol among the present invention; Additives are a kind of, two or more the combination in pH regulator agent, stabilizing agent, isoosmotic adjusting agent and the proppant.Wherein injection solvent is preferably two or more combination of the water for injection that accounts for injection 0.5%～99.9% (volume ratio), ethanol, propylene glycol, glycerol, isopropyl alcohol, isobutanol, Polyethylene Glycol, more preferably a kind of, two or more combination in water for injection, ethanol, glycerol and the Polyethylene Glycol of injection solvent among the present invention.
Additives are a kind of, two or more the combination in pH regulator agent, stabilizing agent, isoosmotic adjusting agent, the proppant among the present invention.
PH regulator agent among the present invention in the additives can be one or more in the following material: phosphoric acid and salt thereof, sodium hydroxide, hydrochloric acid, organic amine, potassium hydroxide, calcium hydroxide, tartaric acid and salt thereof, carbonic acid and salt thereof, borate family, citric acid and salt thereof, lactic acid and salt thereof; Stabilizing agent can be one or more sodium sulfite, sodium sulfite, sodium pyrosulfite, ascorbic acid, EDTA and salt thereof, glycine, cysteine, citric acid and salt thereof, tartaric acid and salt thereof, the methionine in the following material; Isoosmotic adjusting agent can be one or more sorbitol, fructose, sodium chloride, calcium chloride, potassium chloride, magnesium chloride, ammonium sulfate, glucose, Chile saltpeter, potassium nitrate, Borax, boric acid, the glycerol in the following material; Proppant is glycine, mannitol, lactose, dextran, dextran, sucrose or sodium chloride.
Rare ginsenoside injection of the present invention can also contain solubilizing agent, wherein solubilizing agent is polyglycol distearate, Tweens, poloxamer or polyoxyethylene castor oil, more preferably polyoxyethylene castor oil or poloxamer (poloxamer), wherein the content of solubilizing agent is 0.1～30% (w/v) that accounts for the injection volume.
Effective active composition dissolving of the present invention can adopt water for injection to add the method for solubilizing agent; The method that also can adopt the composite injection solvent method or adopt the composite injection solvent to add solubilizing agent is dissolved.
The rare ginsenoside injection is an injection among the present invention.Injection of the present invention contains ginsenoside-Rh
2, injection solvent and PH regulator, injection solvent of the present invention is a kind of, two or more combination in water for injection, ethanol, glycerol, propylene glycol and the Polyethylene Glycol; Be preferably the double solvents of PEG-water, ethanol-water, PEG-alcohol-water or glycerol-alcohol-water; More preferably PEG accounts for the 20-50% (volume) of double solvents volume, and ethanol accounts for the 20-50% (volume) of double solvents volume, and all the other are the PEG-alcohol-water double solvents of water for injection; The PH regulator is phosphoric acid and salt buffer solution phosphate, tartrate, borate or dilute sodium hydroxide, is preferably phosphoric acid and salt buffer solution thereof.
The pH scope of injection solution of the present invention is 4～9, and preferred PH scope is 6-8.
The rare ginsenoside injection solution can also contain solubilizing agent among the present invention, and wherein solubilizing agent is polyoxyethylene castor oil or poloxamer (poloxamer).
Rare ginsenoside injection among the present invention can also further can also contain stabilizing agent, and wherein stabilizing agent is EDTA-2Na, tartaric acid or sodium sulfite; The best is EDTA-2Na, and wherein the content of stabilizing agent is 0.002～0.02% (w/v) that accounts for the injection total amount.
The preparation method preparation of the conventional injection in this area that injection preparation can adopt among the present invention.
Radix Ginseng saponin-Rh of the present invention
2Injection can be the frozen powder for injection pin, and when being the frozen powder for injection pin, it contains ginsenoside-Rh
2, injection solvent and proppant, wherein injection solvent be water, ethanol, propylene glycol, glycerol, isopropyl alcohol, isobutanol and Polyethylene Glycol any, two or more combination; Be preferably a kind of, two or more combination of water for injection, ethanol, glycerol, Polyethylene Glycol; Proppant is glycine, mannitol, lactose, dextran, dextran, sucrose or sodium chloride, more preferably mannitol or glycine.
Freeze-dried powder injection of the present invention can also contain solubilizing agent and pH regulator agent, and wherein solubilizing agent is polyoxyethylene castor oil or poloxamer (poloxamer), and the pH regulator agent is phosphoric acid and salt thereof.
Injection freeze-dried powder preparation method of the present invention can adopt conventional preparation method preparation, and the preparation method of preferred lyophilized injectable powder of the present invention is: get ginsenoside-Rh
2, add the injection solvent dissolving, can add solubilizing agent as required, add proppant, activated carbon adsorption, filtration, packing then, adopt conventional freeze-dry process lyophilizing promptly, wherein when containing low boiling point solvent in the injection solvent that adopts, should before lyophilizing, boil off this low boiling point solvent.
Ginsenoside-Rh among the present invention
2Injection is transfusion, and the present invention's transfusion contains ginsenoside-Rh
2, injection solvent, etc. ooze adjusting, wherein injection solvent is a kind of, two or more the combination in water, ethanol, propylene glycol, glycerol, isopropyl alcohol, isobutanol and the Polyethylene Glycol; Isoosmotic adjusting agent is one or more sorbitol, fructose, sodium chloride, calcium chloride, potassium chloride, magnesium chloride, ammonium sulfate, glucose, Chile saltpeter, potassium nitrate, Borax, the boric acid in the following material, preferred isoosmotic adjusting agent is sodium chloride or glucose, and wherein the isoosmotic adjusting agent addition can add as the case may be in right amount.
The present invention's transfusion can also contain solubilizing agent, wherein solubilizing agent is polyoxyethylene castor oil or poloxamer.
The preparation method of infusing among the present invention can adopt the injection preparation preparation of this area routine.
Radix Ginseng saponin Rh of the present invention
2Injection, it is good to have good effect, bioavailability height, dissolubility, steady quality.
The specific embodiment
Embodiment 1
Take by weighing 0.50g 20 (S)-ginsenoside-Rh
2, add 50g PEG-400, make the saponin dissolving; The phosphate buffer of preparation 50g pH5.5 takes by weighing the 0.20g procaine hydrochloride, the 0.02g sodium sulfite joins in the above-mentioned phosphate buffer; Buffer is joined in the PEG solution of saponin, mix homogeneously adds 100 ℃ of insulations of 0.01% needle-use activated carbon 30 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um, and filtered liquid medicine is distributed into 50 of the injections that 2ml/ props up, and divides the directly tamponade of injection, the jewelling that install to cover into injection.
Embodiment 2
Take by weighing 0.50g 20 (R)-ginsenoside-Rh
2, add 50g PEG-400, make the saponin dissolving.The phosphate buffer of preparation 50g PH5.5 takes by weighing the 0.20g procaine hydrochloride, the 0.02g sodium sulfite joins in the above-mentioned phosphate buffer; Buffer is joined in the PEG solution of saponin, mix homogeneously adds 100 ℃ of insulations of 0.01% needle-use activated carbon 30 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um; Filtered liquid medicine is distributed in the cillin bottle that 2ml/ props up, and makes freeze-dried powder through the freeze dryer lyophilizing.
Embodiment 3
Take by weighing 1.00g20 (R, S)-ginsenoside-Rh
2Adding 20ml ethanol melts saponin fully, add 40ml glycerol mix homogeneously again, the EDTA-2Na of 0.20g tetracaine hydrochloride, 0.02g is joined in the 40ml water for injection, adjuvant is dissolved fully, and above-mentioned aqueous solution is joined in the drug solution, mix homogeneously, sodium hydroxide and dilute hydrochloric acid adjusting pH value with 0.01mol/L are 5.5 ± 1.0,85 ℃ of insulations of the needle-use activated carbon of adding 0.1% 15 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um, and filtrate is sub-packed in the 7ml cillin bottle, every loading amount 2ml.
Embodiment 4
Take by weighing 1.50g 20 (S)-ginsenoside-Rh
2, add 20ml ethanol and stir, saponin is dissolved fully, in above-mentioned alcoholic solution, add the 15.00g poloxamer, be heated to 50 ℃ poloxamer is melted, add the 0.10g benzyl alcohol again, stir and make dissolving; 0.9% sodium chloride solution 80ml with tartaric acid and salt thereof preparation pH5.5 adds the 0.02g ascorbic acid in sodium chloride solution, stir and make dissolving fully; Sodium chloride solution is joined in the saponin solution, make mix homogeneously, add 80 ℃ of 0.05% needle-use activated carbons insulation 15 minutes, filter successively with the microporous filter membrane of sintered glass funnel and 0.22um, filtrate dress 100ml infusion bottle is made ginsenoside-Rh2 and is infused.
Embodiment 5
Take by weighing 1.50g 20 (S)-ginsenoside-Rh
2Adding 20ml ethanol stirs, saponin is dissolved fully, in above-mentioned alcoholic solution, add the 15.00g poloxamer, being heated to 50 ℃ melts poloxamer, add the 0.10g benzyl alcohol again, stir and make dissolving, with the aqueous solution 80ml of tartaric acid and salt preparation pH5.5 thereof, in sodium chloride solution, add the 0.02g ascorbic acid, stirring makes dissolving fully, and sodium chloride solution is joined in the saponin solution, makes mix homogeneously, add 80 ℃ of insulations of 0.05% needle-use activated carbon 15 minutes, microporous filter membrane with sintered glass funnel and 0.22um filters successively, and be filled in the 7ml cillin bottle filtrate branch, can be made into injection.
Embodiment 6
Take by weighing 1.00g ginsenoside-Rh
2, use an amount of anhydrous alcohol solution, add 5.00g polyoxyethylene castor oil acid esters, make dissolving fully, add glucose injection and be diluted to 100ml, add the dissolving of 0.02g methionine; Add 80 ℃ of 0.05% needle-use activated carbons insulation 15 minutes, filter successively with the microporous filter membrane of sintered glass funnel and 0.22um, filtrate is adorned the 100ml infusion bottle and is made ginsenoside-Rh
2Transfusion.
Embodiment 7
Take by weighing 1.00g 20 (S)-ginsenoside-Rh
2, use an amount of anhydrous alcohol solution, add 5.00g polyoxyethylene castor oil acid esters, make dissolving fully; 60 degree drying under reduced pressure are removed ethanol, add glucose injection and be diluted to 100ml, add the dissolving of 0.02g methionine, 4% mannitol, add 0.05% needle-use activated carbon afterwards and be incubated 15 minutes for 80 ℃, filter successively with the microporous filter membrane of sintered glass funnel and 0.22um; Packing, freeze-dried powder is made in lyophilizing.
Embodiment 8
Take by weighing 1.00g20 (R)-ginsenoside-Rh
2Use an amount of anhydrous alcohol solution, add single month esters of silicon acis of 8.00g cetomacrogol 1000, make dissolving fully, add 0.9% sodium chloride injection and be diluted to 100ml, add the dissolving of 0.02g glycosides propylhomoserin, add 80 ℃ of insulations of 0.05% needle-use activated carbon 15 minutes, microporous filter membrane with sintered glass funnel and 0.22um filters successively, and filtrate dress 100ml infusion bottle is made ginsenoside-Re transfusion; Filtrate also can be divided and is filled in the 7ml cillin bottle, makes the injection that 2ml/ props up.
Embodiment 9
Take by weighing 1.00g 20 (R, S)-ginsenoside-Rh
2Use an amount of anhydrous alcohol solution, add single month esters of silicon acis of 8.00g cetomacrogol 1000, make dissolving fully, 60 degree drying under reduced pressure are removed ethanol, add 0.9% sodium chloride injection and are diluted to 100ml, add the dissolving of 0.02g glycosides propylhomoserin, add 4% mannitol, add 80 ℃ of 0.05% needle-use activated carbons insulation 15 minutes, filter successively with the microporous filter membrane of sintered glass funnel and 0.22um, filtrate, packing, lyophilizing are made and are contained the freeze-dried powder that ginsenoside Re 20mg/ props up.
Embodiment 10
Take by weighing 0.80g ginsenoside-Rh
2Adding 30ml ethanol melts saponin fully, add 30ml isopropyl alcohol mix homogeneously again, 0.10g hydrochloric acid first is sent caine, the sodium pyrosulfite of 0.02g joins in the 40ml water for injection, make dissolving fully, and above-mentioned aqueous solution joined in the drug solution, mix homogeneously, it is 5.5 ± 1.0 that triethanolamine with 10% and sodium bicarbonate are regulated pH value, the needle-use activated carbon 85 degree insulations of adding 0.1% 15 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um, and filtrate is sub-packed in the 7ml cillin bottle, every loading amount 2ml.
Embodiment 11
Take by weighing 1.00g 20 (S)-ginsenoside-Rh
2, the propylene glycol that adds 20ml n-butyl alcohol and 30ml melts saponin fully, and the citric acid of 0.15g tetracaine hydrochloride, 0.02g is joined in the 40ml water for injection, makes dissolving fully, and above-mentioned aqueous solution is joined in the drug solution mix homogeneously; Regulating pH value with Borax and boric acid is 5.5 ± 1.0; 85 ℃ of insulations of the needle-use activated carbon of adding 0.1% 30 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um; Filtrate is sub-packed in the 7ml cillin bottle, every loading amount 2ml.
Claims (1)
1. antineoplastic injection, it is characterized in that containing 20 (R, S)-ginsenoside-Rh
2, ethanol, glycerol, EDTA-2Na, water for injection, its ratio is 1g:20ml:40ml:0.02g:40ml; PH value is 5.5 ± 1.0.
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| CN106806393A (en) * | 2015-11-30 | 2017-06-09 | 湖南恒生制药股份有限公司 | Ginsenoside vein small-volume injection and preparation method thereof |
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| CN104688669A (en) * | 2013-12-10 | 2015-06-10 | 沈阳药科大学 | Ginsenoside concentrated liquid and medical application thereof |
| CN114129513A (en) * | 2021-12-29 | 2022-03-04 | 江苏科兴诺生物技术有限公司 | Antineoplastic drug thelenota ananas saponin D injection and preparation method thereof |
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Non-Patent Citations (2)
| Title |
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| 药剂学. 奚念朱编，73,172-173,195，人民卫生出版社. 1996 |
| 药剂学. 奚念朱编，73,172-173,195，人民卫生出版社. 1996 * |
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| CN106806393A (en) * | 2015-11-30 | 2017-06-09 | 湖南恒生制药股份有限公司 | Ginsenoside vein small-volume injection and preparation method thereof |
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