CN104688669A - Ginsenoside concentrated liquid and medical application thereof - Google Patents
Ginsenoside concentrated liquid and medical application thereof Download PDFInfo
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- CN104688669A CN104688669A CN201310666950.3A CN201310666950A CN104688669A CN 104688669 A CN104688669 A CN 104688669A CN 201310666950 A CN201310666950 A CN 201310666950A CN 104688669 A CN104688669 A CN 104688669A
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Abstract
The invention discloses a ginsenoside concentrated liquid, which comprises active component ginsenoside, a solubilizer, a mixed solvent, an antioxidant, and a pH modifier, is characterized in that the weight ratio of the solubilizer to the ginsenoside is (10:1) to (100:1); the concentration of the ginsenoside in the concentrated liquid is 5-50mg/mL; and the mixed solvent is selected from one or more of ethanol-water, ethanol-glycerinum, ethanol-propylene glycol, tert-butyl alcohol-water, tert-butyl alcohol-glycerinum, tert-butyl alcohol-propylene glycol, propylene glycol-water and propylene glycol-glycerinum. The ginsenoside concentrated liquid can be applied to oral administration or parenteral administration after being diluted with sterile water for injection, a glucose injection, a 0.9% sodium chloride injection and 0-20% F68 solution, and can also be mixed with a filler and (or) a freeze-drying protecting agent to prepare a powder preparation or a freeze-dried agent by a spray drying or freeze-drying technique.
Description
Technical field:
The invention belongs to field of pharmaceutical preparations, open ginsenoside's concentrated type liquid formula and medical usage thereof.
Background technology:
Radix Ginseng is the traditional rare Chinese medicine of China, and complex chemical composition, biological activity is extensive.Along with the progress of modern separation technology and analytical technology, the chemical composition of Radix Ginseng obtains further to be illustrated, and what ginsenoside was considered to Radix Ginseng mainly contains effective substance, accounts for 4%.According to the difference of sapogenin, ginsenoside is divided into protopanoxadiol saponins, Protopanaxatriol's saponins and oleanolic acid saponins.Up to the present, isolation identification goes out more than 40 and plants ginsenoside monomer.The research of modern pharmacology shows that the pharmacological action of ginsenoside mainly comprises following several times:
(1) antineoplastic potentiation
Ginsenoside Rh2 has certain inhibitory action to kinds of tumors, and Rh2 and paclitaxel or mitoxantrone hydrochloride use in conjunction have potentiation.The potentiation experiment display of anti-prostate tumor, for the LNCaP cell of In vitro culture, when ED50, ED75, Rh2 and paclitaxel or mitoxantrone hydrochloride use in conjunction all have potentiation, and at ED95, Rh2 and paclitaxel or mitoxantrone hydrochloride use in conjunction but all show antagonism, and this shows that the dosage rate of use in conjunction is crucial.Rh2 and mitoxantrone hydrochloride use in conjunction then do not show significant benefit for anti-LNCaP tumor in testing in vivo.
(2) Endocrine, immune impact
Fixing stress tests shows, GTS or Rc intraperitoneal administration can significantly reduce fixing stress or the plasma corticosterone levels that causes of lumbar injection thyroliberin, but do not affect the rising of the fixing plasma adrenocorticotropic hormonal readiness that stress cause.This shows, GTS and Rc suppresses the fixing plasma corticosterone levels that stress cause to increase by blocking thyroliberin to adrenal effect.
(3) to neural effect
Experiment in vitro result of study shows, add Radix Ginseng total saponins (ginseng total saponins in advance, GTS) any one or in Rb2, Rc, Rd, Re, Rf, Rg1, Rg2, can suppress the formation of the myo-inositol phosphates in the cortical neuron stimulated through carbachol.Radix Ginseng total saponins can in the lethal toxicity dose-dependently weakening KA induction, and this perhaps will give the credit to wherein contained Rd composition.Rd may play the role of certain upstream path of ERK phosphorylation blocking-up person of KA induction, and Rd can also cause the reverse of the phosphorylation CREB dephosphorylation of being induced by KA intracerebral ventricle injection.Researcher is had to use the neural degeneration animal model of 3-nitropropionic acid modeling to observe the neuroprotective of Rb1, Rb3 and Rd; found that; the administration in advance of Rb1, Rb3 and Rd all can obviously improve animal movement obstacle, reduces mortality of animals and reduces striatum infringement volume.
(4) on the impact of intracellular signaling
Research display, ginsenoside can increase the Ca in macrophage, NIH3T3 and endotheliocyte
2+concentration, can suppress the gated Ca of the high threshold voltage of pheochromocyte and sensory neuron
2+passage, can also activate the Ca of vascular smooth muscle
2+activity K
+passage.Cell (neuronal cell) interior Ca is reduced for ginsenoside
2+the approach of level may be by directly suppressing voltage-dependent Ca
2+passage and indirectly reduce the InsP3 stimulated by receptor agonists and formed.Ginsenoside shows protein tyrosine kinase (PTK) the activity influence experiment activated by hypoxia-reoxygenation in the Human umbilical vein endothelial cells of cultivating, and Rb1, Rd, Ra1 and Ro all show significant inhibitory action.Ginsenoside Rd also by block C6 rat neurogliocytoma cells ERK phosphorylation, suppress early stage fast response gene outcome successively and suppress the generation of the NO jointly induced by lipopolysaccharide and tumor necrosis factor.
(5) anti-aging effects
In old theory, free-radical theory is thought, the toxic action of free radical is relevant with the deterioration in aging course, and the enhancing of antioxidation defence system function can reduce the infringement that free radical causes, thus the process of delaying senility.The antioxidation using mice to accelerate aging model observation ginsenoside Rd finds, Rd can improve glutathion (GSH) content, reduces the ratio that glutathione bisulphide (GSSG) improves GSH SSG.And Rd can also increase the activity of glutathion peroxidase and glutathion reductase.Rd does not affect superoxide dismutase (SOD) and catalatic activity, but can reduce the content of the lipid peroxidation identification product malonaldehyde in serum and liver.Infer from result of study, the action site of Rd is at cytoplasm and mitochondrial matrix.
(6) hypoglycemic activity
Use the diabetes rat model of streptozotocin induction to observe the impact experiment of ginsenoside Rh2 on blood glucose and show that the rat model intravenous injection Rh2 of fasting is more than after 120min, rat blood sugar declines, and this hypoglycemic activity is dose dependent.Hypoglycemic study mechanism prompting, Rh2 perhaps works by increasing endorphins secretion, and endorphins can activate opiate receptor, and the latter can cause glucose transporter hypotype 4 (GLUT4) to be expressed to be increased.
(7) on the impact of burn wound healing
In Radix Ginseng Rubra, isolated ginsenoside Rb1 can promote mice burn wound healing when low concentration very by force, and this Promotive union effect is perhaps with to promote that blood vessel occurs during the reparation of Rb1 skin wound relevant.And the Rb1 mechanism promoting blood vessel to occur and the stimulation generating the VEGF (VEGF) increased, the increase that in keratinocyte, hypoxia inducible factor is expressed, and the raising of macrophage IL1 content caused by burn wound collection is relevant.
In sum, ginsenoside has pharmacologically active widely, but ginsenoside's water solublity is poor, in addition, because P-glycoprotein is arranged outward and intestinal flora metabolism effect, cause oral administration biaavailability lower, have bibliographical information ginsenoside Rh2 to be 17.6% (male) and 24.8% (female) in the bioavailability of dog, thus to its carry out dosage form research still tool be of great significance.
At present, preparation research about ginsenoside is relatively less, mainly comprise the capsule (as " modern good fortune capsule " that Zhejiang Province yaker Pharmaceutical Co., Ltd produces) of ginsenoside monomer, the liposome of the ginsenoside Rg1 of the preparation such as Zhou Hongwei, ginsenoside Rh2's self-microemulsifying drug delivery system of the preparation such as Sun Kaoxiang, ginsenoside's nano-emulsion of the preparation such as Cao Fahao, other ginsenoside's cyclodextrin clathrate and ginsenoside's solid dispersion in addition, their ubiquity drug loading are little, supplementary product consumption is large, the defect that taking dose is large, so far, have no and ginsenoside is prepared into concentrated type liquid formula, with the multiple that suitable medium is suitable before clinical administration, then for oral or injection.
Summary of the invention:
Inventor, through further investigation, provides ginsenoside's concentrated type liquid formula and medical usage thereof.
Ginsenoside's concentrated type liquid formula provided by the present invention, is characterized in that: this concentrated type liquid formula comprises reactive compound ginsenoside, solubilizing agent, mixed solvent, antioxidant and pH adjusting agent, wherein:
Solubilizing agent is selected from polysorbas20, Tween 80, phospholipid, PLURONICS F87 (F68), poloxamer 237(F87), Pluronic/Lutrol F 108 (F108), poloxamer188 (F127), poly-third hands over fat-ethylene glycol copolymer (PDLLA-mPEG2000, PDLLA-mPEG5000), HS15 (HS15), Oleum Ricini gathers hydrocarbon oxygen ester (Cremophor EL, Cremophor ELP), one in polyoxyethylene hydrogenated Oleum Ricini (RH40) and polyethylene glycol 1000 vitamin E succinic acid ester (TPGS) or several, the weight ratio of solubilizing agent and ginsenoside is 10:1 ~ 100:1, preferred 20:1 ~ 100:1.
Mixed solvent is selected from " alcohol-water ", " alcoholic-glycerine ", " ethanol-propylene glycol ", " tertiary butanol and water ", " tert-butyl alcohol-glycerol ", " tert-butyl alcohol-propylene glycol ", " propylene glycol-water ", one or more in " propylene glycol-glycerol ", preferably " alcohol-water ", " tertiary butanol and water ", " propylene glycol-water ", in each mixed solvent, ethanol, ratio shared by the tert-butyl alcohol is: 50% ~ 90%(v/v), water, glycerol and the ratio shared by propylene glycol are 50% ~ 10%(v/v), the ratio of mixed solvent shared by concentrated type liquid formula is enough to allow reactive compound ginsenoside dissolve and keeps stable.
Antioxidant is selected from sulphite, bisulfites, dithiocar-bamate, ascorbic acid, citric acid, malic acid, sorbitol, ascorbic acid cetylate, hydrogen butylcoumariii, vitamin E, ethanolamine, fabaceous lecithin, cephalin, propyl gallate, butylated hydroxyarisol, ditertbutylparacresol, nordihydroguaiaretic acid, EDTA and Ethylenediaminetetraacetic Acid Calcium Salt, and consumption accounts for 0.00001 ~ 0.2w/v% of concentrated type liquid formula.
PH adjusting agent is selected from hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, malic acid, aspartic acid, glutamic acid, glutamine, glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, methionine, hydroxyproline, sodium hydroxide, phosphate-buffered salt, sodium acetate, sodium tartrate, sodium citrate, natrium malicum, sodium carbonate and sodium bicarbonate, and its consumption is that the pH value of pharmaceutical composition is adjusted to 4 ~ 9.
Ginsenoside's concentrated type liquid formula provided by the present invention, it is characterized in that: described ginsenoside is selected from ginsenoside Re, ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rb3, Ginsenoside Rc, ginsenoside Rd, ginsenoside Rg3, ginsenoside Rh2, ginseng saponin Rg1, ginsenoside Rg2 and ginsenoside Rh1, and in miniature liquid formula, the concentration of ginsenoside is 5 ~ 50mg/mL.
Ginsenoside's concentrated type liquid formula provided by the present invention, it is characterized in that: described ginsenoside's concentrated type liquid formula can use sterilized water for injection, glucose injection, oral or drug administration by injection after the F68 solution dilution of 0.9% sodium chloride injection and 0%-20%, also can mix with filler and (or) freeze drying protectant, powder formulation or lyophilized formulations is prepared into through spraying dry or Freeze Drying Technique, the powder formulation of gained or lyophilized formulations can be used for being prepared into pharmaceutically acceptable tablet, capsule, granule, powder, ointment, suspensoid, syrup, oral liquid, suppository, nasal drop or powder ampoule agent for injection, administration by rights.
Described filler comprises starch, microcrystalline Cellulose, dextrin, can die mould starch, lactose, mannitol, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose, dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, hard magnesium, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, a kind of or several mixture in polyethylene glycols and magnesium laurylsulfate.
Described freeze drying protectant comprises a kind of or several mixture in glucose, xylose, ganglioside (GM1), fructose, sucrose, maltose, lactose, galactose, trehalose, mannitol, xylitol, maltol.
Compared with prior art, present invention offers obvious technique effect, be mainly reflected in:
(1) ginsenoside's concentrated type liquid formula provided by the present invention makes ginsenoside's preparation with concentrated, stable liquid state or the state of freeze-dried powder exists, significantly improve the concentration of ginsenoside in unit volume preparation, reduce the volume of preparation needed for therapeutic dose, and then reduce the packaging volume of preparation under therapeutic dose, preparation human and material resources required in storage and transportation and financial resources are significantly reduced, in addition, because the volumes of formulation of therapeutic dose and quantity significantly reduce, facilitate the use of doctor and patient.
(2) ginsenoside's concentrated type liquid formula provided by the present invention can ensure to be particularly conducive to the existence that reactive compound ginsenoside is stable and to prevent medicine from separating out in storage process.
It should be noted that: ginsenoside's concentrated type liquid formula provided by the invention, emphasis is on " concentrated type ", although there are relatively many solubilizing agents to carry out solubilising ginsenoside in prescription, but the ratio of solubilizing agent provided by the invention and ginsenoside must be the ratio in concentrated solution, if prepare ginsenoside's non-concentrated liquid formulation with the ratio of solubilizing agent of the present invention and ginsenoside separately, prepared preparation stability extreme difference, room temperature is placed and namely can be separated out a large amount of medicines in 12 hours, the serious drug administration by injection limiting ginsenoside.
Detailed description of the invention:
For a more clear understanding of the present invention, next with test example by the following examples the present invention is described in further detail, but be not limited only to this.
Embodiment 1: the preparation (weight ratio of ginsenoside Re and solubilizing agent is 1:20) of ginsenoside Re's concentrated solution
Prescription:
Ginsenoside Re 20g
F68 200g
Dehydrated alcohol 680mL
Sterilized water for injection adds to 1000mL
Technique:
1, the ginsenoside Re measuring recipe quantity, in 2000mL beaker, adds the dehydrated alcohol of recipe quantity,
In 80 DEG C of water-baths, magnetic agitation is to complete drug dissolution, continues to be placed in 80 DEG C of water-baths, obtains ginsenoside Re's ethanol, stand-by.
2, take recipe quantity F68, join in above-mentioned ginsenoside Re's ethanol, in 80 DEG C of water-baths, magnetic agitation to system is uniform solution, add 120mL sterilized water for injection wherein under stirring, adjust ph to 6, sterilized water for injection adds to 1000mL, continue to stir 30min, to obtain final product.
Formulation aesthetics:
The ginsenoside Re's concentrated solution prepared is the liquid of clear, slightly thickness.
The dilution of ginsenoside Re's concentrated solution:
Get 14 parts of above-mentioned ginsenoside Re's concentrated solutions, every part of 1mL, use sterilized water for injection (SterileWater respectively, be abbreviated as SW), 0.9% sodium chloride injection (0.9%Nacl), 10% glucose injection (10%Glucose Injection, be abbreviated as 10%GI), 5%F68 solution, 10%F68 solution, 15%F68 solution and 20%F68 solution dilution 10 times and 20 times, after having diluted, observe formulation aesthetics, result shows, after different diluent media dilutes 10 times and 20 times, gained preparation is clear transparent solutions, room temperature and 4 DEG C are placed 72 hours, have no medicine to separate out.
Embodiment 2: antioxidant is on the impact of ginsenoside Re's concentrated type liquid formula stability
Get the ginsenoside Re's ethanol concentrated solution 100mL in " embodiment 1 ", be divided into 10 bottles, every bottle of 10mL, 1 vial formulation is used for measuring ginsenoside Re's content, and measured value, as initial value, is decided to be 100%; Separately get 1 vial formulation and do not add any antioxidant, in contrast, remaining 8 bottles by weight volume ratio add the sodium sulfite of 0.5 times of limitation, sodium sulfite, nabam, ascorbic acid, ditertbutylparacresol, nordihydroguaiaretic acid, EDTA and Ethylenediaminetetraacetic Acid Calcium Salt respectively, at 80 DEG C, placement measured content after 10 days, the content of the content recorded and initial preparation is contrasted, tries to achieve percentage ratio.Result is as shown in table 3.
Table 3 antioxidant is on the impact of ginsenoside Re's concentrated type liquid formula stability
Result shows, the ginsenoside Re's ethanol concentrated solution not adding any antioxidant is placed content after 10 days and reduced close to 20% at 80 DEG C, and then content is almost constant to add the group of antioxidant, conforms to quality requirements.As can be seen here, the stability added for ginsenoside Re's concentrated type liquid formula of antioxidant has a significant impact.Therefore, appropriate antioxidant should be added in ginsenoside Re's concentrated type liquid formula of the present invention, constant to guarantee this concentrated type liquid formula stable content in long-term process of placing.
Embodiment 3:pH regulator is on the impact of ginsenoside Re's concentrated type liquid formula stability
Prepare the PBS buffer of pH2.0 ~ 12.0 with reference to 2005 editions " Chinese Pharmacopoeias ", and correct with pH meter, the phosphate buffer of different pH value.
Get the ginsenoside Re's concentrated solution 180mL in " embodiment 1 ", be divided into 9 parts, every part of 20mL, by the phosphate buffer adjust ph of above-mentioned different pH value, be followed successively by 3.0 ~ 11.0, measure the content of the preparation under each pH value respectively, as initial content, be designated as initial content, be 100%, afterwards the preparation under each pH value is placed at 60 DEG C after 5 days and measure content, the content of the content recorded and initial preparation is contrasted, tries to achieve percentage ratio.Result is as shown in table 4.
Table 4 pH is on the impact of ginsenoside Re's concentrated type liquid formula stability
Result shows, after being placed 5 days at 60 DEG C by the preparation of different pH value, when pH value is more than or equal to 10, ginsenoside Re's content all significantly decreases, and the content of pH value ginsenoside Re 4.0 ~ 9.0 time is without significant change.Therefore, for ensureing the stability of ginsenoside Re's concentrated type liquid formula provided by the invention, the pH value of this concentrated type liquid formula should be maintained in the scope of 4.0 ~ 9.0.
Embodiment 4: the preparation (weight ratio of ginsenoside Re and solubilizing agent is with the ratio in " embodiment 1 ") of ginsenoside Re's liquid preparation (non-concentrated liquid)
Ginsenoside Re 2g
F68 40g
Dehydrated alcohol 20mL
Sterilized water for injection adds to 1000mL
Technique:
1, the ginsenoside Re measuring recipe quantity, in 2000mL beaker, adds the dehydrated alcohol of recipe quantity, and in 90 DEG C of water-baths, magnetic agitation is to complete drug dissolution, continues to be placed in 90 DEG C of water-baths, obtains ginsenoside Re's ethanol, stand-by.
2, recipe quantity F68 is taken, join in above-mentioned ginsenoside Re's ethanol, in 90 DEG C of water-baths, magnetic agitation to system is uniform solution, add wherein under stirring 800mL synthermal under sterilized water for injection, adjust ph to 5, sterilized water for injection adds to 1000mL, continues to stir 30min, to obtain final product.
Formulation aesthetics:
Be clear transparent solutions when the ginsenoside Re's liquid preparation prepared is in 90 DEG C of water-baths, when taking-up during preparation is by 90 DEG C of water-baths is put to room temperature, preparation becomes muddy, occurs a large amount of drug precipitation.
Embodiment 5: the preparation (weight ratio of ginsenoside Re and solubilizing agent is 1:100) of ginsenoside Re's concentrated solution
Ginsenoside Re 20g
F68 400g
Dehydrated alcohol 600mL
Sterilized water for injection adds to 1000mL
Technique: with the technique in " embodiment 1 ".
Similar with the preparation prepared by " embodiment 1 ", the ginsenoside Re's concentrated solution prepared is the liquid of clear, slightly thickness.
The preparation (weight ratio of ginsenoside Re and solubilizing agent is 1:100) of ginsenoside Re's liquid preparation (non-concentrated liquid)
Ginsenoside Re 2g
F68 200g
Dehydrated alcohol 30mL
Sterilized water for injection adds to 1000mL
Technique: with the technique in " embodiment 4 ".
Formulation aesthetics:
Similar with the preparation prepared by " embodiment 4 ", be clear transparent solutions when the ginsenoside Re's liquid preparation prepared is in 90 DEG C of water-baths, when preparation is put to room temperature by 90 DEG C, preparation starts to become muddy, occurs a large amount of drug precipitation.
Embodiment 6: the preparation of ginsenoside Rb1's concentrated solution
Prescription:
Technique:
1, the ginsenoside Rb1 measuring recipe quantity, in 2000mL beaker, adds the dehydrated alcohol of recipe quantity, and in 80 DEG C of water-baths, magnetic agitation is to complete drug dissolution, continues to be placed in 80 DEG C of water-baths, obtains ginsenoside Rb1's ethanol, stand-by.
2, recipe quantity HS15 is taken, join in above-mentioned ginsenoside Rb1's ethanol, in 80 DEG C of water-baths, magnetic agitation to system is uniform solution, 200mL sterilized water for injection (wherein adding the EDTA of 10mg) is added wherein under stirring, continue to stir 30min, sterilized water for injection adds to 1000mL, to obtain final product.
Formulation aesthetics:
The ginsenoside Rb1's concentrated solution prepared is the liquid of clear, slightly thickness.
The dilution of ginsenoside Rb1's ethanol concentrated solution:
Get 14 parts of above-mentioned ginsenoside Rb1's ethanol concentrated solutions, every part of 1mL, use sterilized water for injection (Sterile Water respectively, be abbreviated as SW), 0.9% sodium chloride injection (0.9%Nacl), 10% glucose injection (10%Glucose Injection, be abbreviated as 10%GI), 5%F68 solution, 10%F68 solution, 15%F68 solution and 20%F68 solution dilution 10 times and 20 times, after having diluted, observe formulation aesthetics, result shows, after different diluent media dilutes 10 times and 20 times, gained preparation is clear transparent solutions, room temperature and 4 DEG C are placed 72 hours, have no medicine to separate out.
Embodiment 7: the preparation of ginsenoside Re's concentrated solution lyophilized formulations
Prescription:
Technique:
1, the ginsenoside Re measuring recipe quantity, in 200mL beaker, adds the tert-butyl alcohol of recipe quantity, and in 60 DEG C of water-baths, magnetic agitation is to complete drug dissolution, continues to be placed in 60 DEG C of water-baths, obtains ginsenoside Re's tert-butyl alcohol liquid, stand-by.
2, recipe quantity F68 is taken, join in above-mentioned ginsenoside Re's tert-butyl alcohol liquid, in 60 DEG C of water-baths, magnetic agitation to system is uniform solution, 10mL sterilized water for injection (wherein adding the Ethylenediaminetetraacetic Acid Calcium Salt of 10mg) is added wherein under stirring, continue to stir 30min, sterilized water for injection adds to 100mL, obtains ginsenoside Re's tert-butyl alcohol concentrated solution, by this concentrated solution lyophilizing, obtain ginsenoside Re's concentrated solution lyophilized formulations.
Embodiment 8: the preparation of Ginsenoside Rc's concentrated solution lyophilized formulations
Prescription:
Technique:
1, the Ginsenoside Rc measuring recipe quantity, in 200mL beaker, adds the tert-butyl alcohol of recipe quantity, and in 60 DEG C of water-baths, magnetic agitation is to complete drug dissolution, continues to be placed in 60 DEG C of water-baths, obtains Ginsenoside Rc's tert-butyl alcohol liquid, stand-by.
2, recipe quantity F68 is taken, join in above-mentioned Ginsenoside Rc's tert-butyl alcohol liquid, in 60 DEG C of water-baths, magnetic agitation to system is uniform solution, 20mL sterilized water for injection is added wherein under stirring, continue to stir 30min, obtain Ginsenoside Rc's concentrated solution, by this concentrated solution lyophilizing, obtain Ginsenoside Rc's concentrated solution lyophilized formulations.
Embodiment 9: the preparation of ginsenoside Rg3's concentrated solution
Prescription:
Technique:
1, the ginsenoside Rg3 measuring recipe quantity, in 200mL beaker, adds the dehydrated alcohol of recipe quantity, and in 60 DEG C of water-baths, magnetic agitation is to complete drug dissolution, continues to be placed in 60 DEG C of water-baths, obtains ginsenoside Rg3's ethanol, stand-by.
2, recipe quantity F68 and HS15 is taken, join in above-mentioned ginsenoside Rg3's ethanol, in 60 DEG C of water-baths, magnetic agitation to system is uniform solution, 10mL sterilized water for injection (wherein adding the ascorbic acid of 8mg) is added wherein under stirring, continue to stir 30min, sterilized water for injection adds to 100mL, to obtain final product.
Formulation aesthetics:
The ginsenoside Rg3's concentrated solution prepared is the liquid of clear, slightly thickness.
The dilution of ginsenoside Rg3's ethanol concentrated solution:
Get 14 parts of above-mentioned ginsenoside Rg3's concentrated solutions, every part of 1mL, use sterilized water for injection (SterileWater respectively, be abbreviated as SW), 0.9% sodium chloride injection (0.9%Nacl), 10% glucose injection (10%Glucose Injection, be abbreviated as 10%GI), 5%F68 solution, 10%F68 solution, 15%F68 solution and 20%F68 solution dilution 10 times and 20 times, after having diluted, observe formulation aesthetics, result shows, after different diluent media dilutes 10 times and 20 times, gained preparation is clear transparent solutions, room temperature and 4 DEG C are placed 72 hours, have no medicine to separate out.
Embodiment 10: the preparation of ginsenoside Rd's concentrated solution
Prescription:
Technique:
1, the ginsenoside Rd measuring recipe quantity, in 200mL beaker, adds the dehydrated alcohol of recipe quantity, and in 60 DEG C of water-baths, magnetic agitation is to complete drug dissolution, continues to be placed in 60 DEG C of water-baths, obtains ginsenoside Rd's ethanol, stand-by.
2, take recipe quantity F68 and TPGS, join in above-mentioned ginsenoside Rd's ethanol, in 60 DEG C of water-baths, magnetic agitation to system is uniform solution, adds 10mL propylene glycol wherein under stirring, continues to stir 30min, to obtain final product.
Embodiment 11: the preparation of ginsenoside Re's concentrated solution
Prescription:
Technique:
1, the ginsenoside Re measuring recipe quantity, in 200mL beaker, adds the dehydrated alcohol of recipe quantity, and in 60 DEG C of water-baths, magnetic agitation is to complete drug dissolution, continues to be placed in 60 DEG C of water-baths, obtains ginsenoside Re's ethanol, stand-by.
2, recipe quantity F68, RH40 is taken, join in above-mentioned ginsenoside Re's ethanol, in 60 DEG C of water-baths, magnetic agitation to system is uniform solution, adds 30mL glycerol (wherein adding the sodium sulfite of 10mg) under stirring wherein, continue to stir 30min, to obtain final product.
Formulation aesthetics:
The ginsenoside Re's concentrated solution prepared is the liquid of clear, slightly thickness.
The dilution of ginsenoside Re's ethanol concentrated solution:
Get 14 parts of above-mentioned ginsenoside Re's ethanol concentrated solutions, every part of 1mL, use sterilized water for injection (Sterile Water respectively, be abbreviated as SW), 0.9% sodium chloride injection (0.9%Nacl), 10% glucose injection (10%Glucose Injection, be abbreviated as 10%GI), 5%F68 solution, 10%F68 solution, 15%F68 solution and 20%F68 solution dilution 10 times and 20 times, after having diluted, observe formulation aesthetics, result shows, after different diluent media dilutes 10 times and 20 times, gained preparation is clear transparent solutions, room temperature and 4 DEG C are placed 72 hours, have no medicine to separate out.
Embodiment 12: the preparation of ginsenoside Rh2's concentrated solution
Prescription:
Technique:
1, the ginsenoside Rh2 measuring recipe quantity, in 200mL beaker, adds the dehydrated alcohol of recipe quantity, and in 60 DEG C of water-baths, magnetic agitation is to complete drug dissolution, continues to be placed in 60 DEG C of water-baths, obtains ginsenoside Rh2's ethanol, stand-by.
2, recipe quantity Cremophor EL is taken, join in above-mentioned ginsenoside Rh2's ethanol, in 60 DEG C of water-baths, magnetic agitation to system is uniform solution, 30mL sterilized water for injection (wherein adding the sodium sulfite of 10mg) is added wherein under stirring, continue to stir 30min, sterilized water for injection adds to 100mL, to obtain final product.
Formulation aesthetics:
The ginsenoside Rh2's concentrated solution prepared is the liquid of clear, slightly thickness.
The dilution of ginsenoside Rh2's concentrated solution:
Get above-mentioned ginsenoside Rh2's concentrated solution, every part of 1mL, use sterilized water for injection (Sterile Water respectively, be abbreviated as SW), 0.9% sodium chloride injection (0.9%Nacl), 10% glucose injection (10%GlucoseInjection, be abbreviated as 10%GI), 5%F68 solution, 10%F68 solution, 15%F68 solution and 20%F68 solution dilution 10 times, 20 times, 30 times and 40 times, after having diluted, observe formulation aesthetics, gained preparation is clear transparent solutions, room temperature and 4 DEG C are placed 72 hours, have no medicine and separate out.
Embodiment 13: the preparation of ginsenoside Re's granule
Prescription:
Technique:
1, the ginsenoside Re measuring recipe quantity, in dosing hopper, adds the dehydrated alcohol of recipe quantity wherein, and in 800 DEG C of water-baths, magnetic agitation is to complete drug dissolution, continues to be placed in 80 DEG C of water-baths, obtains ginsenoside Re's ethanol, stand-by.
2, recipe quantity F68 is taken, join in above-mentioned ginsenoside Re's ethanol, in 80 DEG C of water-baths, magnetic agitation to system is uniform solution, adds the distilled water (wherein having dissolved the lactose of 50g) of recipe quantity under stirring wherein, continue to be stirred to system homogeneous, obtain ginsenoside Re's concentrated solution.
3, by ginsenoside Re's concentrated solution spraying dry of gained, add suitable distilled water after fully mixing with the microcrystalline Cellulose of recipe quantity, subpackage after granulating, obtains ginsenoside Re's granule.
Embodiment 14: the preparation of ginsenoside Re's capsule
Get the granule of " embodiment 13 " gained, fill with capsule shells, obtain ginsenoside Re's capsule.
Claims (9)
1. ginsenoside's concentrated type liquid formula, is characterized in that: this concentrated type liquid formula comprises reactive compound ginsenoside, solubilizing agent, mixed solvent, antioxidant and pH adjusting agent, wherein:
Solubilizing agent is selected from one or more that hand over fat-ethylene glycol copolymer, HS15, Oleum Ricini to gather in hydrocarbon oxygen ester, polyoxyethylene hydrogenated Oleum Ricini (RH40) and polyethylene glycol 1000 vitamin E succinic acid ester from polysorbas20, Tween 80, phospholipid, PLURONICS F87, poloxamer 237, Pluronic/Lutrol F 108, poloxamer188, poly-third; The weight ratio of solubilizing agent and ginsenoside is 10:1 ~ 100:1;
Mixed solvent is selected from " alcohol-water ", " alcoholic-glycerine ", " ethanol-propylene glycol ", " tertiary butanol and water ", " tert-butyl alcohol-glycerol ", " tert-butyl alcohol-propylene glycol ", " propylene glycol-water ", one or more in " propylene glycol-glycerol ", in each mixed solvent, ratio shared by ethanol, the tert-butyl alcohol is: 50% ~ 90%(v/v), the ratio shared by water, glycerol and propylene glycol is 50% ~ 10%(v/v);
Antioxidant is selected from sulphite, bisulfites, dithiocar-bamate, ascorbic acid, citric acid, malic acid, sorbitol, ascorbic acid cetylate, hydrogen butylcoumariii, vitamin E, ethanolamine, fabaceous lecithin, cephalin, propyl gallate, butylated hydroxyarisol, ditertbutylparacresol, nordihydroguaiaretic acid, EDTA and Ethylenediaminetetraacetic Acid Calcium Salt, and consumption accounts for 0.00001 ~ 0.2w/v% of concentrated type liquid formula;
PH adjusting agent is selected from hydrochloric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, malic acid, aspartic acid, glutamic acid, glutamine, glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, methionine, hydroxyproline, sodium hydroxide, phosphate-buffered salt, sodium acetate, sodium tartrate, sodium citrate, natrium malicum, sodium carbonate and sodium bicarbonate, and its consumption is that the pH value of pharmaceutical composition is adjusted to 4 ~ 9.
2. ginsenoside's concentrated type liquid formula according to claim 1, it is characterized in that: described ginsenoside is selected from ginsenoside Re, ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rb3, Ginsenoside Rc, ginsenoside Rd, ginsenoside Rg3, ginsenoside Rh2, ginseng saponin Rg1, ginsenoside Rg2 and ginsenoside Rh1, and in miniature liquid formula, the concentration of ginsenoside is 5 ~ 50 mg/mL.
3. ginsenoside's concentrated type liquid formula according to claim 1, is characterized in that: the weight ratio of solubilizing agent and ginsenoside is 20:1 ~ 100:1.
4. ginsenoside's concentrated type liquid formula according to claim 1, is characterized in that: mixed solvent is selected from " alcohol-water ", " tertiary butanol and water ", one or more in " propylene glycol-water ".
5. ginsenoside's concentrated type liquid formula according to claim 1, is characterized in that: described ginsenoside's concentrated type liquid formula can use with after the F68 solution dilution of sterilized water for injection, glucose injection, 0.9% sodium chloride injection and 0.01%-20%.
6. a pharmaceutical preparation, is characterized in that, comprises the ginsenoside concentrated type liquid formula of claim 1-4 described in any one and pharmaceutically acceptable carrier.
7. pharmaceutical preparation according to claim 6, it is characterized in that, described pharmaceutical preparation is tablet, capsule, granule, powder, ointment, suspensoid, syrup, oral liquid, suppository, nasal drop or the powder ampoule agent for injection that the powder of ginsenoside's concentrated type liquid formula and pharmaceutically acceptable carrier are made.
8. pharmaceutical preparation according to claim 6, it is characterized in that, described carrier is selected from starch, microcrystalline Cellulose, dextrin, can die mould starch, lactose, mannitol, starch slurry, sodium carboxymethyl cellulose, hydroxypropyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl emthylcellulose, dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, hard magnesium, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, a kind of or several mixture in polyethylene glycols or magnesium laurylsulfate.
9. pharmaceutical preparation according to claim 7; it is characterized in that, the freeze drying protectant in described powder ampoule agent for injection is selected from a kind of or several mixture in glucose, xylose, ganglioside, fructose, sucrose, maltose, lactose, galactose, trehalose, mannitol, xylitol, maltol.
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| CN106550945A (en) * | 2016-10-26 | 2017-04-05 | 中国中医科学院中药研究所 | Panaxsaponin mixture and its application in as two-way telomere regulator |
| CN107669790A (en) * | 2017-12-02 | 2018-02-09 | 广州立达尔生物科技股份有限公司 | A kind of method that soapberry soap fruit extract solution directly freezed drying prepares saponin(e powder |
| CN108619200A (en) * | 2018-07-11 | 2018-10-09 | 山西省芮城县红宝兽药有限责任公司 | General ginsenoside injection for animals |
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| CN1526405A (en) * | 2003-01-06 | 2004-09-08 | 山东绿叶天然药物研究开发有限公司 | Antitumor ginsenoside Rg3 injection and its prepn process |
| CN1526407A (en) * | 2003-01-06 | 2004-09-08 | 山东绿叶天然药物研究开发有限公司 | Antitumor protopanoxadiol injection and its prepn process |
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| CN1526404A (en) * | 2003-01-06 | 2004-09-08 | 山东绿叶天然药物研究开发有限公司 | Antitumor ginsenoside C-K injection and its prepn process |
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| CN107669790A (en) * | 2017-12-02 | 2018-02-09 | 广州立达尔生物科技股份有限公司 | A kind of method that soapberry soap fruit extract solution directly freezed drying prepares saponin(e powder |
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