CN101091714A - Liposome of precursor containing ginsenoside Rh2, and preparation method - Google Patents
Liposome of precursor containing ginsenoside Rh2, and preparation method Download PDFInfo
- Publication number
- CN101091714A CN101091714A CN 200710024809 CN200710024809A CN101091714A CN 101091714 A CN101091714 A CN 101091714A CN 200710024809 CN200710024809 CN 200710024809 CN 200710024809 A CN200710024809 A CN 200710024809A CN 101091714 A CN101091714 A CN 101091714A
- Authority
- CN
- China
- Prior art keywords
- ginsenoside
- liposome
- pro
- phospholipid
- polyethylene glycol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The present invention belongs to the field of medicine preparation, in the concrete, it relates to a precursor liposome containing ginsenoside Rh2. The invented precursor liposome is fromed from ginsenoside Rh2 or ginsenoside Rh2 phospholipid compound, phospholipids, cholesterol, surfactant and water-soluble carrier. Said invention adopts ethyl alcohol injection method or film-homogeneous dispersion method to prepare ginsenoside Rh2 liposome, and adopts freeze-drying method, spray-drying method and vacuum drying method to prepare precursor liposome. Said ginsenoside Rh2 precursor liposome can be made into oral tablet preparation, capsule preparation and granules preparation.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, but be specifically related to contain the pro-liposome of ginsenoside Rh 2 or ginsenoside Rh 2 phosphatide complexes and the preparation method of industrial applications.
Background technology
Ginsenoside Rh 2 has another name called protopanoxadiol-3 β-D-glucopyanoside, belong to panoxadiol's saponins, it is a kind of rare panaxoside monomer, separate from Radix Ginseng Rubra by Japanese scholar's Beichuan merit the earliest and obtain, configuration difference according to 20 chiral carbon atoies, be divided into 20 (S)-ginsenoside Rh 2s and 20 (R)-ginsenoside Rh 2s again, both are epimer each other, has identical physicochemical property.Studies show that ginsenoside Rh 2 has stronger antitumor action, can be by inducing tumor cell differentiation and apoptosis, the growth and the propagation that effectively suppress kinds of tumor cells are to normal cytotoxicity very low (Xu Jingda, Changbai Mountain Chinese medicine research and development, 1996,5 (5): 48).Because the glycosyl of joining in ginsenoside's chemical constitution reduces, water solublity and polarity reduce, and ginsenoside Rh 2 dissolves in ethanol and methanol, and is atomic molten in ethyl acetate, chloroform, and almost insoluble in water, it is fat-soluble also relatively poor.Ginsenoside Rh 2 is to take off a main metabolites of joining glycosyl in panaxoside Rg 3 bodies, because ginsenoside Rh 2 poor solubility, metabolism and degraded take place under gastric acid environment easily, so absorb in the Beagle dog body than slow and poor, absolute bioavailability is 16.1%.Ginsenoside Rh 2 is the substrate of P-glycoprotein in addition, and the P-glycoprotein also is to cause to absorb the main cause that reduces to its effect that effluxes.Because intestinal microbial population is to ginsenoside's desaccharide base metabolism, ginsenoside Rh 2 may be converted into desaccharide thing aglycon PPD at intestinal, cause the medicine absolute bioavailability low (Gu Yi, Wang Guangji etc. Chinese clinical pharmacology and therapeutics 2006,5:(1) 13).
CN1626101A discloses nano-emulsion of a kind of ginsenoside of containing and its production and use, this patent nano-emulsion is made up of oil phase, surfactant, water and stabilizing agent, can change saponin after the intravenous injection in the intravital distribution of people, medicine is concentrated in tumor locus, improved the tumor-inhibiting action of medicine.CN1526403A discloses a kind of ginsenoside Rh2's injection and preparation method, this patent disclosure a kind of method of dissolving the solvent for injection and the additives of ginsenoside Rh 2.The intravenous injection fatty emulsion of ginsenoside Rh 2 has been developed in the woods East Sea etc., with the soybean oil is oil phase, egg yolk lecithin and Poloxamer188 are emulsifying agent, prepared intravenous injection emulsion, expectation raising bioavailability of medicament reaches targeted therapy effect (the woods East Sea to tumor, Deng. Chinese Pharmaceutical Journal, 2006,41 (11): 842).
CN1883497A discloses a kind of ginsenoside Rh 2 hydroxypropyl-beta-cyclodextrin inclusion and preparation and preparation method, and hydroxy propyl-Beta cyclodextrin inclusion compound medicine is adopted in this invention, improves its water solublity, and freeze-dried powder or preparation tablet, capsule etc. are made in lyophilization.ZL 94112420.7 discloses a kind of preparation method of ginsenoside's liposome, adopt filmogens such as ether dissolution phospholipid, cholesterol, join in the ampoule that the water solublity ginsenoside is housed, vacuum drying is removed ether, seals behind the adding water for injection and makes liposome turbid liquor.That this patent relates to is the water solublity ginsenoside, and its preparation finished product is a liposome turbid liquor.But problems such as oxydrolysis, particle accumulation, solution layering, drug leakage appear when liposome exists with the suspension state easily.At present, domestic and foreign literature there is no the report of ginsenoside Rh 2 proliposome preparation, the present invention adopts the pro-liposome entrapped drug, increase stability and the bioavailability of medicine in gastrointestinal tract, and can be made into the solid dosage forms administrations such as tablet, enteric coated tablet and capsule of pro-liposome, to significantly improve the bin stability of Liposomal formulation.
Summary of the invention
The invention discloses a kind of proliposome preparation of ginsenoside Rh 2, medicine is encapsulated in the phospholipid bilayer of liposome, can reduce the metabolic conversion of ginsenoside Rh 2 in gastrointestinal tract after the said preparation oral administration, improve medicine in gastrointestinal stability, increase the cross-cell membrane ability of encapsulated medicine, significantly improve the oral bioavailability of insoluble drug; Behind this pro-liposome drug administration by injection, fusion or endocytosis by cell membrane are delivered to medicine in the target cell, discharge medicine through the enzyme effect, reach long circulation purpose with the holdup time in the prolong drug body; The ginsenoside Rh 2 pro-liposome preparation method of development can be implemented suitability for industrialized production.
Technical scheme of the present invention is as follows:
Ginsenoside Rh 2 pro-liposome of the present invention, contain following component and ratio of weight and number:
Ginsenoside Rh 21
Phosphatidase 12～35
Cholesterol 0.1～10
Surfactant 1～20
Water-solubility carrier 4～25.
The preferred ratio of weight and number of above-mentioned each component is:
Ginsenoside Rh 21
Phosphatidase 15～30
Cholesterol 1～8
Surfactant 3～15
Water-solubility carrier 6～20.
Wherein phospholipid is selected from Ovum Gallus domesticus Flavus lecithin, soybean phospholipid, hydrogenated phospholipid, two Cetyl Phosphates, natural or synthetic cuorin, cephalin, Phosphatidylserine, phosphatidic acid, two Semen Myristicae phosphatidylcholines, two Semen Myristicae PHOSPHATIDYL ETHANOLAMINE, two Semen Myristicae phosphatidyl glycerols, the dioleoyl phospholipid phatidylcholine, DOPE, dipalmitoyl phosphatidyl choline, two palmityl phosphatidyl glycerols, two palmityl PHOSPHATIDYL ETHANOLAMINE, distearoyl phosphatidylcholine, in distearyl phosphatidyl glycerol or the distearyl phospholipid ethanolamine one or more.
Above-mentioned surfactant be selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxalkol, Polyethylene Glycol-8-glycerol sad/in decanoin, cholic acid, deoxycholic acid, cholate or the dexycholate one or more.
Ginsenoside Rh 2 pro-liposome of the present invention also can contain additives, the preferred DC-cholesterol of additives, chitosan or derivatives thereof, 18-amine., stearylamine, stearic acid, oleic acid, Phosphatidylserine and two Cetyl Phosphates etc.After being used for oral ginsenoside Rh 2 pro-liposome and having added these additives, positively charged easier and electronegative intestinal mucosa cells effect promotes the ginsenoside Rh 2 liposome to enter enterocyte, improves the ability that it strides the goldbeater's skin transhipment.
But the pro-liposome of ginsenoside Rh 2 of the present invention also contains the hydrophilic material of modified liposome, as polyethylene glycol-lactic acid (PEG-PLA); The phospholipid derivative of PEG such as Polyethylene Glycol-phosphatidylcholine (PEG-PC), Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE (PEG-PE), Polyethylene Glycol-distearoyl phosphatidylcholine (PEG-DSPC), Polyethylene Glycol-distearyl phosphatidyl ethanol (PEG2000-DSPE), Polyethylene Glycol-monocarboxylic acid 3000-two palmityl phosphatidyl diethanolamine (DPPE-PEG3000-COOH), poly glycol monomethyl ether 2000 cholesterol succinates, Ganglioside GM1, the polyethylene glycol-caprolactone, polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide, polyoxyethylene fatty acid ester (Myrij), polyoxyethylene aliphatic alcohol ether (Brii), polyethylene glycol-cetyl cyanoacrylate, Polyethylene Glycol (PEG), in the polyvinyl alcohol (PVA) etc. one or more.Preferred PEG-PLA and PEG-DSPC.After the ginsenoside Rh 2 proliposome preparation that is used for injecting adds these additives, make its surface expose hydrophilic polyhydroxy group or polysaccharide etc. by long recycled material modification, reduced the effect of albumen, opsonin, antibody or enzyme etc. in conventional liposome and the blood plasma, prevent the quick seepage of entrapped drug and absorbed by the identification of reticuloendothelium system (RES), the long circulation pro-liposome of ginsenoside Rh 2 is the holdup time of prolong drug in blood more enduringly, avoid engulfing of RES, spontaneous arrival targeting moiety performance drug effect.Calculate 1 part of phospholipid by weight and preferably add 0.08～0.5 part of above-mentioned hydrophilic material.
Above-mentioned water-solubility carrier is selected from one or more in sorbitol, mannitol, lactose, glucose, sodium chloride, sucrose, cyclodextrin, trehalose, fructose or the dextran, preferred mannitol and/or glucose.
The present invention also can make the pro-liposome of ginsenoside Rh 2 again with behind ginsenoside Rh 2 and the phospholipid elder generation preparation phosphatide complexes with phospholipid, cholesterol, surfactant and water-solubility carrier.
Discover, add proper amount of surfactant in the ginsenoside Rh 2 pro-liposome of the present invention, the particle diameter of liposome turbid liquor is reduced gradually, the difficult gathering, improve the stability of liposome turbid liquor; With the increase of dosage of surfactant, the flowability of bimolecular lamellar lipid membrane, permeability increase, and particle diameter reduces.Prescription is formed in parts by weight (w/w): ginsenoside Rh 2: surfactant: phospholipid: cholesterol, and surfactant the results are shown in Table 1 and table 2 to the influence of liposome particle diameter:
Table 1 Pluronic F68 is to the influence of liposome particle diameter and envelop rate
| Prescription is formed (w/w) | Particle diameter (nm) | Envelop rate (%) |
| Do not add Pluronic F68 1: 1.5: 13: 21: 6: 13: 21: 9: 13: 2 | 205.9 170.6 114.5 82.9 | 84.8 85.3 87.0 88.2 |
Table 2 tween 80 is to the influence of liposome and pro-liposome physical characteristic
| Liposome turbid liquor | Pro-liposome | |||
| Prescription is formed (w/w) | Particle diameter (nm) | Envelop rate (%) | Mean diameter (nm) | Envelop rate (%) |
| Do not add |
196.9 153.7 102.5 72.9 | 86.4 88.2 90.7 87.5 | 293.6 265.3 152.8 126.2 | 87.5 88.4 89.6 88.7 |
Table 1 and table 2 show, add surfactant in the liposome turbid liquor, can obviously reduce the liposome mean diameter of drug administration by injection, more deep studies show that, in ginsenoside Rh 2 is 1 part of weight, and then surfactant preferably adds 3～15 parts, in this scope envelop rate is not had influence substantially.
Discover, phospholipid and cholesterol consumption and proportioning are the key factors of preparation liposome, adopt the liposome turbid liquor of alcohol injection preparation, prescription is formed in parts by weight (w/w): ginsenoside Rh 2: phospholipid: cholesterol: surfactant, investigate of the influence of phospholipid consumption by experiment of single factor, the results are shown in Table 3 liposome particle diameter and envelop rate.
Table 3 phospholipid consumption is to the influence of liposome physical characteristic
| Prescription is formed (w/w) | Particle diameter (nm) | Envelop rate (%) |
| 1∶0.5∶3∶8 1∶2∶3∶8 1∶10∶3∶8 1∶25∶3∶8 1∶30∶3∶8 1∶35∶3∶8 1∶45∶3∶8 | 231.0 118.7 124.8 126.3 130.5 135.0 141.2 | 39.3 65.7 88.4 90.2 89.5 88.1 87.5 |
Found out that by table 3 the phospholipid parts by weight are less than 2, the envelop rate of liposome is less than 40%, and particle diameter increases; Increase with the phospholipid consumption, the envelop rate of medicine obviously improves, and when phospholipid during greater than 35 weight portions, particle diameter, envelop rate is changed little, is 1 part of weight in ginsenoside Rh 2 therefore, 2～35 parts of the suitable amount ranges of phospholipid, preferred 5～30 parts.
In addition, among the present invention, the kind of water-solubility carrier and consumption are also very important to the shaping and the quality of pro-liposome.
With phospholipid, cholesterol is that filmogen, Tween 80 are carrier, the consumption of ginsenoside Rh 2 and phospholipid, cholesterol and surfactant is counted 1: 13: 2 with parts by weight: 4, other components unchanged in fixed lipid plastid prescription and the technology, with mannitol is example, change the consumption of mannitol, the preparation pro-liposome, observe the outward appearance and the redispersibility of lyophilized powder, measure envelop rate and mean diameter after lyophilized powder adds the water reconstruction, the results are shown in Table 4, wherein prescription consists of ginsenoside Rh 2: phospholipid: cholesterol: surfactant: water-solubility carrier.
Table 4 mannitol consumption is to the influence of liposome physical characteristic
| Prescription is formed (w/w) | Particle diameter (nm) | Envelop rate (%) | The lyophilized powder outward appearance | Redispersibility |
| 1∶13∶2∶4∶3 1∶13∶2∶4∶6 1∶13∶2∶4∶15 1∶13∶2∶4∶20 1∶13∶2∶4∶24 | 109.5 113.8 120.7 119.0 117.4 | 87.3 90.1 88.5 85.7 89.4 | Softening, it is fluffy to subside, flowability is better fluffy, good fluidity is fluffy, good fluidity is fluffy, good fluidity | Difference is better good carefully |
The result shows that the consumption of freeze drying protectant does not have influence substantially to envelop rate and particle diameter, mainly influences the outward appearance and the redispersibility of pro-liposome.When the consumption of mannitol was lower than 4 weight portions, the outward appearance of lipid freeze-dry powder was relatively poor, softening subsiding occurred, and assembled in bulk easily and caused the redispersion difficulty, so the parts by weight of water-solubility carrier are advisable preferred 6～20 parts with 4～25 parts.
Ginsenoside Rh 2 pro-liposome preparation method of the present invention can be with following any method:
(1) takes by weighing ginsenoside Rh 2, phospholipid, cholesterol and surfactant with dehydrated alcohol or dissolve with methanol, make lipoids solution, remove organic solvent; Slowly inject the aqueous solution contain mannitol again, liposome turbid liquor is through the high pressure homogenize, and lyophilization promptly gets the pro-liposome of ginsenoside Rh 2.
(2) take by weighing phospholipid and cholesterol, with dehydrated alcohol or dissolve with methanol, other takes by weighing ginsenoside Rh 2 and adds surfactant and disperse in right amount, and with two kinds of abundant mixing and emulsifyings of solution, rotary evaporation is removed organic solvent.Take by weighing mannitol and be dissolved in pure water, add the liposome solutions mix homogeneously again, spray-dried, promptly get the pro-liposome of ginsenoside Rh 2.
(3) take by weighing ginsenoside Rh 2 and soybean phospholipid is dissolved in dehydrated alcohol, stir and make it be dissolved to clear, 40 ℃ of decompression rotary evaporations are removed ethanol, and vacuum drying 24 h promptly get the ginsenoside Rh 2 phosphatide complexes.Other takes by weighing ginsenoside Rh 2 phosphatide complexes, soybean phospholipid (phosphatidylcholine content 90%), cholesterol and surfactant and is dissolved in dehydrated alcohol or methanol, form lipoids solution, remove organic solvent, add the aqueous solution that contains mannitol, through lyophilization or spray drying, promptly get the pro-liposome of ginsenoside Rh 2 phosphatide complexes.
Adopt the prepared pro-liposome envelop rate of the present invention greater than 80%, mature preparation process of the present invention, constant product quality need not special process equipment, are suitable for suitability for industrialized production.
Above-mentioned pro-liposome lyophilized powder is with water for injection or 5% glucose solution, 0.9% sodium chloride solution hydration, the liposome turbid liquor that forms, in the composition of liposome, add hydroaropic substances such as a certain proportion of PEG-phospholipid derivative or PEG-PLA and prepare long circulating liposomes, can reduce liposome and nurse one's health proteic the combination, the time of staying of prolong drug in blood with blood plasma.When medicine by liposomal encapsulated in lipid film after, can protect medicine not by gastric acid and intestinal flora metabolic degradation, reach the targeted therapy effect.
Above-mentioned pro-liposome also can add pharmaceutic adjuvant commonly used and be prepared into solid orally ingestible, pharmaceutic adjuvant such as filler, disintegrating agent, lubricant, dry adhesives etc., filler such as lactose, spray-dried lactose, Lactis Anhydrous, microcrystalline Cellulose, amylum pregelatinisatum and starch etc., disintegrating agent such as polyvinylpolypyrrolidone (PVPP), cross-linking sodium carboxymethyl cellulose (CC-Na), carboxymethyl starch sodium (CMS-Na), low substituted carboxymethyl sodium cellulosate (L-HPC) etc., lubricant such as magnesium stearate, micropowder silica gel or two kinds of mixing are used, and adopt the preparation method of solid preparation can be prepared into tablet, hard capsule, soft capsule, dosage forms such as granule are for oral administration.Further can adopt the enteric material coating, to increase medicine in gastrointestinal stability, wherein enteric-coating material comprises Eudragit L100, Eudragit L100-55, EudragitL30D-55, Eudragit S100, cellulose acetate phthalate ester (CAP), hypromellose phthalate ester (HPMCP) and Hydroxypropyl Methyl Cellulose Phthalate (HPMCAS), but be not limited to these enteric materials, can adopt hypromellose (HPMC) or hydroxypropyl cellulose (HPC) bag contagion gown between enteric-coating material and the pro-liposome.
Description of drawings
Fig. 1 is that Radix Ginseng Saponin Rh2 pro-liposome sheet of the present invention and ordinary tablet are at 0.1molL
-1Stripping curve in the hydrochloric acid solution (n=6)
Fig. 2 is Radix Ginseng Saponin Rh2 pro-liposome enteric coatel tablets of the present invention and the release profiles (n=6) of ordinary tablet in the pH6.8 phosphate buffer
The specific embodiment
Embodiment 1
Take by weighing the 0.5g ginsenoside Rh 2,6.0g lecithin (containing phosphatidyl choline 70%), 1.2g Phosphatidylserine, 1.0g cholesterol and 3.0g Pluronic F68 dissolve with dehydrated alcohol 80mL under 30 ℃ of conditions, make lipoids solution, 5.0g mannitol is scattered in the lipoids solution, and rotary evaporation is flung to ethanol.Use 0.45 μ m, 0.22 μ m filtering with microporous membrane successively, in 30 ℃ of vacuum drying 24h, crushing screening promptly gets the ginsenoside Rh 2 oral proliposome.Adopt the sephadex chromatography post to measure envelop rate 87.2%, the particle diameter that adopts the Zetamaster photon correlation spectrometer to measure pro-liposome is 135.6nm.
Embodiment 2
Take by weighing the 0.5g ginsenoside Rh 2,5.0g soybean phospholipid (containing phosphatidyl choline 80%), 0.5g phosphatidic acid, 1.0g cholesterol and 2.5g tween 80 are made lipoids solution with dehydrated alcohol 80mL dissolving under 30 ℃ of conditions, slowly inject the aqueous solution that is dissolved with the 4g sorbitol, continue to stir until ethanol and wave to the greatest extent, use 0.45 μ m, 0.22 μ m filtering with microporous membrane successively, lyophilization promptly gets the ginsenoside Rh 2 pro-liposome.Take by weighing pro-liposome and spray-dried lactose, pregelatinized Starch, cross-linked carboxymethyl cellulose and micropowder silica gel mix homogeneously, directly powder is pressed into tablet.Envelop rate 89.5%, particle diameter 293.6nm.
Press 2005 editions two dissolution three therapeutic methods of traditional Chinese medicine of Chinese Pharmacopoeia and measure, dissolution medium is 0.1mol.L
-1Hydrochloric acid 250mL, 37 ℃ of temperature, mixing speed are 50r.min
-1, respectively at 10,20,30,45,60,90,120, the 180min 5mL that takes a sample, add medium 5mL simultaneously, filter, get filtrate and add the dilution of methanol rupture of membranes in right amount, filter, draw 20 μ L and inject HPLC and analyze.The pro-liposome tablet is at 0.1molL
-1120min stripping medicine reaches 85.6% in the hydrochloric acid solution, does not have the medicine stripping substantially in the conventional tablet 120min, so pro-liposome tablet dissolution of the present invention significantly improves than prior art, stripping curve is seen Fig. 1.
Embodiment 3
Take by weighing the 0.5g ginsenoside Rh 2,5.0g soybean phospholipid (phosphatidylcholine content is 90%), 1.5g cuorin, 2.0g cholesterol, 4.0g Pluronic F68 dissolves with dehydrated alcohol 80mL under 30 ℃ of conditions, make lipoids solution, reduction vaporization is removed ethanol, forms quasi-lipid film, vacuum drying 24h, the aqueous solution that adds 6.0g mannitol, the high pressure breast is even, uses 0.8 μ m, 0.45 μ m membrane filtration successively, reuse 0.22 μ m microporous filter membrane aseptic filtration, to disperse thing to be sub-packed in the cillin bottle lyophilization.Record envelop rate 88%, particle diameter 112.6nm.This pro-liposome can directly adopt 5% glucose injection hydration to be redeveloped into liposome turbid liquor for drug administration by injection.
Embodiment 4
Take by weighing the 0.5g ginsenoside Rh 2,0.75g synthetic phospholipid (phosphatidylcholine content is 90%) is dissolved in the 30mL dehydrated alcohol, and stirring and dissolving is to clear, and 40 ℃ of decompression rotary evaporations are removed ethanol, and vacuum drying 24h gets the ginsenoside Rh 2 phosphatide complexes.Other takes by weighing 1.0g ginsenoside Rh 2 phosphatide complexes, 3.0g hydrogenated soya phosphatide, 1.2g Phosphatidylserine, 2.0g Tween 80,1.0g cholesterol is made lipoids solution with dehydrated alcohol 70mL dissolving under 30 ℃ of conditions, reduction vaporization is removed ethanol, forms quasi-lipid film, adds the aqueous solution hydration of 3.0g mannitol, high pressure homogenization, use 0.8 μ m, 0.45 μ m, 0.22 μ m filtering with microporous membrane successively, spray drying promptly gets the ginsenoside Rh 2 pro-liposome.Envelop rate 87.4%, particle diameter 185.2nm.This liposome fill in hard capsule, is capsule.
Embodiment 5
Take by weighing the 0.5g ginsenoside Rh 2,5g soybean phospholipid (phosphatidylcholine content is 90%), 1.0gPEG-DSPE, 2.5g Tween 80,0.8g cholesterol is made lipoids solution with dehydrated alcohol 80mL dissolving under 30 ℃ of conditions, stir down with the slow 37 ℃ of aqueous solution hydration mediums that contain the 4.0g lactose of injection at the uniform velocity of class lipoprotein solution, continue to stir until ethanol and wave to the greatest extent, high pressure homogenize, use 0.8 μ m, 0.45 μ m, 0.22 μ m filtering with microporous membrane successively, obtain liposome turbid liquor, lyophilization promptly gets the ginsenoside Rh 2 pro-liposome.Envelop rate 90.3%, particle diameter 175.2nm.With this pro-liposome and Lactis Anhydrous, microcrystalline Cellulose, polyvinylpolypyrrolidone and micropowder silica gel mix homogeneously, directly enteric coated behind the pressed powder.
Embodiment 6
Take by weighing the 0.5g ginsenoside Rh 2,7.0g soybean phospholipid (phosphatidylcholine content is 90%), 2.4gPEG-PLA, 1.5g cholesterol, 2.5g Pluronic F68 with dehydrated alcohol 80mL dissolving, are made lipoids solution under 30 ℃ of conditions, reduction vaporization is removed ethanol, the aqueous solution that adds the 6.0g glucose forms liposome turbid liquor, and the high pressure breast is even, use 0.8 μ m, 0.45 μ m membrane filtration successively, reuse 0.22 μ m microporous filter membrane aseptic filtration will disperse thing to be sub-packed in the cillin bottle lyophilization.This pro-liposome can directly adopt 5% glucose injection hydration to be redeveloped into liposome turbid liquor for drug administration by injection.Envelop rate 89.5%, particle diameter 208.7nm.
Embodiment 7
Take by weighing 1 part of the pro-liposome of embodiment 1 preparation, add 0.4 part of microcrystalline Cellulose, 0.3 part of spray-dried lactose, 0.1 part of polyvinylpolypyrrolidone and an amount of mix homogeneously of micropowder silica gel, directly powder compaction label according to conventional method; In addition label is adopted high-efficiency coating equipment, with HPMC alcohol-water solution bag sealing coat (weightening finish 2%), reuse EudragitL30D-55 is enteric coated earlier, and the coating weightening finish is 15%.
Press 2005 editions two release three therapeutic methods of traditional Chinese medicine of Chinese Pharmacopoeia and measure, release medium is pH6.8 phosphate buffer 250mL, and temperature is 37 ℃, and mixing speed is 50r.min
-1, respectively at 20,30,45,60,90,120,180,210, the 240min 5mL that takes a sample, replenish medium 5mL simultaneously, filter, to get filtrate and add the dilution of methanol rupture of membranes in right amount, 0.45 μ m membrane filtration is drawn 20 μ L and is injected HPLC and measure.Ginsenoside Rh 2 pro-liposome enteric coatel tablets 120min in the pH6.8 phosphate buffer discharges medicine and reaches 82.2%, substantially there is not drug release in the conventional tablet 120min, data show that so pro-liposome enteric coated tablet release of the present invention significantly improves than prior art, release profiles is seen Fig. 2.
Claims (10)
1, a kind of ginsenoside Rh 2 pro-liposome is characterized in that containing following component and ratio of weight and number:
Ginsenoside Rh 21
Phosphatidase 12～35
Cholesterol 0.1～10
Surfactant 1～20
Water-solubility carrier 4～25.
2, the ginsenoside Rh 2 pro-liposome of claim 1 is characterized in that containing following component and ratio of weight and number:
Ginsenoside Rh 21
Phosphatidase 15～30
Cholesterol 1～8
Surfactant 3～15
Water-solubility carrier 6～20.
3, claim 1 or 2 ginsenoside Rh 2 pro-liposome, wherein phospholipid is selected from Ovum Gallus domesticus Flavus lecithin, soybean phospholipid, hydrogenated phospholipid, two Cetyl Phosphates, natural or synthetic cuorin, cephalin, Phosphatidylserine, phosphatidic acid, two Semen Myristicae phosphatidylcholines, two Semen Myristicae PHOSPHATIDYL ETHANOLAMINE, two Semen Myristicae phosphatidyl glycerols, the dioleoyl phospholipid phatidylcholine, DOPE, dipalmitoyl phosphatidyl choline, two palmityl phosphatidyl glycerols, two palmityl PHOSPHATIDYL ETHANOLAMINE, distearoyl phosphatidylcholine, in distearyl phosphatidyl glycerol or the distearyl phospholipid ethanolamine one or more.
4, claim 1 or 2 ginsenoside Rh 2 pro-liposome, wherein water-solubility carrier is selected from one or more in sorbitol, mannitol, lactose, glucose, sodium chloride, sucrose, cyclodextrin, trehalose, fructose or the dextran.
5, the ginsenoside Rh 2 pro-liposome of claim 4, wherein water-solubility carrier is mannitol and/or lactose.
6, claim 1 or 2 ginsenoside Rh 2 pro-liposome, wherein surfactant be selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxalkol, Polyethylene Glycol-8-glycerol sad/in decanoin, cholic acid, deoxycholic acid, cholate or the dexycholate one or more.
7, claim 1 or 2 ginsenoside Rh 2 pro-liposome also contain polyethylene glycol-lactic acid, Polyethylene Glycol-phosphatidylcholine, Polyethylene Glycol-PHOSPHATIDYL ETHANOLAMINE, Polyethylene Glycol-distearoyl phosphatidylcholine, Polyethylene Glycol-distearyl phosphatidyl ethanol, Polyethylene Glycol-monocarboxylic acid 3000-two palmityl phosphatidyl diethanolamine, poly glycol monomethyl ether 2000 cholesterol succinates, ganglioside GM
1, in polyethylene glycol-caprolactone, polyethylene glycol-Acetic acid, hydroxy-, bimol. cyclic ester lactide, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether, polyethylene glycol-cetyl cyanoacrylate, Polyethylene Glycol or the polyvinyl alcohol one or more, its weight be phospholipid 0.08～0.5 times.
8, claim 1 or 2 ginsenoside Rh 2 pro-liposome also contain in DC-cholesterol, chitosan or derivatives thereof, 18-amine., stearylamine, stearic acid, oleic acid, Phosphatidylserine or two Cetyl Phosphates one or more.
9, the preparation method of claim 1 or ginsenoside's pro-liposome of 2 comprises: ginsenoside Rh 2, phospholipid, cholesterol and surfactant are dissolved in dehydrated alcohol or the methanol, form lipoids solution, remove organic solvent; Slowly inject the aqueous solution contain water-solubility carrier again, liposome turbid liquor is through the high pressure homogenize, and lyophilization promptly gets the pro-liposome of ginsenoside Rh 2.
10, the preparation method of claim 9 also can prepare phosphatide complexes earlier with ginsenoside Rh 2 and phospholipid, makes the ginsenoside Rh 2 pro-liposome with phospholipid, cholesterol, surfactant and water-solubility carrier again.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710024809 CN101091714A (en) | 2007-07-02 | 2007-07-02 | Liposome of precursor containing ginsenoside Rh2, and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200710024809 CN101091714A (en) | 2007-07-02 | 2007-07-02 | Liposome of precursor containing ginsenoside Rh2, and preparation method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101091714A true CN101091714A (en) | 2007-12-26 |
Family
ID=38990272
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710024809 Pending CN101091714A (en) | 2007-07-02 | 2007-07-02 | Liposome of precursor containing ginsenoside Rh2, and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101091714A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101966161A (en) * | 2010-09-06 | 2011-02-09 | 海南美兰史克制药有限公司 | Rabeprazole sodium liposome enteric-coated tablets |
| CN102078299A (en) * | 2011-01-04 | 2011-06-01 | 海南美大制药有限公司 | Citicoline sodium liposome solid preparation |
| CN103585466A (en) * | 2013-11-21 | 2014-02-19 | 吉林大学 | Sapodilla saponin composite precursor liposome and preparation method thereof |
| CN106038493A (en) * | 2016-05-30 | 2016-10-26 | 肖雯婧 | Paxilline lipidosome powder injection and preparation method and application thereof |
| WO2017028811A1 (en) * | 2015-08-19 | 2017-02-23 | Shanghai Ginposome Pharmatech Co., Ltd. | Liposomes with ginsenoside as membrane material and preparations and use thereof |
| CN111228219A (en) * | 2018-11-29 | 2020-06-05 | 上海参素药物技术有限公司 | Blank liposome taking ginsenoside Rg3 or analogues thereof as membrane material, preparation method and application thereof |
| CN112401009A (en) * | 2020-12-08 | 2021-02-26 | 汤臣倍健股份有限公司 | Liposome, preparation method and application thereof |
-
2007
- 2007-07-02 CN CN 200710024809 patent/CN101091714A/en active Pending
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101966161A (en) * | 2010-09-06 | 2011-02-09 | 海南美兰史克制药有限公司 | Rabeprazole sodium liposome enteric-coated tablets |
| CN101966161B (en) * | 2010-09-06 | 2012-05-23 | 海南美兰史克制药有限公司 | Rabeprazole sodium liposome enteric-coated tablets |
| CN102078299A (en) * | 2011-01-04 | 2011-06-01 | 海南美大制药有限公司 | Citicoline sodium liposome solid preparation |
| CN102078299B (en) * | 2011-01-04 | 2012-09-26 | 海南美大制药有限公司 | Citicoline sodium liposome solid preparation |
| CN103585466A (en) * | 2013-11-21 | 2014-02-19 | 吉林大学 | Sapodilla saponin composite precursor liposome and preparation method thereof |
| CN103585466B (en) * | 2013-11-21 | 2016-04-06 | 吉林大学 | Herba Herminii saponin's composite precursor liposome and preparation method |
| CN106466299A (en) * | 2015-08-19 | 2017-03-01 | 上海本素医药科技有限公司 | Blank liposome with ginsenoside as membrane material, its preparation method and application |
| WO2017028811A1 (en) * | 2015-08-19 | 2017-02-23 | Shanghai Ginposome Pharmatech Co., Ltd. | Liposomes with ginsenoside as membrane material and preparations and use thereof |
| EP3337456A4 (en) * | 2015-08-19 | 2019-04-24 | Shanghai Ginposome Pharmatech Co., Ltd. | Liposomes with ginsenoside as membrane material and preparations and use thereof |
| CN111920770A (en) * | 2015-08-19 | 2020-11-13 | 上海本素医药科技有限公司 | Paclitaxel liposome and preparation method thereof |
| CN106466299B (en) * | 2015-08-19 | 2021-09-28 | 上海本素医药科技有限公司 | Blank liposome taking ginsenoside as membrane material, preparation method and application thereof |
| CN111920770B (en) * | 2015-08-19 | 2022-06-14 | 上海本素医药科技有限公司 | Paclitaxel liposome and preparation method thereof |
| CN106038493A (en) * | 2016-05-30 | 2016-10-26 | 肖雯婧 | Paxilline lipidosome powder injection and preparation method and application thereof |
| CN111228219A (en) * | 2018-11-29 | 2020-06-05 | 上海参素药物技术有限公司 | Blank liposome taking ginsenoside Rg3 or analogues thereof as membrane material, preparation method and application thereof |
| CN111956614A (en) * | 2018-11-29 | 2020-11-20 | 上海参素药物技术有限公司 | Paclitaxel liposome and preparation method thereof |
| EP3870153A4 (en) * | 2018-11-29 | 2021-12-15 | Shanghai Ginsome Pharmatech Co., Ltd. | A novel blank liposome with ginsenoside rg3 or its analog as membrane materials and preparations and uses thereof |
| CN111956614B (en) * | 2018-11-29 | 2022-09-30 | 上海参素药物技术有限公司 | Paclitaxel liposome and preparation method thereof |
| CN111228219B (en) * | 2018-11-29 | 2023-01-06 | 上海参素药物技术有限公司 | Blank liposome taking ginsenoside Rg3 or analogue thereof as membrane material, preparation method and application thereof |
| CN112401009A (en) * | 2020-12-08 | 2021-02-26 | 汤臣倍健股份有限公司 | Liposome, preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101091714A (en) | Liposome of precursor containing ginsenoside Rh2, and preparation method | |
| CN112843019A (en) | Nucleic acid lipid nanoparticle composition, pharmaceutical preparation containing same, and preparation method and application thereof | |
| JP3267611B2 (en) | Liposome-polyene preliposome powder and method for producing the same | |
| CN102018672B (en) | Freeze-dried liposome composition of water-soluble medicament and preparation method thereof | |
| CN101474155A (en) | Lung-targeted medicine carrying precursor liposome for injection and method of use thereof | |
| US9283190B2 (en) | Highly efficient and long-acting slow-release formulation of poorly soluble drugs and preparation method thereof | |
| CN101366698A (en) | Biogastrone acid prosome liposome with long circulation function and preparation method thereof | |
| CN101087588B (en) | Coated drug delivery formulations | |
| US20100021538A1 (en) | Pharmaceutical compositions containing heparin derivatives | |
| JP3202999B2 (en) | Hepatic liposome preparation | |
| CN116270473B (en) | Co-carried liposome and preparation method thereof | |
| KR20190070653A (en) | Oral pharmaceutical composition comprising pemetrexed and method for preparing the same | |
| CN108289832A (en) | For carrying out the Levosimendan of intravenously administrable with infusion or injection form and being transfused the improvement formula of concentrate | |
| JP2002532389A (en) | Phospholipid composition | |
| CN102805729A (en) | Vinflunine liposome preparation and preparation method of vinflunine liposome preparation | |
| CN101693010B (en) | Cefathiamidine prosoma liposome preparation | |
| CN101554371A (en) | Preparation and application of Silybin/Silymarin polymer micelle | |
| CN102028655B (en) | Zanamivir solid lipid nanosphere oral preparation and preparation method thereof | |
| CN1326525C (en) | 10-hydroxy camptothecin long cyclic liposome and its freeze aried preparation | |
| CN107802600B (en) | Icariin bone targeting nano liposome as well as preparation method and application thereof | |
| CN102327222B (en) | Tropisetron hydrochloride liposome injection | |
| CN107281106B (en) | Cholate modified cationic vitamin D3 oral liposome and freeze-dried preparation thereof | |
| CN101732232B (en) | Docetaxel nano-particle composition | |
| CN101721461A (en) | High dispersion preparation of rabdosia rubescens total terpenoid extract | |
| CN105616354A (en) | Neogambogic acid liposome injection and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Open date: 20071226 |