CN103417479A - Ginsenoside Rg3 liposome and preparation method thereof - Google Patents
Ginsenoside Rg3 liposome and preparation method thereof Download PDFInfo
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Abstract
The invention provides ginsenoside Rg3 liposome and a preparation method thereof, a drug is encapsulated by using the manner of liposome and proliposome, the obtained liposome has a high encapsulation rate and a stable property, and can significantly improve the absorbable degree and bioavailability of the ginsenoside Rg3, meanwhile enhance the targeting property thereof to a tumor tissue, and improve drug efficacy. At the same time, the obtained liposome can be dosed in a plurality of manners such as oral taking, injection, inhalation by lung, and the like, and can improve the application scope of drugs and the compliance of patients.
Description
Technical field
The present invention relates to medical technical field, a kind of ginsenoside Rg3's liposome and preparation method thereof is provided especially, and as the application of medicine and health product.
Background technology
The ginsenoside Rg3 is a kind of tetracyclic triterpene saponin be present in the natural drug Radix Ginseng, and molecular formula is C
42H
72O
13, relative molecular weight is 784.The ginsenoside Rg3 has the effect that suppresses tumor growth, and Main Function is in the G2/M phase of cell generation cycle, inducing apoptosis of tumour cell, the selectivity inhibition tumor cell sticks and infiltrates, anti metastasis, suppress tumor angiogenesis, also has the effects such as the body's immunity of adjusting simultaneously.
But ginsenoside Rg3's human pharmacokinetics research discovery, oral rear plasma concentration is very low, and recording the maximum plasma concentration value after oral 3.2mg/kg is only (16
6) ug/L.This may be because ginsenoside Rg3's utmost point is insoluble in water, thereby causes oral absorption efficiency low, has limited the performance of its drug effect.
Liposome (claims again the lipoid bead, liposome), means drug encapsulation in the lipoids bilayer and the miniature vesicle that forms.Liposome is a kind of novel passive target preparation, enter in body after easily by reticuloendothelial system (as liver, spleen, bone marrow) picked-up, by macrophage, as external foreign body, engulfed rapidly.Pass through endocytosis, liposome can concentrate medicine in the cell chamber worked specifically, also can make to reach in lysosome by the medicine of serous coat, enter after lysosome the digested medicine that discharges rapidly, can make medicine maintain higher concentration in these target tissues.Liposome is little to the body toxic and side effects in addition, and its lipid bilayer and biomembrane have larger similarity and histocompatibility, is easy to be absorbed by tissue.Wrapping kmedicine by liposome is physical process, do not change the molecular structure of medicine, drug encapsulation is become to liposome, can reduce renal excretion and metabolism and the holdup time of prolong drug in blood, medicine is slowly discharged in vivo, thereby extended the action time of medicine, can reduce dosage, reduced toxicity.
Simultaneously, the size of drug molecule amount no matter, all can be by liposome.As a kind of carrier, liposome has advantage aspect some cancer therapy drugs of transmission.Liposome not only can improve by sealing insoluble drug the dissolubility of medicine, and can change by the targeted delivery medicine pharmacological action of medicine.Because the characteristics of liposome component, it can impel liposome to be removed by reticuloendothelial system, like this can be by liposome targeting kinds cancer tissue.Convenient for the ease of the storage before the liposome aquation, also can be made into pro-liposome, the pro-liposome of good fluidity also is conducive to tablet, the preparation of the solid preparations such as capsule simultaneously.
The preparation technology of liposome is comparatively simple, is applicable to industrial scale production.But it is very remarkable that the envelop rate of medicine is subject to the impact of used phospholipid kind and preparation method, also often there is obvious gap in Simultaneous Stabilization.So will carry out Integrated Selection to phospholipid and preparation method when being sealed for medicine.At the envelop rate of preparation, stability, reach comprehensive optimum on the drug leakage rate.The preparation key of liposome is suitable medicine fat ratio, and suitable adjuvant makes the liposome finally obtained at envelop rate, and stability all reaches the standard of clinical practice on drug loading.
At present, the Patents of the ginsenoside Rg3 being made to liposome or pro-liposome is not yet arranged.
Summary of the invention
The invention provides a kind of ginsenoside Rg3's liposome, there is envelop rate high, stable in properties, but can significantly improve ginsenoside Rg3's trap and bioavailability characteristics.
This method also provides a kind of ginsenoside Rg3's pro-liposome, has an envelop rate high, stable in properties, but can significantly improve ginsenoside Rg3's trap and bioavailability characteristics.
The invention also discloses the preparation method of above-mentioned ginsenoside Rg3's liposome and pro-liposome, be applicable to suitability for industrialized production.
Ginsenoside Rg3's liposome disclosed by the invention it is characterized in that being made by weight by following raw material:
1 part of ginsenoside Rg3,0～20 part of phosphatidase 11,2～10 parts, cholesterol;
Described phospholipid is selected from soybean lecithin or Ovum Gallus domesticus Flavus lecithin.
The preparation method of described ginsenoside Rg3's liposome comprises the following steps:
1) by phospholipid, cholesterol, the ginsenoside Rg3 is dissolved in n-butyl alcohol fully, and every part of ginsenoside uses 50～100mL n-butyl alcohol, decompression rotary evaporation film forming under 30～50 degrees centigrade;
2) vacuum drying 24h will have the n-butyl alcohol removal of volatilizing fully;
3) add the phosphate buffered solution of pH6.0-7.5, every part of ginsenoside Rg3 adds the 20mL phosphate buffered solution, and 40 degrees centigrade of aquation 30min obtain ginsenoside Rg3's liposome turbid liquor;
4) by the ginsenoside Rg3's liposome turbid liquor obtained, the liposome turbid liquor that obtains, through 3 circulations of high pressure homogenization, then is extruded to granulate 2 times through extruding instrument 100nm polycarbonate membrane, obtain the liposome turbid liquor of mean diameter at 100nm.
The preparation method of described ginsenoside Rg3's liposome comprises the following steps:
1) by phospholipid, cholesterol, the ginsenoside Rg3 is dissolved in dehydrated alcohol, and every part of ginsenoside uses 50～100mL ethanol;
2) ethanol solution at the uniform velocity is injected under 30～50 degrees centigrade in constant temperature pH6.0-7.5 phosphate buffered solution, every part of ginsenoside Rg3 uses 20～40mL phosphate buffered solution
3) continue to stir 2h and obtain ginsenoside Rg3's liposome turbid liquor;
4) by the ginsenoside Rg3's liposome turbid liquor obtained, the liposome turbid liquor that obtains, through 3 circulations of high pressure homogenization, then is extruded to granulate 2 times through extruding instrument 100nm polycarbonate membrane, obtain the liposome turbid liquor of mean diameter at 100nm.
5) liposome turbid liquor obtained is removed to ethanol through the ultrafilter membrane ultrafiltration and concentration of molecular cut off 5000.
Ginsenoside Rg3's pro-liposome disclosed by the invention it is characterized in that being made by weight by following raw material:
1 part of ginsenoside Rg3,0～20 part of phosphatidase 11,2～10 parts, cholesterol, 4～8 parts of sorbitol;
Ginsenoside Rg3's pro-liposome of mentioning in the present invention can adopt the following methods preparation:
Spray drying: ginsenoside Rg3's liposome turbid liquor is mixed homogeneously according to proper proportion with water-solubility carrier solution, spray-driedly can make ginsenoside Rg3's pro-liposome.
Spray drying condition: 120 degrees centigrade of inlet temperatures, sample introduction flow velocity 10mL/min, atomizing pressure 140kPa, wind speed 0.5-1m
3/ min.
Lyophilization: ginsenoside Rg3's liposome turbid liquor is proportionally mixed homogeneously with sorbitol solution, through lyophilization, can make ginsenoside Rg3's pro-liposome.
Lipid and sorbitol proportionally are mixed with to solution, are sub-packed in the 5ml cillin bottle, every bottle of 2ml, in-80 degrees centigrade of pre-freeze 12h, vacuum lyophilization 48h, obtain pro-liposome.
The liposome form homogeneous made according to the above ratio, particle size distribution range is narrow, and average particle size distribution 100～140nm is encapsulated in more than 80%, stability, drug loading all can reach the clinical practice requirement; The pro-liposome made according to the above ratio after rehydration, the liposome form homogeneous obtained, particle size distribution range is narrow, average particle size distribution 100～150nm is encapsulated in more than 80%, stability, drug loading all can reach the clinical practice requirement.
The positive progressive effect of ginsenoside Rg3's liposome that the present invention mentions is:For poorly water soluble drugs Rg3 look for suitable form of administration, and filtered out the phospholipid adjuvant that is applicable to Rg3, prescription composition and preparation technology are optimized simultaneously, gained liposome mean diameter is 100～140nm, is a thermodynamics and kinetics Dual Stabilization system, and drug loading is more than 80% simultaneously, meet the pharmacopeia requirement, liposome body percolation ratio is low, and medicine is difficult for running off, thereby guarantees that medicine has higher concentration and action time in the zone of action.And this liposome also can further be developed as pro-liposome, thereby has enlarged its route of administration, be applicable to different medication crowds, preparation technology is simple and easy to do simultaneously, economical reliable, is the Rg3 novel form of a practicality.
Ginsenoside Rg3's liposome of the present invention can adopt various ways and dosage form administration, can adopt and comprise injection in intravenous injection, lumbar injection, intramuscular injection, subcutaneous injection, tumor body, the various ways administration that oral, pulmonary sucks, concrete dosage form can comprise injectable powder, Injectable liposomal suspension, injection or transfusion, oral administration mixed suspension, soft capsule, aerosol and spray.
Ginsenoside Rg3's pro-liposome of the present invention can adopt the multiple administering mode that comprises that oral, injection, pulmonary suck, and its dosage form can be tablet, enteric coated tablet, hard capsule, soft capsule, granule, powder inhalation, injectable powder.
The prepared ginsenoside Rg3's pro-liposome envelop rate of the present invention is greater than 80%, stable in properties, and preparation method is easy, is applicable to industry's enlarging production.
Good effect of the present invention is:The present invention adopts the mode entrapped drug of liposome and pro-liposome, and the liposome encapsulation obtained is high, stable in properties, but can significantly improve ginsenoside Rg3's trap and bioavailability, strengthen its targeting to tumor tissues simultaneously, improve drug effect.Can adopt the various ways administrations such as oral, injection, pulmonary's suctions, the scope of application of raising medicine and patient's compliance simultaneously.
The accompanying drawing explanation
Fig. 1 blood plasma Chinese medicine concentration changes with time curve;
Fig. 2 ginsenoside Rg3 liposome optical microscope photograph (amplifying 200 times);
Fig. 3 ginsenoside Rg3 pro-liposome sheet and ginsenoside Rg3's crude drug stripping curve.
The specific embodiment
Below with embodiment, the present invention is described in detail, but the present invention is not limited to following examples.
Embodiment 1
Take the 0.5g ginsenoside Rg3,7.5g Ovum Gallus domesticus Flavus lecithin, 1.25g cholesterol is dissolved in the 50ml n-butyl alcohol, solution is placed in to pear shape bottle, remove n-butyl alcohol at the above reduction vaporization of rotary evaporation, make phospholipid form homogeneous film on the bottle wall, vacuum drying 24h is by the organic solvent removal of volatilizing fully, add the fully hydration on the phospholipid phase transition temperature of 10ml 10mM pH6.5 phosphate buffered solution, obtain ginsenoside Rg3's liposome turbid liquor.By the liposome turbid liquor that obtains, through homogeneous 3 circulations of high pressure homogenizer, then through extruding instrument under high pressure respectively through 2 granulate of 100nm polycarbonate membrane, the envelop rate of final gained liposome is 87.3%, and mean diameter is 131nm.
Take the 0.5g ginsenoside Rg3, the 5g soybean lecithin, 1.25g cholesterol is dissolved in 50ml ethanol, with microsyringe, the phospholipid alcoholic solution slowly is injected in the 20mM pH6.5 phosphate buffered solution 20mL of 50 degrees centigrade of water bath with thermostatic control concussions, obtain ginsenoside Rg3's liposome turbid liquor, by the liposome turbid liquor that obtains through homogeneous 3 circulations of high pressure homogenizer, then through extruding instrument under high pressure respectively through 2 granulate of 100nm polycarbonate membrane, select the ultrafilter membrane of molecular cut off 5000, mode with ultrafiltration and concentration is removed ethanol, final gained liposome encapsulation is 81.2%, mean diameter is 136nm.
Embodiment 3
Take the 0.5g ginsenoside Rg3, 7.5g Ovum Gallus domesticus Flavus lecithin, 1.25g cholesterol is dissolved in 50ml ethanol, with microsyringe, the phospholipid alcoholic solution slowly is injected in the 10mM pH6.5 phosphate buffered solution 20mL of 50 degrees centigrade of water bath with thermostatic control concussions, obtain ginsenoside Rg3's liposome turbid liquor, by the liposome turbid liquor that obtains through homogeneous 3 circulations of high pressure homogenizer, then through extruding instrument under high pressure respectively through 2 granulate of 100nm polycarbonate membrane, select the ultrafilter membrane of molecular cut off 5000, mode with ultrafiltration and concentration is removed ethanol, final gained liposome encapsulation is 81.2%, mean diameter is 105nm.
Embodiment 4
Take the 0.5g ginsenoside Rg3, the 10g soybean lecithin, 1.25g cholesterol is dissolved in 50ml ethanol, with microsyringe, the phospholipid alcoholic solution slowly is injected in the 10mM pH6.5 phosphate buffered solution 20mL of 50 degrees centigrade of water bath with thermostatic control concussions, obtain ginsenoside Rg3's liposome turbid liquor, by the liposome turbid liquor that obtains through homogeneous 3 circulations of high pressure homogenizer, then through extruding instrument under high pressure respectively through 2 granulate of 100nm polycarbonate membrane, select the ultrafilter membrane of molecular cut off 5000, mode with ultrafiltration and concentration is removed ethanol, final gained liposome encapsulation is 81.2%, mean diameter is 137nm.
Embodiment 5
Take the 0.5g ginsenoside Rg3, the 5g Ovum Gallus domesticus Flavus lecithin, 1.25g cholesterol is dissolved in the 50ml n-butyl alcohol, solution is placed in to pear shape bottle, remove n-butyl alcohol at the above reduction vaporization of rotary evaporation, make phospholipid form homogeneous film on the bottle wall, vacuum drying 24h is by the organic solvent removal of volatilizing fully, add the fully hydration on the phospholipid phase transition temperature of 15ml 10mM pH6.5 phosphate buffered solution, obtain ginsenoside Rg3's liposome turbid liquor, by the liposome turbid liquor that obtains through homogeneous 3 circulations of high pressure homogenizer, then through extruding instrument under high pressure respectively through 2 granulate of 100nm polycarbonate membrane, add again the aqueous solution that is dissolved with the 2g sorbitol, mix homogeneously, spray-driedly make Powdered ginsenoside Rg3's pro-liposome.Envelop rate 86.4%, mean diameter 101nm.This pro-liposome powder is filled in hard capsule, obtains hard capsule.
Embodiment 6
Take the 0.5g ginsenoside Rg3, 7.5g Ovum Gallus domesticus Flavus lecithin, 1.25g cholesterol is dissolved in the 50ml n-butyl alcohol, solution is placed in to pear shape bottle, remove n-butyl alcohol at the above reduction vaporization of rotary evaporation, make phospholipid form homogeneous film on the bottle wall, vacuum drying 24h is by the organic solvent removal of volatilizing fully, add the fully hydration on the phospholipid phase transition temperature of 15ml 10mM pH6.5 phosphate buffered solution, obtain ginsenoside Rg3's liposome turbid liquor, by the liposome turbid liquor that obtains through homogeneous 3 circulations of high pressure homogenizer, then through extruding instrument under high pressure respectively through 2 granulate of 100nm polycarbonate membrane, add the aqueous solution that is dissolved with the 4g sorbitol, by 0.22 μ m membrane filtration degerming, in packing and cillin bottle, lyophilization, obtain ginsenoside Rg3's pro-liposome injectable powder.Envelop rate 83.7%, mean diameter 147nm.
Experimental example 1
Take the 0.5g ginsenoside Rg3, the 6g soybean lecithin, 1.5g cholesterol is dissolved in the 50ml n-butyl alcohol, solution is placed in to pear shape bottle, remove n-butyl alcohol at the above reduction vaporization of rotary evaporation, make phospholipid form homogeneous film on the bottle wall, vacuum drying 24h is by the organic solvent removal of volatilizing fully, add the fully hydration on the phospholipid phase transition temperature of 15ml 10mM pH6.5 phosphate buffered solution, obtain ginsenoside Rg's liposome turbid liquor, add the aqueous solution that is dissolved with the 5g sorbitol, mix homogeneously, spray-driedly make Powdered ginsenoside Rg3's pro-liposome.
By this precursor liposome powder and micropowder silica gel, cross-linked carboxymethyl cellulose, the crosslinked starch mixed pressuring plate, can make oral tablet.Contrasted by pharmacopeia mensuration dissolution and ginsenoside Rg3's crude drug, be the results are shown in Figure 2.Data show that, after stripping 4h, the drug dissolution of pro-liposome reaches more than 80%, and the dissolution of ginsenoside Rg3's crude drug does not almost have.Can prove conclusively the ginsenoside Rg3 is prepared as after pro-liposome to the dissolution that can significantly improve medicine.
This oral tablet can, by coating the enteric coating overlay film, obtain enteric coated tablet.
Embodiment 7
The prepared ginsenoside Rg3's pro-liposome of embodiment 4 is packed in the powder quantitatively suction apparatus, can obtain powder inhalation.Powder body aerodynamic size average out to 5 μ m, be suitable for pulmonary administration.
The prepared ginsenoside Rg3's liposome of embodiment 1 is packed in the aerosol device together with propellant, obtain ginsenoside Rg3's liposome aerosols.
Ginsenoside Rg3's liposome that embodiment 1 and 2 is made, after 0.22 μ m membrane filtration degerming, be sub-packed in cillin bottle under gnotobasis, obtains ginsenoside Rg3's lipidosome injection.This injection is applicable to injection in intramuscular injection, subcutaneous injection, tumor body.
Show advantage of the present invention by following experiment:
Test example 1
The impact of different phospholipid materials on liposome encapsulation
Test material
Soybean lecithin, Ovum Gallus domesticus Flavus lecithin, dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, DPPE, DPPA, ginsenoside Rg3, cholesterol;
The liposome of embodiment 1, embodiment 2 preparations;
Matched group 1: ginsenoside Rg3: dipalmitoyl phosphatidyl choline: cholesterol;
Matched group 2: ginsenoside Rg3: distearoyl phosphatidylcholine: cholesterol;
Matched group 3: ginsenoside Rg3: DPPE: cholesterol;
Matched group 4: ginsenoside Rg3: DPPA: cholesterol;
The raw material addition of above each group is mass ratio, and ratio is the ginsenoside Rg3: phospholipid: cholesterol=1:15:2.5;
Envelop rate is the important indicator of investigating liposome property, and liposome is low to the envelop rate of medicine is a great problem that liposome need to overcome.In experiment, find, there is appreciable impact in the kind of phospholipid to the envelop rate of liposome, adopts thin film to disperse to prepare liposome turbid liquor, by experiment of single factor, investigates the impact of phospholipid quality on liposome encapsulation, the results are shown in Table 1:
The impact of the different phospholipid of table 1 on liposome encapsulation and particle diameter
| Ginsenoside Rg3: phospholipid: cholesterol (w/w) | Particle diameter (nm) | Envelop rate (%) |
| Embodiment 1 | 131 | 87.2 |
| |
136 | 88.7 |
| Matched group 1 | 125 | 52.1 |
| Matched |
105 | 39.5 |
| Matched group 3 | 111 | 65.3 |
| Matched group 4 | 135 | 62.8 |
Conclusion: as can be seen from the table,
Soybean lecithin and Ovum Gallus domesticus Flavus lecithinTo the ginsenoside Rg3 to seal effect better, can reach the envelop rate more than 80% that pharmacopeia requires, but dipalmitoyl phosphatidyl choline, distearoyl phosphatidylcholine, DPPE, DPPA to ginsenoside Rg3's the ability of sealing relatively a little less than, this is because the saturation in the phospholipid molecule structure of two palmityl classes and distearyl class is higher, be unfavorable for the insertion of Rg3, thereby envelop rate is descended.
Test example 2
The impact of phospholipid consumption on envelop rate
In experiment, find, the consumption of phospholipid is the key factor that affects the liposome quality, adopts thin film to disperse to prepare liposome turbid liquor, by experiment of single factor, investigates the impact of phospholipid consumption on liposome particle diameter and envelop rate.
The liposome of embodiment 2, embodiment 3, embodiment 4 preparations;
Matched group 1: ginsenoside Rg3: soybean lecithin: cholesterol 1:0.5:2.5;
Matched group 2: ginsenoside Rg3: Ovum Gallus domesticus Flavus lecithin: cholesterol 1:5:2.5;
Matched group 3: ginsenoside Rg3: Ovum Gallus domesticus Flavus lecithin: cholesterol 1:25:2.5;
Matched group 4: ginsenoside Rg3: Ovum Gallus domesticus Flavus lecithin: cholesterol 1:30:2.5;
The results are shown in Table 2:
The impact of table 2 phospholipid consumption on liposome particle diameter and envelop rate
| Ginsenoside Rg3: phospholipid: cholesterol (w/w) | Particle diameter (nm) | Envelop rate (%) |
| Matched group 1 | 174 | 20.1 |
| Matched |
125 | 45.8 |
| |
136 | 82.9 |
| Embodiment 3 | 105 | 87.3 |
| Matched group 4 | 111 | 90.4 |
| Matched group 3 | 135 | 88.6 |
| Matched group 4 | 124 | 87.2 |
Sum up: as seen from the table, the envelop rate of liposome is subject to the impact of phospholipid consumption comparatively remarkable, when medicine fat ratio is greater than 1:10, envelop rate, lower than 80%, does not reach pharmacopeia and requires the regulation of liposome medicament more than 80%, increase with the phospholipid consumption, envelop rate rises thereupon, when medicine fat ratio is less than 1:20, although envelop rate can reach more than 80%, but drug loading is too low, can't meet clinical instructions for use.Find when the consumption of phospholipid more than 20 parts the time simultaneously, the viscosity of system increases, cause hydration time to increase, have more than original 30min hydration extends to 1h, the prolongation of hydration time certainly will cause the oxidized amount of phospholipid to increase, phospholipid after oxidation has toxicity, this safety to liposome is disadvantageous, the phospholipid of excessive concentrations also can make the comparatively difficulty of suspension when extruding the instrument extruding simultaneously, there is medicine carrying phospholipid can't pass through polycarbonate membrane simultaneously, thereby the response rate of medicine is descended, through measuring and calculating, can cause the response rate of medicine to descend at least 20%, the consumption of comprehensive consideration phospholipid is advisable with 10～20 parts.
Test 3
The investigation of drug leakage rate
Liposome is stablized the percolation ratio that an important indicator is medicine.The liposome obtained after ginsenoside Rg3's liposome and the reconstruction of Rg3 pro-liposome aquation is loaded in bag filter in right amount, and phosphate buffer is as release medium, and 25 degrees centigrade of constant temperature were placed after 3 months, its envelop rate of sampling and measuring, and the percolation ratio computing formula is as follows:
Q
Leak=(EF
1-EF
2)/EF
1* 100%
EF
1For initial envelop rate, EF
2For storing envelop rate after 3 months.
Table 3 ginsenoside Rg3 liposome percolation ratio
| Ginsenoside Rg3: phospholipid: cholesterol (w/w) | Percolation ratio (%) |
| Embodiment 1 | 5.3 |
| |
5.9 |
| Embodiment 3 | 6.8 |
| Embodiment 4 | 5.7 |
The percolation ratio of medicine is being 5.3～6.8% after 3 months store, and the seepage of medicine is very slow, and constructed liposome has the stronger ability of sealing to Rg3 to medicine, and stability can meet clinical use.
Embodiment 4
The granulate of liposome
Usually the liposome turbid liquor that obtains is carried out to granulate by high pressure homogenization or the method extruded, but it is unsatisfactory in experiment, to find to use separately these two kinds of methods to carry out the granulate effect to ginsenoside Rg3's liposome, if only be suitable for high pressure homogenization, the particle size distribution obtained is inhomogeneous, only use the extrusion molding liposome to cross the film ability poor, the response rate of medicine is lower simultaneously, below 40%, by the liposome turbid liquor that obtains through homogeneous 3 circulations of high pressure homogenizer, then through extruding instrument under high pressure respectively through 2 granulate of 100nm polycarbonate membrane, the liposome particle size distribution that discovery obtains is even, distribution is narrow, the response rate of medicine is improved simultaneously, can reach more than 75%.
Selection embodiment 1～4 carries out the investigation of different granulate modes on the liposome property impact, and wherein the high pressure homogenization granulate is only carried out in the A representative, and the B representative is capable extrusion molding granulate only, and C passes through the extrusion molding granulate after representing first high pressure homogenization again.
The impact of the different granulate modes of table 4 on liposome property
| The granulate mode | The medicine response rate (%) | Particle diameter (nm) |
| Embodiment 1A | 62 | 145～240 |
| Embodiment 2A | 75 | 157～324 |
| Embodiment 3A | 81 | 133～232 |
| Embodiment 4A | 77 | 109～318 |
| Embodiment 1B | 37 | 124 |
| Embodiment 2B | 35 | 117 |
| Embodiment 3B | 29 | 127 |
| Embodiment 4B | 33 | 120 |
| Embodiment 1C | 82 | 131 |
| Embodiment 2C | 87 | 136 |
| Embodiment 3C | 76 | 105 |
| Embodiment 4C | 79 | 111 |
Selection and the consumption of finding water-solubility carrier in preparing the process of pro-liposome have vital impact to the structure of pro-liposome and the character of the rear liposome of reconstruction.
Preparing the carrier that pro-liposome is commonly used has sorbitol, mannitol, lactose, sucrose etc., wherein better with the effect of sorbitol.This is mainly because sorbitol has cellular structure, and contained phospholipid amount is large, and dispersibility is better during aquation.The water solublity of lactose is not as sorbitol, and during aquation, dispersibility is bad, and after placing, lamination is arranged.Mannitol is easy to wet knot occurs in preparation process, is not suitable for being undertaken by this method the preparation of pro-liposome.Therefore finally selecting sorbitol is carrier material.
Test example 5
Fixedly the consumption of ginsenoside Rg3, phospholipid, cholesterol is 1:15:2.5, take sorbitol as example, prepares pro-liposome, investigates outward appearance, the redispersibility of pro-liposome, obtains particle diameter and the envelop rate of liposome after reconstruction, is grouped as follows:
Embodiment 5: the ginsenoside Rg3: soybean lecithin: cholesterol: sorbitol 1:15:2.5:4;
Embodiment 6: the ginsenoside Rg3: Ovum Gallus domesticus Flavus lecithin: cholesterol: sorbitol 1:15:2.5:8;
Matched group 1: ginsenoside Rg3: soybean lecithin: cholesterol: sorbitol 1:15:2.5:2;
Matched group 2: ginsenoside Rg3: Ovum Gallus domesticus Flavus lecithin: cholesterol: sorbitol 1:15:2.5:4;
Matched group 3: ginsenoside Rg3: soybean lecithin: cholesterol: sorbitol 1:15:2.5:24;
The results are shown in Table 3:
The impact of the consumption of table 5 sorbitol on pro-liposome character
| Ginsenoside Rg3: phospholipid: cholesterol: sorbitol (w/w) | The pro-liposome outward appearance | Redispersibility | Particle diameter (nm) | Envelop rate (%) |
| Matched group 1 | Soften, subside | Poor | 143 | 86.2 |
| Matched |
Slightly soften, subside | Generally | 114 | 87.5 |
| Embodiment 5 | Fluffy, good fluidity | Good | 101 | 90.2 |
| Embodiment 6 | Fluffy, good fluidity | Good | 147 | 88.4 |
| Matched group 3 | Fluffy, good fluidity | Good | 192 | 87.7 |
As can be seen from Table 5, there are certain influence in add particle diameter and the envelop rate to pro-liposome aquation reconstruction liposome of water-solubility carrier, but impact is not remarkable.But the redispersibility in pro-liposome aquation process of reconstruction and the outward appearance of pro-liposome are existed to appreciable impact.When the consumption of sorbitol is less than 4 parts by weight, the outward appearance of pro-liposome is poor, occurs softening and subsides, and occurs the situation of assembling in the aquation process of reconstruction, the redispersion difficulty.For improve the system drug loading as far as possible, the consumption of water-solubility carrier is chosen as 4～8 parts.
Test example 6
The raising of liposome to drug effect
The investigation of pharmacokinetics:
Take Self-control method, adopt 5 Wistar rats that do not carry out experiment, every single dose administration ginsenoside Rg3 liposome (dosage 5mg/kg).12h fasting before administration.Allow free diet after administration 4h.Extract blank blood before administration, after administration, respectively at 0.25,0.5,0.75,1,1.5,2,2.5,3,3.5,4,5,6,8,10,12h, get blood 0.5mL to the heparinization centrifuge tube, 4000rpm is centrifugal, and the 10min separation obtains blood plasma.The blood plasma obtained ,-20 ℃ of preservations, waits to be analyzed.Every Wistar rat single dose administration ginsenoside suspension of second week (dosage 5mg/kg).All the other operate same experimental group.
After the laboratory animal administration, blood drug level---time graph, the time point determination of plasma concentration the results are shown in Table 4 and 5.Blood plasma Chinese medicine concentration changes with time curve is shown in Fig. 1 (■-ginsenoside Rg3's pro-liposome sheet stripping curve;-◆-ginsenoside Rg3 crude drug stripping curve).
Table 6 ginsenoside suspension plasma drug level
| Time (h) | 1 | 2 | 3 | 4 | 5 | Meansigma methods | SD |
| 0.25 | 2.61 | 12.31 | 10.57 | 8.45 | 52.69 | 17.326 | 20.10448 |
| 0.5 | 9.56 | 27.92 | 19.57 | 55.73 | 128.67 | 48.29 | 48.10428 |
| 0.75 | 138.62 | 84.08 | 44.87 | 60.15 | 21.41 | 69.826 | 44.71109 |
| 1 | 64.19 | 124.45 | 282.71 | 77.36 | 34.13 | 116.568 | 98.41498 |
| 1.5 | 73.51 | 207.67 | 404.24 | 185.91 | 116.69 | 197.604 | 127.3606 |
| 2 | 371.81 | 167.59 | 259.34 | 347.69 | 478.73 | 325.032 | 117.7158 |
| 2.5 | 54.72 | 141.99 | 78.95 | 216.42 | 276.73 | 153.762 | 92.99447 |
| 3 | 126.35 | 25.53 | 99.13 | 109.37 | 220.16 | 116.148 | 69.76224 |
| 3.5 | 102.19 | 43.72 | 56.18 | 65.01 | 15.16 | 56.452 | 31.75063 |
| 4 | 65.35 | 10.22 | 60.42 | 24.35 | 102.21 | 52.51 | 36.3282 |
| 5 | 77.57 | 53.56 | 48.21 | 34.14 | 8.72 | 44.44 | 25.38204 |
| 6 | 50.02 | 45.67 | 24.72 | 5.47 | 40.43 | 33.262 | 18.24507 |
| 8 | 22.03 | 16.8 | 14.16 | 37.44 | 40.22 | 26.13 | 11.97481 |
| 10 | 11.82 | 18.02 | 22.75 | 5 | 7.43 | 13.004 | 7.36003 |
| 12 | 1.14 | 7.78 | 10.22 | 2.32 | 18.12 | 7.916 | 6.83151 |
Table 7 ginsenoside Rg3 liposome group
| Time (h) | 1 | 2 | 3 | 4 | 5 | Meansigma methods | SD |
| 0.25 | 103.29 | 69.64 | 45.93 | 71.48 | 14.78 | 61.024 | 32.92535 |
| 0.5 | 261.48 | 121.67 | 101.77 | 213.43 | 75.32 | 154.734 | 79.12794 |
| 0.75 | 221.71 | 141.77 | 210.42 | 305.36 | 277.37 | 231.326 | 63.54307 |
| 1 | 218.73 | 367.44 | 347.41 | 381.77 | 492.72 | 361.614 | 97.78366 |
| 1.5 | 502.61 | 457.82 | 342.59 | 387.11 | 421.51 | 422.328 | 61.85468 |
| 2 | 318.52 | 441.55 | 406.74 | 327.53 | 349.69 | 368.806 | 53.21769 |
| 2.5 | 442.86 | 298.11 | 252.35 | 331.45 | 388.61 | 342.676 | 74.86271 |
| 3 | 196.19 | 309.67 | 335.77 | 275.34 | 372.48 | 297.89 | 67.06102 |
| 3.5 | 286.82 | 305.31 | 166.22 | 243.67 | 331.98 | 266.8 | 64.77574 |
| 4 | 341.21 | 97.49 | 127.45 | 225.61 | 282.34 | 214.82 | 102.5301 |
| 5 | 120.76 | 253.57 | 97.62 | 164.37 | 55.49 | 138.362 | 75.4765 |
| 6 | 120.79 | 151.11 | 24.62 | 64.43 | 50.39 | 82.268 | 52.15568 |
| 8 | 11.44 | 37.39 | 20.78 | 45.51 | 61.82 | 35.388 | 19.95002 |
| 10 | 13.14 | 21.32 | 9.42 | 31.37 | 5.57 | 16.164 | 10.30371 |
| 12 | 3.45 | 15.27 | 4.77 | 24.52 | 1.36 | 9.874 | 9.79067 |
By table 4 and table 5 and Fig. 1 (■-ginsenoside Rg3's pro-liposome sheet stripping curve;-◆-ginsenoside Rg3 crude drug stripping curve) known, the peak reaching time of blood concentration T of ginsenoside Rg3's liposome
maxReach, the highest blood drug level C
maxObviously increase.
The compartment model pharmacokinetic parameter
Average blood drug level data analysis with 3P97 pharmacokinetics program to ginsenoside Rg3's liposome and commercially available ginsenoside Rg3's crude drug, then with compartment model, the average blood drug level of liposome and marketable material medicine is carried out to matching, take AIC (Akaike ' s information criterion) value and R (correlation coefficient between match value and measured value) comprehensively compares as index, the AIC value is less, the R value is larger, and fitting degree is higher.As calculated, the pharmacokinetic parameters of liposome and marketable material medicine sees the following form respectively 6.
The pharmacokinetic parameters of table 8 Rg3 liposome and marketable material medicine
| Parameter | The Rg3 liposome | The marketable material medicine |
| A(μg/mL) | 1171.256840 | 182.930450 |
| Ke(1/h) | 0.426852 | 0.270996 |
| Ka(1/h) | 1.004604 | 1.526343 |
| Lag Time(h) | 0.158983 | 0.172734 |
| T1/2(ka)(h) | 0.689970 | 0.454123 |
| T1/2(ke)(h) | 1.623859 | 2.557775 |
| Tmax(h) | 1.481451 | 2.176930 |
| Cmax(μg/mL) | 357.905460 | 103.596184 |
| AUC(μg·h/mL) | 1578.053710 | 555.180910 |
| CL/F(s)(mg·mL/(h·μg)) | 0.003168 | 0.009006 |
| V/F(c)(mg·μg/mL) | 0.007423 | 0.033233 |
As shown in Table 8, the Tmax of Rg3 liposome is about 1.48h, and the Tmax of commercially available ginsenoside Rg3's crude drug is about 2.18h, the Cmax of Rg3 liposome is about 357.90 μ g/mL, the Cmax of crude drug is about 103.60 μ g/mL, and the Tmax of Rg3 liposome moves forward to some extent, and Cmax obviously increases.Result shows, the blood drug level data of Rg3 Liposomal formulation and marketable material medicine all with the 3P97 program in the 7th kind of model (single compartment one-level absorbs, and weight is/lC
2) fitting degree is the highest.
Relative bioavailability
Result is long-pending (AUC) data below above-mentioned average blood drug level one time graph recorded, and calculate the relative bioavailability Fr of commercially available slice of self emulsifying dosage form to same dose, and computing formula is
Calculate with area under the drug-time curve AUC, by the relative bioavailability formula, draw Fr (SEDDS)=1578.053710/555.180910 * 100%=284.24%.With the marketable material medicine, compare, the bioavailability of Rg3 Liposomal formulation is enhanced.
The removal of organic solvent does not adopt conventional heated and stirred to remove organic solvent method, and this is because this method length consuming time, has increased the probability of phospholipid oxidation, simultaneously not thorough to the removal of organic solvent, very easily cause residual, thereby affect the safety of product.So select the ultrafilter membrane of molecular cut off 5000 in the present invention, remove ethanol in the mode of ultrafiltration and concentration, can make easily alcohol residue below 400ppm, guarantee the safety of product.
Claims (5)
1. ginsenoside Rg3's liposome it is characterized in that being made by weight by following raw material:
1 part of ginsenoside Rg3,0～20 part of phosphatidase 11,2～10 parts, cholesterol
Described phospholipid is selected from soybean lecithin or Ovum Gallus domesticus Flavus lecithin.
2. the preparation method of ginsenoside Rg3's liposome as claimed in claim 1 comprises the following steps:
1) by phospholipid, cholesterol, the ginsenoside Rg3 is dissolved in n-butyl alcohol fully, and every part of ginsenoside uses 50～100mL n-butyl alcohol, decompression rotary evaporation film forming under 30～50 degrees centigrade;
2) vacuum drying 24h will have the n-butyl alcohol removal of volatilizing fully;
3) add the phosphate buffered solution of pH6.0-7.5, every part of ginsenoside Rg3 adds the 20mL phosphate buffered solution, and 40 degrees centigrade of aquation 30min obtain ginsenoside Rg3's liposome turbid liquor;
4) by the ginsenoside Rg3's liposome turbid liquor obtained, the liposome turbid liquor that obtains, through 3 circulations of high pressure homogenization, then is extruded to granulate 2 times through extruding instrument 100nm polycarbonate membrane, obtain the liposome turbid liquor of mean diameter at 100nm.
3. the preparation method of ginsenoside Rg3's liposome as claimed in claim 1 comprises the following steps:
1) by phospholipid, cholesterol, the ginsenoside Rg3 is dissolved in dehydrated alcohol, and every part of ginsenoside uses 50～100mL ethanol;
2) ethanol solution at the uniform velocity is injected under 30～50 degrees centigrade in constant temperature pH6.0-7.5 phosphate buffered solution, every part of ginsenoside Rg3 uses 20mL～40mL phosphate buffered solution;
3) continue to stir 2h and obtain ginsenoside Rg3's liposome turbid liquor;
4) by the ginsenoside Rg3's liposome turbid liquor obtained, the liposome turbid liquor that obtains, through 3 circulations of high pressure homogenization, then is extruded to granulate 2 times through extruding instrument 100nm polycarbonate membrane, obtain the liposome turbid liquor of mean diameter at 100nm;
5) liposome turbid liquor obtained is removed to ethanol through the ultrafilter membrane ultrafiltration and concentration of molecular cut off 5000, obtain.
4. ginsenoside Rg3's pro-liposome it is characterized in that being made by weight by following raw material:
1 part of ginsenoside Rg3,0～20 part of phosphatidase 11,2～10 parts, cholesterol, 4～8 parts of sorbitol.
5. the preparation method of ginsenoside Rg3's pro-liposome as claimed in claim 4 comprises the following steps:
Ginsenoside Rg3's liposome turbid liquor claimed in claim 2 is mixed with sorbitol, and spray-dried, lyophilization can make ginsenoside Rg3's pro-liposome;
1) spray drying condition: 120 degrees centigrade of inlet temperatures, sample introduction flow velocity 10mL/min, atomizing pressure 140kPa, wind speed 0.5-1m3/min;
2) lyophilization condition: ginsenoside Rg3's liposome turbid liquor and sorbitol are mixed and made into to solution, are sub-packed in the 5ml cillin bottle, every bottle of 2ml, in-80 degrees centigrade of pre-freeze 12h, vacuum lyophilization 48h, obtain pro-liposome.
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