CN108815160A - A kind of rapamycin liposome nano granule and preparation method thereof - Google Patents
A kind of rapamycin liposome nano granule and preparation method thereof Download PDFInfo
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- CN108815160A CN108815160A CN201810792191.8A CN201810792191A CN108815160A CN 108815160 A CN108815160 A CN 108815160A CN 201810792191 A CN201810792191 A CN 201810792191A CN 108815160 A CN108815160 A CN 108815160A
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- rapamycin
- nanoparticle
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- phase solution
- nano granule
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
The invention discloses a kind of rapamycin liposome nano granules and preparation method thereof.The nanoparticle is prepared from the following raw materials according to the mass fraction：1 part of rapamycin, -20 parts of phosphatidase 1.The nanoparticle can also including cholesterol etc. stabilizers, with the proportion of rapamycin by for：1:0.1-0.8.Preparation method is：Raw material rapamycin, phosphatide or stabilizer are dissolved in organic solvent according to the ratio, obtain oil-phase solution；Oil-phase solution is added in aqueous phase solution, is stirred at room temperature, ultrasonication, 40 DEG C of rotary evaporations are to get the nanoparticle.The bioavilability of rapamycin in vivo has been significantly increased in the present invention, has slow releasing function and targeting, reduces toxic side effect；Administering rapamycin mode can be made no longer to be limited by bracket by drug administration by injection, so as to adjust dosage, be of great significance according to the different time span of the state of an illness.
Description
Technical field
The present invention relates to the improving dosage form of rapamycin, especially a kind of rapamycin liposome nano granule and its preparation side
Method.
Background technique
Cardiovascular and cerebrovascular disease caused by atherosclerosis seriously threatens human health, the lethal disability rate of patients with terminal
Height causes huge burden on society and medical expense, and the targeted therapy for lacking specificity is always treatment of atherosclerosis
One of bottleneck problem.It is more for the mechanism theory of atherosclerosis at present, but specific mechanism is still still not clear, and
The pathological change of vascular smooth muscle cells is considered as the important pathological characters of atherosclerosis.Percutaneous cardiac interventional procedure and blood
The placement of pipe inner support is to treat intravascular narrow main means at present, but in-stent restenosis rate is still up to 15%~25%.
Clinic solves the problems, such as restenosis mostly with coating stent of medicine such as rapamycins, but still there are following drawbacks：1. advanced stage bracket
Thrombosis.It is considered with the anti-proliferative drugs on bracket while inhibiting vascular smooth muscle cells hyper-proliferative, also inhibits
The growth of intravascular cortex, the normal healing influenced at injury of blood vessel are related；2, in-stent restenosis.When medication coat is released completely
After putting, drug effect disappears, and restenosis incidence is caused to be gradually increasing.Research report, coating stent of medicine are placed in 36 months, MACE
The incidence of (in-stent restenosis, myocardial infarction, cardiac death) 4.2% rose to 15.7% by 12 months.
Rapamycin is a kind of hydrophobicity macrolide immunosuppressants, by be accordingly immunized in conjunction with thermophilic element RMBP press down
Cell cycle G0 phase and G1 phase processed block G1 to enter the S phase and play a role.It is the strong immunosupress with hypotoxicity
Agent is widely used in transfer operation.The study found that rapamycin can also effectively inhibit vascular smooth muscle cells after injury of blood vessel
Proliferation and migration, to reduce the generation of reangiostenosis, therefore be most common drug in bracket for eluting medicament.Due to thunder pa
The water solubility of mycin is very poor, affects it in the absorptivity of gastrointestinal tract, causes the bioavilability of oral solution and tablet all very low,
The bioavilability of oral administration only has 15%, therefore the unsatisfactory curative effect of the drug Formulations for systemic administration.In treatment atherosclerosis phase
Always using medication coat in the method for bracket in the disease of pass, local application is in atherosclerotic lesion, though it is widely applied
In clinic, but since administration mode, dosage, administration time such as are restricted at the factors, and easily cause advanced stage Thrombosis in sten
With the clinical safeties problem such as in-stent restenosis, therefore new form of administration is developed, administration mode keeps rapamycin treatment dynamic
Related disease caused by pulse atherosclerosis is no longer limited by bracket, so that dosage is adjusted according to the different time span of the state of an illness,
It is of great significance.
Summary of the invention
The present invention provides a kind of rapamycin liposome nano granule and its freeze drying powder injections, and further disclose its preparation
Method.The nanoparticle has uniform and stable particle diameter distribution, and drug is greatly improved in stable encapsulation rate and drugloading rate
Water-soluble and safety and bioavilability.
Rapamycin liposome nano granule of the invention, is prepared from the following raw materials according to the mass fraction：1 part of rapamycin,
Phosphorus
1-20 parts of rouge, optimum ratio is：1 part of rapamycin, -10 parts of phosphatidase 3.
The phosphatide is selected from egg yolk lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, brain phosphorus
Rouge, phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, sphingomyelins, diphosphatidylglycerol, dipalmitoylphosphatidylcholine,
One or more of hydrolecithin, dioleoylphosphatidylethanolamine or distearoylphosphatidylethanolamine.
The nanoparticle further includes stabilizer, the proportion of the stabilizer and rapamycin by for：1:0.1-0.8, it is described
Stabilizer is one or more of cholesterol, cholesterol sulfate sodium or ethyl polyenoate.
The preferred average grain diameter of nanoparticle is 50-200nm, drugloading rate 1-15%, and encapsulation rate is 85% or more to receive
The grain of rice.
The preparation method of the nanoparticle includes the following steps：
(1) raw material rapamycin, phosphatide or stabilizer are dissolved in organic solvent according to the ratio, obtain oil-phase solution；
(2) above-mentioned oil-phase solution is slowly added in aqueous phase solution, is stirred at room temperature, homogeneous, 40 DEG C of rotary evaporations are to get institute
State nanoparticle.
The preferred methylene chloride of organic solvent.The preferred distilled water of the aqueous phase solution, physiology fliud flushing, cell culture fluid,
Body fluid, tissue fluid, buffer or glucose injection.
Freeze drying powder injection of the present invention further includes freeze drying protectant, and the mass ratio for accounting for nanoparticle is：3%-10%, institute
Stating freeze drying protectant is one or more of lactose, glucose, mannitol or sucrose.Preparation method is：The present invention is received
Freeze drying protectant is added in the grain of rice according to the ratio, is sterile filtered, freeze-drying to get.
The present invention has the following advantages that relative to existing rapamycin medicinal product：
1, solubility of the rapamycin in water phase is greatly improved in rapamycin liposome nano granule of the invention,
And then improve its bioavilability in vivo.
2, administering rapamycin mode can be made no longer to be limited by bracket, so as to according to the state of an illness by drug administration by injection
Different time span adjusts dosage, is of great significance.
3, nanoparticle of the invention has slow releasing function, reduces toxic side effect.And the phospholipid as rapamycin carrier
And cholesterol, it can be with natural degradation, to be absorbed and pass through metabolism discharge in vivo under physiological condition in vivo, it will not be right
Body generates stimulation or foreign body reaction, safely and effectively.
4, animal experiments prove that, rapamycin liposome nano granule injection can effectively prevent and treat artery congee
Sample hardens relevant disease and vascular stenosis, effectively prevention vessel overgrowth.
5, preparation method is simple, process stabilizing, is suitble to large-scale production, and product is stablized, long shelf-life.
Detailed description of the invention
Fig. 1 is the Time-activity-curve of rapamycin liposome nano granule；
Fig. 2 is the amount effect curve of rapamycin liposome nano granule；
Fig. 3 is treatment results analysis chart of the rapamycin liposome to atherosclerosis；
Fig. 4 is rapamycin liposome to intravascular narrow exercising result analysis chart.
Specific embodiment
Combined with specific embodiments below, the present invention is furture elucidated, and following embodiment is merely to illustrate rather than limits
The scope of the present invention.
Embodiment 1：The preparation of rapamycin liposome nano granule
Precision weighs 5mg rapamycin, 40mg phosphatide, and 3.75mg cholesterol is dissolved in 3mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 24mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 2：The preparation of rapamycin liposome nano granule
Precision weighs 15mg rapamycin, 90mg phosphatide, and 11.25mg cholesterol is dissolved in 4mL methylene chloride.Then will
The organic liquid mixture is slowly added dropwise in 40mL water phase dropwise, mechanical stirring 60min, and after having stirred, homogenizer (900bar) is equal
Matter 3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, it is canned, it is cold
It is lyophilized dry.
Embodiment 3：The preparation of rapamycin liposome nano granule
Precision weighs 20mg rapamycin, 100mg phosphatide, and 15mg cholesterol is dissolved in 5mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 50mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 4：The preparation of rapamycin liposome nano granule
Precision weighs 100mg rapamycin, 500mg phosphatide, and 75mg cholesterol is dissolved in 10mL methylene chloride.Then will
The organic liquid mixture is slowly added dropwise in 100mL water phase dropwise, mechanical stirring 120min, after having stirred, homogenizer (900bar)
Homogeneous 3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, it is canned,
Freeze-drying.
Embodiment 5：The preparation of rapamycin liposome nano granule
Precision weighs 50mg rapamycin, 350mg phosphatide, and 31.5mg cholesterol is dissolved in 10mL methylene chloride.Then will
The organic liquid mixture is slowly added dropwise in 100mL water phase dropwise, mechanical stirring 60min, and after having stirred, homogenizer (900bar) is equal
Matter 3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, it is canned, it is cold
It is lyophilized dry.
Embodiment 6：The preparation of rapamycin liposome nano granule
Precision weighs 50mg rapamycin, 400mg phosphatide, and 31.5mg cholesterol is dissolved in 7mL methylene chloride.Then will
The organic liquid mixture is slowly added dropwise in 100mL water phase dropwise, mechanical stirring 60min, and after having stirred, homogenizer (900bar) is equal
Matter 3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, it is canned, it is cold
It is lyophilized dry.
Embodiment 7：The preparation of rapamycin liposome nano granule
Precision weighs 150mg rapamycin, 750mg phosphatide, and 112.5mg cholesterol is dissolved in 15mL methylene chloride.Then
The organic liquid mixture is slowly added dropwise in 150ml water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar)
Homogeneous 3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, it is canned,
Freeze-drying.
Embodiment 8：The preparation of rapamycin liposome nano granule
Precision weighs 15mg rapamycin, 105mg phosphatide, and 11.25mg cholesterol is dissolved in 5mL methylene chloride.Then will
The organic liquid mixture is slowly added dropwise in 50mL water phase dropwise, mechanical stirring 60min, and after having stirred, homogenizer (900bar) is equal
Matter 3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, it is canned, it is cold
It is lyophilized dry.
Embodiment 9：The preparation of rapamycin liposome nano granule
Precision weighs 40mg rapamycin, 200mg phosphatide, and 30mg cholesterol is dissolved in 5mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 50mL water phase dropwise, mechanical stirring 100min, after having stirred, homogenizer (900bar) homogeneous
3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 10：The preparation of rapamycin liposome nano granule
Precision weighs 40mg rapamycin, 280mg phosphatide, and 30mg cholesterol is dissolved in 5mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 50mL water phase dropwise, mechanical stirring 100min, after having stirred, homogenizer (900bar) homogeneous
3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 11：The preparation of rapamycin liposome nano granule
Precision weighs 80mg rapamycin, 400mg phosphatide, and 60mg cholesterol is dissolved in 10mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 100mL water phase dropwise, mechanical stirring 100min, and after having stirred, homogenizer (900bar) is equal
Matter 3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, it is canned, it is cold
It is lyophilized dry.
Embodiment 12：The preparation of rapamycin liposome nano granule
Precision weighs 5mg rapamycin, 60mg phosphatide, and 2.14mg cholesterol is dissolved in 3mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 24mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 13：The preparation of rapamycin liposome nano granule
Precision weighs 5mg rapamycin, 65mg phosphatide, and 2.14mg cholesterol is dissolved in 3mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 24mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.Add 5% lactose, be sterile filtered, canned, freezing is dry
It is dry.
Embodiment 14：The preparation of rapamycin liposome nano granule
Precision weighs 40mg rapamycin, 400mg phosphatide, and 30mg cholesterol is dissolved in 5mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 50mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 15：The preparation of rapamycin liposome nano granule
Precision weighs 15mg rapamycin, 150mg phosphatide, and 11.25mg cholesterol is dissolved in 5mL methylene chloride.Then will
The organic liquid mixture is slowly added dropwise in 50mL water phase dropwise, mechanical stirring 60min, and after having stirred, homogenizer (900bar) is equal
Matter 3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, it is canned, it is cold
It is lyophilized dry.
Embodiment 16：The preparation of rapamycin liposome nano granule
Precision weighs 5mg rapamycin, 15mg phosphatide, and 0.5mg cholesterol is dissolved in 3mL methylene chloride.Then this is had
Machine mixed liquor is slowly added dropwise in 30mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 17：The preparation of rapamycin liposome nano granule
Precision weighs 15mg rapamycin, 45mg phosphatide, and 12mg cholesterol is dissolved in 5mL methylene chloride.Then this is had
Machine mixed liquor is slowly added dropwise in 50mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 18：The preparation of rapamycin liposome nano granule
Precision weighs 40mg rapamycin, 120mg phosphatide, and 32mg cholesterol is dissolved in 5mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 50mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule., 5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 19：The preparation of rapamycin liposome nano granule
Precision weighs 5mg rapamycin, 30mg phosphatide, and 0.5mg cholesterol is dissolved in 3mL methylene chloride.Then this is had
Machine mixed liquor is slowly added dropwise in 30mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 20：The preparation of rapamycin liposome nano granule
Precision weighs 5mg rapamycin, 15mg phosphatide, and 2.14mg cholesterol is dissolved in 3mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 24mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 21：The preparation of rapamycin liposome nano granule
Precision weighs 40mg rapamycin, 120mg phosphatide, and 17.12mg cholesterol is dissolved in 5mL methylene chloride.Then will
The organic liquid mixture is slowly added dropwise in 50mL water phase dropwise, mechanical stirring 120min, and after having stirred, homogenizer (900bar) is equal
Matter 3 times, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, it is canned, it is cold
It is lyophilized dry.
Embodiment 22：The preparation of rapamycin liposome nano granule
Precision weighs 5mg rapamycin, 20mg phosphatide, and 2.14mg cholesterol is dissolved in 3mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 24mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Embodiment 23：The preparation of rapamycin liposome nano granule
Precision weighs 5mg rapamycin, 30mg phosphatide, and 3.75mg cholesterol is dissolved in 3mL methylene chloride.Then should
Organic liquid mixture is slowly added dropwise in 30mL water phase dropwise, mechanical stirring 60min, after having stirred, homogenizer (900bar) homogeneous 3
It is secondary, 40 DEG C of rotary evaporation 15min.Obtain rapamycin liposome nano granule.5% lactose is added, is sterile filtered, canned, freezing
Drying.
Experimental example 1：It evaluates rapamycin prepared by embodiment 1-23 and replaces font nanoparticle dried frozen aquatic products, evaluation criterion is
Appearance, redispersibility, average grain diameter and encapsulation rate.
Appearance：It to maintain original volume, does not collapse, not shrinkage, uniform color, no piebald, quality exquisiteness is preferred.
Redispersibility：One, freeze-dried lipidosome sample of each embodiment is taken, water for injection is added and redissolves, after shaking dispersion,
It can obtain uniform solution person quickly to be preferred, it is fewer to shake number, better in dispersibility.
Average grain diameter：Using the partial size and particle diameter distribution of Malvern laser particle analyzer measurement liposome, principle is to utilize
Light scattering occurs when particle is irradiated by light and the feature of diffraction occurs for light, and the scattering strength of light and diffracted intensity and particle are big
Small and optical signature related principle measures particle size.
Encapsulation rate：Encapsulation rate is preferable 80% or more.
Entrapment efficiency determination method：Liposome is crossed into 0.22 μm of filter membrane, filtrate is taken to survey the dose that encapsulating is entered；Meanwhile reference
Content determination item method measures total drug content.
Medicament contg uses high effective liquid chromatography for measuring, with methanol-acetonitrile-water (volume ratio 43：:40:It 17) is stream
Dynamic phase, flow velocity 1ml/min, column temperature are 40 DEG C, Detection wavelength 278nm.
Encapsulation rate calculation formula is：Encapsulation rate=encapsulating dose/main ingredient total content X 100%
The encapsulation rate of 1. liposome of table, the variation of drugloading rate and average grain diameter
The above result shows that the encapsulation rate of rapamycin liposome nano granule of the invention is 80% or more, according to ability
The understanding in domain, entrapment efficiency just illustrate product qualification 80% or more.
2 long-time stability of experimental example are investigated
It will obtain qualified lipidosome freeze-dried product and be placed in 2-8 DEG C of constant-temperature constant-humidity environment to place 24 months, and distinguish
Its average grain diameter is investigated, as a result the situation of change of encapsulation rate and content see the table below 2.
The experiment of 3 specific safety of experimental example
Vascular stimulation test：Healthy new zealand white rabbit 6 is taken, is randomly divided into 2 groups, every group of 3 new zealand white rabbits,
Binary vein injects sodium chloride injection and liposome nano granule injection of the invention, injection volume 0.5ml respectively.Daily note
It penetrates once, for three days on end, observes rabbit auricular vein stimulate the reaction.Compared with chloride injection group, liposome nano granule injection group
3 new zealand white rabbits the equal tube wall of auricular vein it is complete, blood vessel is without obvious expansion, and tube wall and surrounding are without obvious inflammatory cell
It infiltrates, has no the lesions such as thrombosis in tube wall.
Hemolytic experiment：It is made into 2% red blood cell suspension with 0.9% sodium chloride injection, 0.9% sodium chloride solution is made empty
White control group, distilled water make positive controls, observe result respectively after incubating 0.5,1,2,3 hour at 37 DEG C.Determine result：Entirely
Portion's haemolysis：The clear and bright red of solution, residual that tube bottom is cell-free；Part haemolysis：The clear and bright red or brownish red of solution, tube bottom have a small amount of red
Cell；Without haemolysis：Red blood cell all sinks, the transparent milky of upper liquid.Experimental result is shown in the following table 3 for hemolytic.
| Project | 0.5h | 1h | 2h | 3h |
| Negative control group | Whole haemolysis | Whole haemolysis | Whole haemolysis | Whole haemolysis |
| Positive controls | Without haemolysis | Without haemolysis | Without haemolysis | Without haemolysis |
| Experimental group | Without haemolysis | Without haemolysis | Without haemolysis | Without haemolysis |
Experimental example 4：The smooth muscle cell of rapamycin liposome nano granule, which rises in value, tests
1, above method is taken to prepare 80% or more encapsulation rate, average grain diameter 50-200nm, drugloading rate is receiving for 1-15%
The grain of rice carries out cell proliferation experiment, human tumour source property smooth muscle using MTT RNA isolation kit and human tumour source property smooth muscle cell
Cell is inoculated in 96 orifice plates with 1x103/hole inoculum concentration, 5%CO2, cultivates 24 hours in 37 DEG C of incubators, respectively by giving
Concentration is 60,40,30,20,10,1,0.1,0.01ug/ml administrations, is cultivated not after various concentration drug and dosing is observed continuously
With the cell activity of time.The results show that being compared with rapamycin bulk pharmaceutical chemicals group, inhibiting rate when rapamycin liposome just starts
Increase suddenly, then reduce, after 24 hours, and begin to ramp up again, started slowly decline again at 50 hours.Show thunder pa is mould
Element is wrapped in liposome, increases its affinity to cell membrane, enables drug quick acting in a short time, then drug
Slow release again, make its to cell act on be released after continuous action again, and rapamycin bulk pharmaceutical chemicals are because of free state
Under, it can just work, therefore be worked slowly after being absorbed by cell.And rapamycin is prepared into liposome, to cell
Inhibiting effect greatly enhances.Show that rapamycin liposome nano granule has certain sustained-release synergistic and increases rapamycin water
The effect of dissolubility.Wherein raw material proportioning is 1 part of rapamycin, and the drug effect of -8 parts of phosphatidase 5 of nanoparticle is substantially better than bulk pharmaceutical chemicals group
And other proportion groups.The Time-activity-curve and amount effect curve of experiment are shown in Fig. 1 and Fig. 2.
Prevention effect of the 5. rapamycin liposome nano granule injection of experimental example to rat aorta atherosis
Animal：Apolipoprotein genes knock-out mice (ApoE-/- mouse), 18-25g are purchased from Peking University experimental animal portion.
The preparation of Atherosclerosis Model mouse：In SPF grades of environment (room temperatures：23 DEG C, relative humidity：65%, 12h are bright
Dark alternating) it raises to 8 week old, start to feed high lipid food and intravenous injection is administered.Dosage regimen is shown in group and dosage regimen,
It takes blood vessel to dye, calculates score shared by plaque area, plaque area score calculation formula is:AA: AA=P/P0.Data mean value
Native standard deviation indicates that statistical analysis is examined using t, and P < 0.05 has significant difference, and all data pass through software and divided
Analysis.
Group and dosage regimen：Blank group：Physiological saline, intravenous injection, injection in every two days is primary, volume 0.2ml；It is right
According to group：Rapamycin original solution is injected intravenously, every two days with normal saline dilution to required concentration (dosage 0.5mg/kg)
Injection is primary；Medicine group：It is divided into senior middle school's low dose group (dosage：High dose group 1.5mg/kg, middle dose group 0.5mg/kg are low
Dosage group 0.25mg/kg), intravenous injection, injection in every two days is primary, and continuous 3 months.Period observes mouse state change.
To the prevention result of atherosclerosis：The percentage A0/A that plaque area accounts for whole aorta area is respectively：
Normal group：0；Modeling group：40.07% ± 11.55%；Rapamycin bulk pharmaceutical chemicals group：6.2% ± 1.21%；Rapamycin
Administration nano-drug administration system low dose group：10.61% ± 4.58%；Rapamycin nanoparticle drug delivery system middle dose group：7.10% ±
4.22%；Rapamycin nanoparticle drug delivery system high dose group：8.97% ± 3.22%；Data carry out variance analysis, p<0.05, it is poor
It is different that there is statistical significance.From the point of view of prevention of arterial atherosis result, drug rapamycin liposome nano granule note of the present invention
Penetrating agent has the function of good prevention of arterial atherosis.
Therapeutic effect of the 6. rapamycin liposome nano granule injection of experimental example to rat aorta atherosis
Animal：Apolipoprotein genes knock-out mice (ApoE-/- mouse), 18-25g are purchased from Peking University experimental animal portion.
The preparation of Atherosclerosis Model mouse：In SPF grades of environment (room temperatures：23 DEG C, relative humidity：65%, 12h are bright
Dark alternating) it raises to 8 week old, start nursing high lipid food and modeled successfully after feeding high lipid food 12 weeks, starts to be administered.It gives
Prescription case is shown in group and dosage regimen, and blood vessel is taken to dye, and calculates score shared by plaque area, plaque area score calculation formula
For:AA: AA=P/P0.Data indicate that statistical analysis is examined using t with mean value soil standard deviation, and P < 0.05 has significant difference,
All data pass through software and are analyzed.
Group and dosage regimen：Blank group：Physiological saline, intravenous injection, injection in every two days is primary, volume 0.2ml；It is right
According to group：Rapamycin original solution is injected intravenously, every two days with normal saline dilution to required concentration (dosage 0.5mg/kg)
Injection is primary；Medicine group：It is divided into senior middle school's low dose group (dosage：High dose group 1.5mg/kg, middle dose group 0.5mg/kg are low
Dosage group 0.25mg/kg), intravenous injection, injection in every two days is primary, and continuous 3 months.Period observes mouse state change.
Fig. 3 is shown in the prevention result of atherosclerosis, plaque area accounts for percentage A0/A points of whole aorta area
It is not：Normal group：；Modeling group：40.49% ± 6.29%；Rapamycin bulk pharmaceutical chemicals group：26.94% ± 4.71%；Thunder pa
Mycin administration nano-drug administration system low dose group：26.94% ± 4.71%；Rapamycin nanoparticle drug delivery system middle dose group：19.90%
± 9.34%；Rapamycin nanoparticle drug delivery system high dose group：20.21% ± 8.12%；Variance analysis, p<0.05, difference tool
It is statistically significant.From the point of view for the treatment of atherosclerotic events, drug rapamycin liposome nano granule injection of the present invention
Has the function of good treatment atherosclerosis.
7. rapamycin liposome nano granule injection of the experimental example prevention effect narrow to rat aorta
Animal：SD rat, 180-250g are purchased from Nanfang Medical Univ
The preparation of hemadostewnosis model：Rat conventional environment is raised after a week, 10% abdominal cavity chloraldurate 0.3ml/100g
After injecting anesthetic rat, weighing.For fixed rat on operating table, skin of neck disinfection cuts off skin in drafting notch, successively blunt
Property separation muscle, find left common carotid artery, separate left common carotid artery, ligature distal end, with hemostatic clamp Temporarily Closed proximal part.Inspection
Look into 2F Fogarty foley's tube whether gas leakage, heparin-saline rinse.A U-typed is cut in ligation section left common carotid artery to cut
Mouthful, it is inserted into foley's tube in incision, conduit of pulling back after Filled Balloon, repetition is pulled 3-4 times.Conduit is pulled out, blood vessel, seam are ligatured
Skin, and intramuscular injection gentamicin sulphate are closed, the rats such as cage is returned to revive.After revival, it is administered immediately.
Group and dosage regimen：Blank group：Physiological saline, intravenous injection, injection in every two days is primary, volume 0.2ml；It is right
According to group：Rapamycin original solution is injected intravenously, every two days with normal saline dilution to required concentration (dosage 0.5mg/kg)
Injection is primary；Medicine group：It is divided into senior middle school's low dose group (dosage：High dose group 1.5mg/kg, middle dose group 0.5mg/kg are low
Dosage group 0.25mg/kg), intravenous injection, injection in every two days is primary, and continuous 2 months.Period observes rat state change.Data
It is indicated with mean value soil standard deviation, statistical analysis is examined using t, and P < 0.05 has significant difference, and all data pass through software
It is analyzed.
Fig. 4 is shown in intravascular narrow prevention result, by carrying out sudan IV stain it has been observed that blank to whole blood vessel
Group blood vessel is thin and high resilience；Modeling group endangium obviously thickens；The middle dose group of rapamycin nanoparticle drug delivery system group and
For the inner membrance of high dose group almost without thickening, vascular wall softness is flexible；Rapamycin bulk pharmaceutical chemicals group and low dose group have slightly
It thickens.It has been observed that modeling group intimal thickening is obvious after pathological section HE dyeing, administration group middle dose group and high dose group are almost
Do not find intimal thickening, rapamycin bulk pharmaceutical chemicals group and low dose group inner membrance have to be thickened in a small amount.The I/M value of each group is:Blank
Group 0；Modeling group 162.8% ± 0.8%；Rapamycin bulk pharmaceutical chemicals group 2.44% ± 1.58%, rapamycin nanoparticle drug delivery system
Low dose group 49.16% ± 27.88%；Rapamycin nanoparticle drug delivery system middle dose group 0.63% ± 0.19%；Rapamycin
Administration nano-drug administration system high dose group 0.205% ± 0.005%.Variance analysis p<0.05, difference has statistical significance.From prevention
From the point of view of intravascular narrow result, drug rapamycin liposome nano granule injection of the present invention has good prevention intravascular
Narrow effect.
Claims (10)
1. a kind of rapamycin liposome nano granule, which is characterized in that the nanoparticle is according to the mass fraction by following raw material system
At：1 part of rapamycin, -20 parts of phosphatidase 1.
2. nanoparticle as described in claim 1, which is characterized in that the raw material proportioning is：1 part of rapamycin, phosphatidase 5-8
Part.
3. nanoparticle as described in claim 1, which is characterized in that the phosphatide is selected from egg yolk lecithin, soybean lecithin, hydrogen
Change egg yolk lecithin, hydrogenated soy phosphatidyl choline, cephalin, phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, sphingomyelins,
Diphosphatidylglycerol, dipalmitoylphosphatidylcholine, hydrolecithin, dioleoylphosphatidylethanolamine or distearyl acyl group phosphatide
One or more of acyl ethanol amine.
4. nanoparticle as described in claim 1, which is characterized in that the nanoparticle further includes stabilizer, the stabilizer with
The proportion of rapamycin by for：1:0.1-0.8, the stabilizer are in cholesterol, cholesterol sulfate sodium or ethyl polyenoate
One or more.
5. the nanoparticle as described in Claims 1-4 any claim, which is characterized in that its average grain diameter is 50-200nm,
Drugloading rate is 1-15%, and encapsulation rate is 85% or more.
6. the freeze drying powder injection of nanoparticle as described in claim 1, which is characterized in that the freeze drying powder injection further includes that freeze-drying is protected
Agent is protected, the mass ratio for accounting for nanoparticle is：3%-10%, the freeze drying protectant are in lactose, glucose, mannitol or sucrose
It is one or more of.
7. the preparation method of nanoparticle as described in claim 1 or 4, it is characterised in that include the following steps：
(1) raw material rapamycin, phosphatide or stabilizer are dissolved in organic solvent according to the ratio, obtain oil-phase solution；
(2) above-mentioned oil-phase solution is slowly added in aqueous phase solution, is stirred at room temperature, homogeneous, 40 DEG C of rotary evaporations are received to get described
The grain of rice.
8. preparation method as claimed in claim 7, which is characterized in that the organic solvent is methylene chloride.
9. preparation method as claimed in claim 7, which is characterized in that the aqueous phase solution is distilled water, physiology fliud flushing, cell
Culture solution, body fluid, tissue fluid, buffer or glucose injection.
10. the preparation method of nano particle freeze-dried powder injection as claimed in claim 6, it is characterised in that include the following steps：
(1) raw material rapamycin, phosphatide or stabilizer are dissolved in organic solvent according to the ratio, obtain oil-phase solution；
(2) above-mentioned oil-phase solution is slowly dropped into aqueous phase solution, is stirred at room temperature, homogeneous, 40 DEG C of rotary evaporations are received to get described
The grain of rice；
(3) freeze drying protectant is added in above-mentioned nanoparticle according to the ratio, is sterile filtered, is freeze-dried, obtains target product.
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| CN115337468A (en) * | 2022-08-23 | 2022-11-15 | 苏州中天医疗器械科技有限公司 | Cell-targeting rapamycin drug balloon and preparation method and application thereof |
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| CN116687860A (en) * | 2023-05-31 | 2023-09-05 | 广州鹏兴医药科技有限公司 | Cisplatin targeted liposome and preparation method and application thereof |
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Application publication date: 20181116 |