CN106389332B - A kind of macrocyclic lycobetaine organic-acid complex novel formulation - Google Patents
A kind of macrocyclic lycobetaine organic-acid complex novel formulation Download PDFInfo
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- CN106389332B CN106389332B CN201610827478.0A CN201610827478A CN106389332B CN 106389332 B CN106389332 B CN 106389332B CN 201610827478 A CN201610827478 A CN 201610827478A CN 106389332 B CN106389332 B CN 106389332B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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Abstract
The present invention provides a kind of macrocyclic lycobetaine organic-acid complex novel formulation, prepares the water-oil phase of the compound and surfactant respectively, nano liposome preparations have been made.Liposome prepared by the present invention has longer circulation time in vivo, higher bioavilability.Meanwhile the novel formulation encapsulation rate and drugloading rate are high, uniform particle diameter is stable, preparation is simple, has the primary condition of industrialized production, have good potential applicability in clinical practice.
Description
Technical field
The present invention relates to a kind of oxidation stones for being obviously prolonged lycobetaine circulation time in vivo and improving bioavilability
The Liposomal formulation and its preparation method and application of alliin organic-acid complex, is related to pharmaceutical technology field.
Background technique
Lycobetaine (Lycobetaine, abridge LBT) also known as ungeremine, are a kind of level Four coffee pyridine Alkaloids, main
It to extract and obtain from amrallid.Lycobetaine acetate (lycoris) is a kind of antitumorigenic substance, and chemistry is entitled
Hydroxyl -9 2-, simultaneously [3,2,1-de] phenanthridines acetate, structure are as follows for 1- first and second oxygroup -4,5- dihydro-pyridos:
Formula 1: the structure of lycobetaine acetate
Lycobetaine alternatively property topoisomerase II beta inhibitor (Barthelmes HU, Niederberger
E, Roth T, et al. Lycobetaine acts as a selective topoisomerase II beta
poison and inhibits the growth of human tumour cells. Brit J Cancer. 2001;85
(10): 1585-1591.), the active group of tumor suppression is that (Weng Zunyao, king start for the part of methylene-dioxy and betaine in structure
Sternly know bright new anti-tumor substance in sea --- ungeremine (ungeremine, AT-1840) and its synthesis and the structure for having related compounds
Effect relationship Acta Pharmaceutica Sinica, 1982,17 (10): 744-749).Research shows that in kinds of tumors model, lycobetaine acetic acid
Salt shows good inhibiting effect to tumour growth and existence, has apparent inhibitory effect to gastric cancer and oophoroma.In addition, oxygen
Fossil alliin is not observed in chemotherapy with the combination of other anti-tumor drugs and radiotherapy combination therapeutic process
Toxic side effects (Wu Yunlin, Wu Yuqi, the lycobetaine such as remaining spring celestial being and the tiny diseases such as common bone marrow suppression, enteron aisle reaction
Experimental study Shanghai medicine of the malicious H-1 to stomach cancer cell lethal effect, 1988,11 (12): 683-688.).Aoxidize short-tube lycoris
Alkali has also clinically carried out antitumor research, is not found apparent toxicity (in the short-tube lycoris such as Hu Qinghe, Lin Zhaoxiang, He Ping
Ammonium (AT-1840) complex treatment gynaecology late malignant tumour --- the attached 43 summaries Zhejiang combination of Chinese tradiational and Western medicine magazine, 1997,7
(3): 134-136).However lycobetaine is there is no clinically promoting the use of in recent years, the main reason is that aqueous solution system
Agent bioavilability is extremely low, and Half-life in vivo is extremely short, and repeatedly large dosage administration is needed undoubtedly to increase to patient to maintain drug effect
Burden.Furthermore lycobetaine belongs to water microsolubility drug, and it is most of to be not suitable for existing nanoparticle, liposome and nano-emulsion etc.
Carrier significantly limits use of the lycobetaine in clinic.Therefore, a kind of novel formulation is developed to improve lycobetaine
Bioavilability reaches better antitumous effect, and a better choice can be provided for clinical treatment.
Patent 201210252981.X and document (Zhao H, Lu H, Gong T, Zhang ZR. Nanoemulsion
loaded with lycobetaine-oleic acid ionic complex: physicochemical
characteristics, in vitro, in vivo evaluation, and antitumor activity. Int.
J. Nanomed. 2013;8:1959-1973.) provide a kind of lycobetaine oleic acid complex nanometer granule preparation, said preparation
Ion-pair complexes are formed using oleic acid and lycobetaine, to increase the fat-soluble of drug.Compound is loaded into nanometer again
In grain, drug circulation time in vivo is extended, the bioavilability of drug is improved, and significantly increases the anti-of lycobetaine
Cancer activity.But this preparation can only also extend lycobetaine circulation time to 10 hours or so in vivo, and medicine is dynamic in rat body
It learns experiment and shows that lycobetaine concentration drops to a very low level in 10 hours or so blood plasma.This result prompts me
, the circulation time in vivo for extending lycobetaine should be the feasible method for improving its curative effect.
In conclusion a kind of can more preferably extend lycobetaine circulation time in vivo, the new of drug bioavailability is improved
Preparation is needed.The research and development of this novel formulation will be helpful to mitigate the burden of patient, more be worth for social creativity.
Summary of the invention
An object of the present invention provides a kind of Liposomal formulation of novel lycobetaine organic acid ion pair.
An object of the present invention provides a kind of Liposomal formulation of macrocyclic lycobetaine organic acid ion pair.
Compared to lycobetaine oleic acid ion pair nanoparticle in patent 201210252981.X, there is more obvious slow release effect.
An object of the present invention, provides a kind of macrocyclic, can significantly improve lycobetaine bioavilability, reduce
Administration frequency extends dosing interval, conducive to the liposome of clinical use.
Inventor is in experimental study, it has unexpectedly been found that, by lycobetaine organic acid ion to being prepared into liposome,
Circulation time in vivo is considerably longer than existing nanometer formulation.
The experimental results showed that by after lycobetaine lipophilization treatment, could prepare compared with high encapsulation rate, uniform particle sizes, steady
Qualitative good lycobetaine Liposomal formulation.
The present invention will prepare lycobetaine organic-acid complex compared with fat-solubility, will using organic solvent appropriate
, with the dissolutions such as phosphatide and other surfactants as oily phase, water uses water after rotary evaporation removes organic solvent as water phase for it
Hydrated films obtain suspension, and the high-pressure homogeneous liposome that is made is to get the Liposomal formulation that can be injected intravenously.
The present inventor the study found that carry lycobetaine liposome than load lycobetaine nano particle preparations have it is smaller
Partial size, higher encapsulation rate.In addition, carrying the liposome of medicine also has a slower drug release feature, longer circulation time, and
The characteristics of higher bioavilability, shows the clear superiority of drug-loaded liposome.
Liposomal particle size provided by the invention is in about 10-500nm, preferably in 50-300nm.
There is provided a kind of liposomes of lycobetaine organic-acid complex for an object of the present invention, mainly by aoxidizing
Compound that lycorine and organic acid are formed, surfactant be made, wherein lycobetaine, organic acid, surfactant
Parts by weight are 1 part of lycobetaine, 1 ~ 10 part of organic acid, 2 ~ 20 parts of surfactant；Preferably, 1 part of lycobetaine, it is organic
1 ~ 5 part, 5 ~ 18 parts of surfactant of acid.
Organic acid of the present invention is the organic acid of eight carbon atoms or more.
Organic acid of the present invention includes oleic acid, linoleic acid, linolenic acid, stearic acid, palmitin selected from middle long chain fatty acids
One of acid, retinotic acid, octanoic acid or a variety of mixtures, preferably oleic acid；Can also include selected from Cholic acids organic acid
Cholic acid, deoxycholic acid, ursodesoxycholic acid, ox deoxycholic aicd, chenodeoxycholic acid, hyodesoxycholic acid, ursodesoxycholic acid, shellfish gallbladder difficult to understand
One of acid, glycocholic acid, cholyltaurine, lithocholic acid or a variety of mixtures.
If organic acid is solid not soluble in water, the organic solvent solution containing organic acid, the organic solvent can be added
From ethyl alcohol, methanol, acetone, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N, one or more of N-2- methylformamide is mixed
Close object, preferred alcohol；The organic solvent is appropriate addition.
Ingredient of the preferred oleic acid of the present invention as lycobetaine organic-acid complex.Oleic acid (oleic acid) scientific name is
Oleic acid is a kind of unsaturated fatty acid.
Suitable surface is added in lycobetaine organic-acid complex Liposomal formulation preparation process of the present invention
Activating agent is selected from soybean lecithin, egg yolk lecithin, dipalmitoyl lecithin, dioleyl lecithin, palmityl haemolysis ovum
Phosphatide, myristoyl lysolecithin, stearoyl lysolecithin, two myristoyl lecithin, 1- palmityl -2- oleoyl
Base lecithin, two mustard acyl group lecithin, double spermaceti phosphatidyls, stearic phosphatidyl, phosphatidic acid, dipalmitophosphatidic acid, two palms
Phatidylcholine, distearoylcholine, phosphatidyl choline, two nutmeg phosphatidyl cholines, distearoyl phosphatidylcholine, phosphatidyl
Inositol, phosphatidyl-ethanolamine, di-mustard acyl phosphatidylethanolamine, two myristoyl phosphatidyl-ethanolamines, distearyl acyl group phosphorus
Acyl ethylethanolamine, two palmityl phosphatidylethanolamines, dioleoyl phospholipid acyl ethanol amine, phosphatidylserine, two oil
Acyl phospholipids acyl serine, cholesterol, cholesterol sodium sulfate, phosphatidyl glycerol, dioleoylphosphatidylglycerol, yolk phospholipid acyl
Glycerol, 1- palmityl -2- oleolyl phosphatidyl glycerol, 1,2- palmityl phosphatidyl glycerol, distearoylphosphatidylglycerol, two
Myristoyl phosphatidyl glycerol, PEGylated phosphatide, dipalmitoylphosphatidylethanolamine-polyethylene glycol, distearyl acyl group phosphatidyl second
Hydramine-polyethylene glycol, Distearoyl Phosphatidylethanolamine-nitrine polyethylene glycol, two myristoyl phosphatidyl-ethanolamines-poly- second
One or more kinds of mixtures of the similar compounds such as glycol；Preferably soya lecithin and cholesterol admixture, the two content are matched
Than being preferably 1:1 ~ 5:1, more preferably 2:1；Or preferably soya lecithin, cholesterol and DSPE-PEG2000Mixture, San Zhehan
Amount proportion is preferably 2:1:1 ~ 2:1:0.1, more preferably 2:1:0.27.
When surfactant is selected from soybean lecithin, cholesterol and DSPE-PEG2000When mixture, the present invention obtains PEG
The liposome of the lycobetaine organic-acid complex of change.
An object of the present invention there is provided a kind of preparation method of lycobetaine organic-acid complex liposome,
Characteristic includes the following steps:
(1) it takes the pharmaceutically acceptable salt of lycobetaine soluble in water, first neutralizes its corresponding acid with alkaline matter
Later；Organic acid mixing is added, lycobetaine organic-acid complex is formed；Wherein, if organic acid is not soluble in water consolidates
The organic solvent containing organic acid can be added in body；
(2) freeze-drying step (1) obtains lycobetaine organic-acid complex, and it is molten to add organic solvent appropriate
Above-mentioned compound is solved, solution is obtained；
(3) it according to the dissolution characteristics of surfactant, is dissolved with water or organic solvent, obtains solution；
(4) by solutionAnd solutionIt is uniformly mixed, is evaporated under reduced pressure and removes organic solvent；
(5) again by its it is mixed with water after, film aquation obtains suspension；
(6) suspension described in step (5) is homogenized and lycobetaine organic-acid complex liposome is made.
Wherein, the alkaline matter in step (1) is mainly used in the pharmaceutically-acceptable salts for neutralizing lycobetaine
Acid group obtains drug molecule form free alkali.
Lycobetaine of the present invention is mainly anti-by the pharmaceutically acceptable salt progress desalination of lycobetaine
Answer and obtain, for example, lycobetaine acetate and alkali substance reaction and obtain.
The alkaline matter is selected from potassium hydroxide, potassium carbonate, saleratus, potassium citrate, sodium hydroxide, sodium carbonate, carbon
Sour hydrogen sodium, sodium citrate, triethylamine, monoethanolamine, diethanol amine, ammonium hydroxide or two or more alkaline matters mixture.
The preferred sodium bicarbonate of step (1) alkaline matter, additional amount are the conventional selections of this field.It is preferred that alkaline matter neutralization pair
The time for the acid answered is 5 minutes.Preferred organic acid is oleic acid.It is preferred that oleic acid and lycobetaine incorporation time are 30 minutes.
Organic solvent in step (2) is selected from chloroform, methylene chloride, ethyl acetate, ethyl alcohol, methanol, tetrahydrofuran, second
Nitrile, acetone, ether, n-hexane, normal heptane, aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbons and its mixture and 2 kinds or two or more this
The mixture of a little solvents or similar solvent, preferably methylene chloride.
Step (3) if in surfactant it is soluble in water, do not need in step (4) by solutionIt is rotated, it will
SolutionIt is mixed as the water phase in step (5).
The mixture or soybean lecithin of surfactant preferably soya lecithin S100 described in step (3) and cholesterol
Rouge, cholesterol and DSPE-PEG2000Mixture.In addition, organic solvent is in the lower evaporation of decompression.Method of evaporating includes being steamed using rotation
Send out device, falling film evaporator, spray dryer, freeze-dryer and similar devices.The preferred rotary evaporator of the present invention.
It is in high pressure and shear conditions that lycobetaine organic acid complex lipid body method is prepared described in step (6)
Under it is homogenized effect formed.Acceptable homogenization process includes being selected from high pressure dispersing emulsification machine, high pressure Microfluidizer, high shear
Mixer, ultrasonic processor, high-shear mixer and similar devices.This homogenization preferably carries out in high pressure dispersing emulsification machine,
Typical operating pressure is range of the preferred pressure in 5000 ~ 15000psi in the range of 3000 ~ 30000psi.
Its preferred scheme is as follows:
(1) it takes the pharmaceutically acceptable salt of lycobetaine soluble in water, first neutralizes its corresponding acid with sodium bicarbonate
Later；Oleic acid mixing is added, lycobetaine oleic acid compound is formed；
(2) freeze-drying step (1) obtains lycobetaine oleic acid compound, adds in methylene chloride dissolution appropriate
Compound is stated, solution is obtained；
(3) according to lecithin, cholesterol (and DSPE-PEG2000) dissolution characteristics, dissolved with methylene chloride, obtain solution；
(4) by solutionAnd solutionIt is uniformly mixed, is evaporated under reduced pressure and removes organic solvent；
(5) again by its it is mixed with water after, film aquation obtains suspension；
(6) oxidation stone is made through high-pressure homogeneous in suspension described in step (5) under the pressure of 5000 ~ 15000psi
Alliin oleic acid composite liposome body.
An object of the present invention provides lycobetaine organic-acid complex liposome in preparation and inhibits tumour growth
Drug in application.
An object of the present invention provides lycobetaine organic-acid complex liposome in the medicine of preparation treatment tumour
Application in object.
An object of the present invention provides lycobetaine organic-acid complex liposome in preparation and inhibits gastric cancer, ovum
Application in nest cancer, lung cancer, breast cancer and the drug of lymph cancer growth.
An object of the present invention provides lycobetaine organic-acid complex liposome in preparation and treats gastric cancer, ovum
Nest cancer, lung cancer, breast cancer and lymph cancer drug in application.
The present invention by preparing lycobetaine organic-acid complex Liposomal formulation, and with lycobetaine oil before
Sour complex nanometer granule preparation is compared, and proves that prepared lycobetaine organic acid is compound with corresponding experiment in vivo
Composite lipidosome improves the bioavilability of drug compared with lycobetaine oleic acid complex nanometer granule, extends circulation time in vivo.
The present invention is further illustrated with embodiment again below, while being said also in relation with attached drawing in embodiment
It is bright, but be definitely not to limit the scope of the present invention.
Beneficial effect
(1) liposome of the invention has higher encapsulation rate, has preferable water-soluble, biocompatibility and biology that can drop
Xie Xing；
(2) liposome of the invention, partial size can obtain the liposome of 10-500nm by prescription screening；
(3) liposome of the invention has more obvious slow release effect and blood circulation inside body time；
(4) preparation process of the invention is simple, and controllably, organic solvent residual is few.
Detailed description of the invention
Hereinafter, carrying out the embodiment that the present invention will be described in detail in conjunction with attached drawing, in which:
Fig. 1 is the saturating of lycobetaine oleic acid composite liposome body and PEGylated lycobetaine oleic acid composite liposome body
Penetrate electron microscope and particle diameter distribution situation.Scale: 200nm
Fig. 2 is the extracorporeal releasing experiment result of the nano particle preparations of preparation and load LBT in Examples 1 and 2.
Fig. 3 is the serum stability experiment result of the nano particle preparations of preparation and load LBT in Examples 1 and 2.
Fig. 4 is the Pharmacokinetic experiments result of the nano particle preparations of preparation and load LBT in Examples 1 and 2.
Fig. 5 is PEGylated lycobetaine oleic acid complex nanometer granule and PEGylated lycobetaine oleic acid composite liposome body
Structural schematic diagram.
Specific embodiment
The following examples are further illustrations of the invention, but never it limits the scope of the present invention.Referring to
Embodiment is further elaborated on the present invention, it should be appreciated to those skilled in the art that the present invention is not limited to these implementations
Example and the preparation method used.Moreover, those skilled in the art's description according to the present invention can be equal to the present invention
Replacement, combination, improvement or modification, but these are intended to be included in the scope of the present invention.
Embodiment 1
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg add soybean lecithin for injection 60mg, cholesterol 30mg, will with methylene chloride
It is dissolved, and after mixing, revolving removes organic solvent.Appropriate water for injection is added, after 37 DEG C of shaking table aquation demouldings, by aquation
Even 7 circulations of liquid cream in high pressure dispersing emulsification machine, partial size 200nm is to get lycobetaine oleic acid composite liposome body.
Embodiment 2
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg, DSPE-PEG20008mg adds soybean lecithin for injection 60mg, cholesterol
30mg is dissolved with methylene chloride, and after mixing, revolving removes organic solvent.Appropriate water for injection, 37 DEG C of shaking tables are added
After aquation demoulding, by hydrating fluid, even 7 circulations of cream, partial size 140nm are oily to get PEGylated lycobetaine in high pressure dispersing emulsification machine
Sour composite liposome body.
Embodiment 3
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg, DSPE-PEG50008mg adds soybean lecithin for injection 60mg, cholesterol
30mg is dissolved with methylene chloride, and after mixing, revolving removes organic solvent.Appropriate water for injection, 37 DEG C of shaking tables are added
After aquation demoulding, by hydrating fluid, even 7 circulations of cream, partial size 158nm are oily to get PEGylated lycobetaine in high pressure dispersing emulsification machine
Sour composite liposome body.
Embodiment 4
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg, DPPE-PEG20008mg adds soybean lecithin for injection 60mg, cholesterol
30mg is dissolved with methylene chloride, and after mixing, revolving removes organic solvent.Appropriate water for injection, 37 DEG C of shaking tables are added
After aquation demoulding, by hydrating fluid, even 7 circulations of cream, partial size 155nm are oily to get PEGylated lycobetaine in high pressure dispersing emulsification machine
Sour composite liposome body.
Embodiment 5
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 10mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 10mg add soybean lecithin for injection 60mg, cholesterol 30mg, will with methylene chloride
It is dissolved, and after mixing, revolving removes organic solvent.Appropriate water for injection is added, after 37 DEG C of shaking table aquation demouldings, by aquation
Even 7 circulations of liquid cream in high pressure dispersing emulsification machine, partial size 210nm or so is to get lycobetaine oleic acid composite liposome body.
Embodiment 6
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 100mg is added, and are vortexed 30 points
Clock, 10000rpm are centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein
Lycobetaine about 10mg, oleic acid about 100mg, add soybean lecithin for injection 60mg, and cholesterol 30mg uses methylene chloride
It is dissolved, after mixing, revolving removes organic solvent.Appropriate water for injection is added, after 37 DEG C of shaking table aquation demouldings, by water
Change even 7 circulations of liquid cream in high pressure dispersing emulsification machine, partial size 220nm or so is to get lycobetaine oleic acid composite liposome body.
Embodiment 7
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and stearic acid 10mg is added, and are vortexed 30 points
Clock, 10000rpm are centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine stearic acid compound is taken after freeze-drying,
Middle lycobetaine about 10mg, stearic acid about 10mg, add soybean lecithin for injection 60mg, and cholesterol 30mg uses dichloro
Methane is dissolved, and after mixing, revolving removes organic solvent.It is added appropriate water for injection, after 37 DEG C of shaking table aquation demouldings,
Hydrating fluid is recycled for cream even 7 in high pressure dispersing emulsification machine, partial size 170nm or so is to get lycobetaine stearic acid compound rouge
Plastid.
Embodiment 8
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and stearic acid 100mg is added, and are vortexed 30 points
Clock, 10000rpm are centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine stearic acid compound is taken after freeze-drying,
Middle lycobetaine about 10mg, stearic acid about 100mg, add soybean lecithin for injection 60mg, and cholesterol 30mg uses dichloro
Methane is dissolved, and after mixing, revolving removes organic solvent.It is added appropriate water for injection, after 37 DEG C of shaking table aquation demouldings,
Hydrating fluid is recycled for cream even 7 in high pressure dispersing emulsification machine, partial size 270nm or so is to get lycobetaine stearic acid compound rouge
Plastid.
Embodiment 9
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and deoxycholic acid 10mg, vortex 30 is added
Minute, 10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying,
Middle lycobetaine about 10mg, deoxycholic acid about 10mg add soybean lecithin for injection 60mg, cholesterol 30mg, with two
Chloromethanes is dissolved, and after mixing, revolving removes organic solvent.Appropriate water for injection, 37 DEG C of shaking table aquation demouldings are added
Afterwards, by hydrating fluid, even 7 circulations of cream, partial size 307nm or so are multiple to get lycobetaine deoxycholic acid in high pressure dispersing emulsification machine
Close composite lipidosome.
Embodiment 10
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and deoxycholic acid 100mg, vortex 30 is added
Minute, 10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying,
Middle lycobetaine about 10mg, deoxycholic acid about 100mg add soybean lecithin for injection 60mg, cholesterol 30mg, with two
Chloromethanes is dissolved, and after mixing, revolving removes organic solvent.Appropriate water for injection, 37 DEG C of shaking table aquation demouldings are added
Afterwards, by hydrating fluid, even 7 circulations of cream, partial size 400nm or so are multiple to get lycobetaine deoxycholic acid in high pressure dispersing emulsification machine
Close composite lipidosome.
Embodiment 11
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and octanoic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, octanoic acid about 30mg, adds soybean lecithin for injection 60mg, cholesterol 30mg, will with methylene chloride
It is dissolved, and after mixing, revolving removes organic solvent.Appropriate water for injection is added, after 37 DEG C of shaking table aquation demouldings, by aquation
Even 7 circulations of liquid cream in high pressure dispersing emulsification machine, partial size 280nm or so is to get lycobetaine octanoic acid composite liposome body.
Embodiment 12
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg add injection egg yolk lecithin 60mg, cholesterol 30mg, will with methylene chloride
It is dissolved, and after mixing, revolving removes organic solvent.Appropriate water for injection is added, after 37 DEG C of shaking table aquation demouldings, by aquation
Even 7 circulations of liquid cream in high pressure dispersing emulsification machine, partial size 204nm or so is to get lycobetaine oleic acid composite liposome body.
Embodiment 13
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg add injection egg yolk lecithin 30mg, soybean lecithin 30mg, cholesterol
30mg is dissolved with methylene chloride, and after mixing, revolving removes organic solvent.Appropriate water for injection, 37 DEG C of shaking tables are added
After aquation demoulding, by hydrating fluid, even 7 circulations of cream, partial size 200nm or so are oily to get lycobetaine in high pressure dispersing emulsification machine
Sour composite liposome body.
Embodiment 14
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The Na of appropriate 50mg/ml is added2CO3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg add soybean lecithin for injection 60mg, cholesterol 30mg, will with methylene chloride
It is dissolved, and after mixing, revolving removes organic solvent.Appropriate water for injection is added, after 37 DEG C of shaking table aquation demouldings, by aquation
Even 7 circulations of liquid cream in high pressure dispersing emulsification machine, partial size 210nm or so is to get lycobetaine oleic acid composite liposome body.
Embodiment 15
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The KHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg add soybean lecithin for injection 60mg, cholesterol 30mg, will with methylene chloride
It is dissolved, and after mixing, revolving removes organic solvent.Appropriate water for injection is added, after 37 DEG C of shaking table aquation demouldings, by aquation
Even 7 circulations of liquid cream in high pressure dispersing emulsification machine, partial size 212nm or so is to get lycobetaine oleic acid composite liposome body.
Embodiment 16
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The K of appropriate 50mg/ml is added2CO3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg add soybean lecithin for injection 60mg, cholesterol 30mg, will with methylene chloride
It is dissolved, and after mixing, revolving removes organic solvent.Appropriate water for injection is added, after 37 DEG C of shaking table aquation demouldings, by aquation
Even 7 circulations of liquid cream in high pressure dispersing emulsification machine, partial size 200nm or so is to get lycobetaine oleic acid composite liposome body.
Embodiment 17
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg add soybean lecithin for injection 60mg, cholesterol 30mg, with methanol that its is molten
Solution, after mixing, revolving remove organic solvent.It is added appropriate water for injection, after 37 DEG C of shaking table aquation demouldings, hydrating fluid is existed
Even 7 circulations of cream in high pressure dispersing emulsification machine, partial size 205nm or so is to get lycobetaine oleic acid composite liposome body.
Embodiment 18
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg add soybean lecithin for injection 60mg, cholesterol 30mg, with chloroform that its is molten
Solution, after mixing, revolving remove organic solvent.It is added appropriate water for injection, after 37 DEG C of shaking table aquation demouldings, hydrating fluid is existed
Even 7 circulations of cream in high pressure dispersing emulsification machine, partial size 210nm or so is to get lycobetaine oleic acid composite liposome body.
Embodiment 19
10mg lycobetaine acetate is taken, ultrasonic dissolution in water, obtains the lycobetaine that concentration is 1 ~ 2mg/ml
Aqueous acetic acid.The NaHCO of appropriate 50mg/ml is added3Solution, strength are vortexed 5 minutes, and oleic acid 30mg is added, and are vortexed 30 minutes,
10000rpm is centrifuged 5 minutes, and complex precipitate is taken to be lyophilized.Suitable lycobetaine oleic acid compound is taken after freeze-drying, wherein oxygen
Fossil alliin about 10mg, oleic acid about 30mg add soybean lecithin for injection 60mg, cholesterol 30mg, will with ethyl acetate
It is dissolved, and after mixing, revolving removes organic solvent.Appropriate water for injection is added, after 37 DEG C of shaking table aquation demouldings, by aquation
Even 7 circulations of liquid cream in high pressure dispersing emulsification machine, partial size 215nm or so is to get lycobetaine oleic acid composite liposome body.
Experimental example 1
Measure common lycobetaine oleic acid composite liposome body (LBT-OA-Liposome) and PEGylated lycobetaine
The form and partial size of oleic acid composite liposome body (LBT-OA-PEG-Liposome).By the liposome dilution in Examples 1 and 2
It is 3mg/ml at lipid concentration, the form of two kinds of liposomes is observed under transmission electron microscope.It is measured and is made using laser particle size analyzer
The partial size and current potential of agent.
Fig. 1 is the transmission electron microscope picture and particle diameter distribution feelings of LBT-OA-Liposome and LBT-OA-PEG-Liposome
Condition.Scale: 200nm.Indicate the result shows that, LBT-OA-Liposome and LBT-OA-PEG-Liposome have apparent phosphatide double
Molecular layer structure, appearance rounding, uniform particle diameter.LBT-OA-Liposome partial size is in 200nm or so, LBT-OA-PEG-
Liposome partial size is in 140nm or so, such as table 1.
Table 1: the property (n=3) of liposome
| Size (nm) | PDI | Zeta potential (mV) | |
| LBT-OA-Lipo | 200.97 ± 7.94 | 0.278 ± 0.012 | -31.3 ± 1.5 |
| LBT-OA-PEG-Lipo | 139.03 ± 5.39 | 0.231 ± 0.012 | -26.4 ± 0.5 |
Experimental example 2
The entrapment efficiency determination of LBT-OA-Lipo and LBT-OA-PEG-Lipo.It is prepared in patent document 201210252981.X
The lycobetaine oleic acid for having gone out a kind of novel lycobetaine oleic acid complex nanometer granule (LBT-OA-NE) and PEGization is multiple
It closes object nanoparticle (LBT-OA-PEG-NE).The nanoparticle of lycobetaine will be carried in this paper subsequent experimental example with present invention research
In load lycobetaine liposome compare.The drug of four preparations is measured with ultrafiltration and sephadex column chromatography
Encapsulation rate.
Ultrafiltration: taking four each 0.4ml of preparation in the super filter tube that molecular cut off is 3000, and 4000rpm is centrifuged 15 points
Zhong Hou respectively takes a certain amount of filtrate to dilute, using the content of fluorescent spectrophotometer assay drug, computational envelope rate.
Column chromatography: after sephadex G -50 is saturated with water, dress column is filled up, 1ml preparation is respectively taken, utilizes ultraviolet detection
Device is detected, and is collected preparation and is partially separated liquid, take a certain amount of dilution, measures drug concentration, computational envelope rate.
As a result such as table 2.As it can be seen that ultrafiltration measures the encapsulation rate of four preparations all 98% or so, and the knot that column chromatographs
Fruit but shows that liposome has encapsulation rate more higher than nanoparticle.The possible reason is the oil inside nanoparticle is mutually as storage
Unique storage cavern of LBT is hidden, lycobetaine oleic acid compound cannot may fully be wrapped in nanoparticle during preparation
Inside is partially attracted to nanoparticle surface, is easy to release during column separation.And the phospholipid bilayer of liposome
Layer can be used to store fat-soluble medicine, and the inner aqueous phase of liposome can also store water soluble drug, in this way, can more wrap
Lycobetaine oleic acid compound is wrapped up in, the opposite reduction of compound of outer liposome surface is adsorbed on, reaches better encapsulation rate.
Table 2: distinct methods measure the encapsulation rate (n=3) of different preparations
| Method | LBT-OA-NE | LBT-OA-PEG-NE | LBT-OA-Lipo | LBT-OA-PEG-Lipo |
| Ultrafiltration | 93.12 ± 2.56 | 95.33 ± 1.24 | 94.55 ±1.47 | 97.44 ± 1.98 |
| Column chromatography | 35.75 ± 2.33 | 40.53 ± 0.76 | 79.77 ±1.57 | 85.46 ± 1.23 |
Experimental example 3
The release in vitro of preparation.By the LBT-OA-NE, LBT-OA-PEG- of LBT solution (1mg/ml) and each 1ml of 1ml
NE, LBT-OA-Lipo, LBT-OA-PEG-Lipo(1mg/ml, by the concentration calculation of LBT) preparation is placed in bag filter (molecule
800 ~ 14000Da of interception).Bag filter is placed in 300ml PBS(pH7.4) conical flask in, in 37 DEG C of shaking tables (70rmp)
Oscillation.1ml dissolution medium is respectively taken in different time points, and adds the blank dissolution medium of respective volume.Using LC-MS
The burst size of method measurement drug.
Fig. 2 is the extracorporeal releasing experiment result of the nano particle preparations of preparation and load LBT in Examples 1 and 2.As a result table
Bright, LBT-OA-PEG-Lipo has better slow release effect.
Experimental example 4
The serum stability of preparation.LBT-OA-Lipo, LBT-OA-PEG-Lipo and the LBT-OA-NE that will be prepared,
LBT-OA-PEG-NE preparation respectively takes 1ml, and after mixing with 50% isometric fetal calf serum, a small amount of mixing is taken under different time points
Object measures the change of size of preparation.
Fig. 3 is the serum stability experiment result of the nano particle preparations of preparation and load LBT in Examples 1 and 2.As a result
Show Liposomal formulation in the whether nano particle preparations of LBT or the present invention, has good stabilization in serum 24 hours
Property.
Experimental example 5
The X-ray photoelectron spectroscopic analysis (XPS) of preparation.The LBT-OA-Lipo that will be prepared, blank liposome and
LBT-OA-NE, blank nano particle preparations respectively fetch drop drop on glass slide, x-ray photoelectron energy are used after moisture evaporation is clean
Spectrum analysis instrument analyzes the content of the carbon of surface 3nm, nitrogen, oxygen and P elements.The results are shown in Table 3 for analysis.Oleic acid is with aoxidizing short-tube lycoris
Alkali all contains oxygen element, and the surface of liposome oxygen element for carrying medicine has compared with blank liposome slightly to be increased, and drug-carrying nanometer particle phase
Compared with blank nanoparticle, oxygen element has more increases, shows that more lycobetaines are packed in inside by liposome, and receives
The grain of rice is then with the presence of the surface of more drug preparations.
Table 3: the surface-element analysis of different preparations
Experimental example 6
The Pharmacokinetic experiments of preparation.25 SD rats are randomly divided into 5 groups, and every group 5, it is molten to give LBT for distribution after fasting 12h
Liquid, LBT-OA-NE, LBT-OA-PEG-NE and LBT-OA-Lipo, LBT-OA-PEG-Lipo, the wherein dosage of LBT
For 10mg/kg.0.083 after tail vein injection, 0.15,0.25,0.5,1,2,4,8,12,24,48h take blood 0.3ml to heparin
In the processed centrifuge tube of sodium, 5000rmp is centrifuged 5 minutes, is taken out 100 μ l of upper plasma, is frozen at -40 DEG C.Blood plasma sample
Product processing: after plasma sample is placed at room temperature, being added 300 μ l acetonitrile precipitation albumen, and the 10000rpm after five minutes that is vortexed is centrifuged
5 minutes, after taking supernatant liquor to cross 0.22 μm of film, using the concentration of LBT in LC-MS/MS measurement blood plasma.Utilize DAS software meter
Calculate pharmacokinetic parameters.Pharmacokinetic parameters are as shown in table 4.As shown in Table, LBT-OA-Lipo can significantly improve the biology benefit of LBT
Expenditure, AUC value are 11.5 times of LBT raw medicine group, and 3.0 times of LBT-OA-NE group, be 1.8 times of LBT-OA-PEG-NE group.
In addition PEGylated liposome has highest bioavilability, and AUC value is 42.6 times of LBT raw medicine group, LBT-OA-NE group
11.2 times, be 6.7 times of LBT-OA-PEG-NE group, be 3.7 times of LBT-OA-Lipo group.
Fig. 4 is the Pharmacokinetic experiments result of the nano particle preparations of preparation and load LBT in Examples 1 and 2.The result shows that
The liposome of LBT, especially PEGylated liposome are carried, the circulation time that can significantly extend drug (still has higher blood medicine dense after for 24 hours
Degree), improve the bioavilability of drug.
Table 4: pharmacokinetic parameters (n=5) of the LBT in different preparations after intravenous injection
P<0.05; a, vs. LBT-OA-liposome; b, vs. LBT-OA-PEG-liposome.
Abbreviation:t 1/2αDistribution half-life;t 1/2βRemove half-life period; AUC0-24h Indicate drug profile in 0 to 24 hours
Lower area;The MRT residence time;CL total body clearance.
Claims (10)
1. a kind of lycobetaine organic-acid complex liposome, it is characterised in that by lycobetaine and contain eight carbon atoms
Compound that above organic acid is formed, surfactant are made, wherein lycobetaine, contain more than eight carbon atoms having
Machine acid, surfactant parts by weight be 1 part of lycobetaine, contain more than eight carbon atoms 1 ~ 10 part of organic acid, surface
2 ~ 20 parts of activating agent；
Wherein, the surfactant is selected from soybean lecithin, egg yolk lecithin, dipalmitoyl lecithin, dioleoyl ovum
Phosphatide, palmityl lysolecithin, myristoyl lysolecithin, stearoyl lysolecithin, two myristoyl lecithin,
1- palmityl -2- oleoyl lecithin, two mustard acyl group lecithin, phosphatidic acid, dipalmitophosphatidic acid, dipalmitoylcholine,
Distearoylcholine, phosphatidyl choline, two nutmeg phosphatidyl cholines, distearoyl phosphatidylcholine, phosphatidylinositols, phosphorus
Acyl ethanol amine, di-mustard acyl phosphatidylethanolamine, two myristoyl phosphatidyl-ethanolamines, distearyl acyl group phosphatidyl second
Hydramine, two palmityl phosphatidylethanolamines, dioleoyl phospholipid acyl ethanol amine, phosphatidylserine, dioleoyl phosphatide
Acyl serine, phosphatidyl glycerol, dioleoylphosphatidylglycerol, yolk phosphatidylglycerol, 1- palmityl -2- oleolyl phosphatidyl
Glycerol, 1,2- palmityl phosphatidyl glycerol, distearoylphosphatidylglycerol, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, PEGylated phosphatide,
Dipalmitoylphosphatidylethanolamine-polyethylene glycol, distearoylphosphatidylethanolamine-polyethylene glycol, distearoylphosphatidyl
Ethanol amine-nitrine polyethylene glycol, two myristoyl phosphatidyl-ethanolamines-polyethylene glycol it is one or more kinds of with cholesterol or
The mixture of cholesterol sodium sulfate.
2. lycobetaine organic-acid complex liposome according to claim 1, which is characterized in that with parts by weight
Agent, 1 part of lycobetaine, 1 ~ 5 part of organic acid, 5 ~ 18 parts of surfactant.
3. lycobetaine organic-acid complex liposome according to claim 1, it is characterised in that liposomal particle size
For 10-500nm.
4. lycobetaine organic-acid complex liposome according to claim 1 or 2, it is characterised in that described to contain eight
Organic acid more than a carbon atom is selected from oleic acid, linoleic acid, linolenic acid, stearic acid, palmitic acid, retinotic acid, octanoic acid, gallbladder
Acid, deoxycholic acid, ox deoxycholic aicd, chenodeoxycholic acid, hyodesoxycholic acid, ursodesoxycholic acid, shellfish cholic acid difficult to understand, glycocholic acid, ox
One of jaundice acid, lithocholic acid or a variety of mixtures.
5. lycobetaine organic-acid complex liposome according to claim 1 or 2, it is characterised in that the surface is living
Property agent be selected from soybean lecithin, cholesterol and DSPE-PEG2000 mixture.
6. a kind of method for preparing lycobetaine organic-acid complex liposome of any of claims 1 or 2, it is characterised in that
Include the following steps:
(1) it takes the pharmaceutically acceptable salt of lycobetaine soluble in water, first uses in alkaline matter and after corresponding acid, with
Containing organic acid mixing more than eight carbon atoms, lycobetaine organic-acid complex is formed；
(2) freeze-drying step (1) obtains lycobetaine organic-acid complex, then above-mentioned multiple with organic solvent appropriate dissolution
Object is closed, solution I is obtained；
(3) it according to the dissolution characteristics of surfactant, is dissolved with organic solvent, obtains solution II；
(4) solution I and solution II are uniformly mixed, are evaporated under reduced pressure and remove organic solvent；
(5) again by its it is mixed with water after, film aquation obtains suspension；
(6) suspension described in step (5) is homogenized and lycobetaine oleic acid composite liposome body is made.
7. the method according to claim 6 for preparing lycobetaine organic-acid complex liposome, it is characterised in that:
Alkaline matter in step (1) is sodium bicarbonate, for obtaining drug molecule form free alkali；It is described to contain eight carbon originals
More than son organic acid is oleic acid, and in the alkaline matter and the time of corresponding acid is 5 minutes, the oleic acid with aoxidize short-tube lycoris
The incorporation time of alkali is 30 minutes；
Organic solvent in step (2) is methylene chloride；
Using the pressure limit preparation of 5000 ~ 15000 psi within high pressure dispersing emulsification machine in step (6).
8. lycobetaine organic-acid complex liposome described in claim 1 is in the drug that preparation inhibits tumour growth
Using.
9. lycobetaine organic-acid complex liposome described in claim 1 answering in the drug of preparation treatment tumour
With.
10. the PEGylated derivative of lycobetaine organic-acid complex liposome described in claim 1.
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| US20140227342A1 (en) * | 2013-02-08 | 2014-08-14 | Michael Farber | Acetylcholinesterase inhibitor composition for sexual use |
| CN105294831A (en) * | 2015-10-10 | 2016-02-03 | 四川大学 | Tumor-targeting novel polypeptide |
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| US20140227342A1 (en) * | 2013-02-08 | 2014-08-14 | Michael Farber | Acetylcholinesterase inhibitor composition for sexual use |
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