CN108403639A - A kind of sugar-modified Curcumol liposome of gala and preparation method thereof - Google Patents
A kind of sugar-modified Curcumol liposome of gala and preparation method thereof Download PDFInfo
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- CN108403639A CN108403639A CN201810372741.0A CN201810372741A CN108403639A CN 108403639 A CN108403639 A CN 108403639A CN 201810372741 A CN201810372741 A CN 201810372741A CN 108403639 A CN108403639 A CN 108403639A
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- liposome
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- A—HUMAN NECESSITIES
- 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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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses a kind of sugar-modified Curcumol liposomes of gala, the sugar-modified Curcumol liposome of gala is by rcumenol, carrier material, olein and galactolipin stearate composition, galactolipin stearate is as galactolipin trim, using rcumenol as inclusion compound.Meanwhile the invention discloses the preparation methods of lactose stearate.The present invention reduces dosage of surfactant, reduces the adverse reaction of drug;The liver enriching quantity for improving drug, improves the anti-liver cancer efficacy of drug;Galactolipin trim is prepared using enzymatic, there is the characteristics of efficient, to be suitble to industrialization production.Rcumenol is developed into galactolipin modified liposome by the present invention, so that it is largely enriched in liver to the gap that improves curative effect, greatly shorten itself and modern antineoplastic chemotherapy medicine, can be provided new Research idea for the research of rcumenol Liver targeting preparation.
Description
Technical field
The present invention relates to pharmaceutical preparation preparing technical fields, more particularly, to a kind of sugar-modified rcumenol lipid of gala
Body and preparation method thereof.
Background technology
Rcumenol is one of important composition composition in Curcuma Aromatic Oil.With anti-liver cancer and anti-, protection liver, anti-inflammatory, antibacterial etc.
Multiple pharmacological effect has the characteristics that toxicity is low and does not cause leukocyte count to reduce compared with traditional chemical drug, in recent years its
Application in liver cancer treatment is increasingly paid attention to.It Yue Wei and pays and big et al. has studied curcuma zedoary Radix Astragali ultrafiltration membrane extract to liver cancer
As a result the apoptosis-induced effect of HepG2 cells prompts the extract to have apparent inhibition to the growth of HepG2 cell lines
Effect, inhibiting effect manifest the positive correlation of work property with dosage and time;Tang Yuan and Li Xiaohui has studied Rhizoma Curcumae extract Cur to liver cancer
The anticancer mechanism of HepG2 cells, the results showed that Rhizoma Curcumae extract can obviously inhibit the growth of HepG2 cells, and induce its apoptosis,
Its mechanism may be by inhibiting HepG2 cell COX-2 and VEGF gene expressions and realizing.However the anti-liver cancer and anti-of rcumenol is made
With the effect with conventional anti-liver cancer and anti-chemotherapeutics such as fluorouracil compared to there are still a certain distance.And rcumenol is insoluble in
Water, therefore common mode administration bioavilability is low, inevitably using the solubilizer with certain toxicity, these disadvantages are given
The clinical application of rcumenol brings certain difficulty.In recent years, many scholars to a variety of dosage forms of rcumenol grind extensively
Study carefully.Xiaoli Zhang and Wu Pinchang et al. have studied the prescription and technique that alcohol injection prepares Curcumol liposome;Cheng Nana and land
Rabbit woods et al. prepares Zedoary Turmeric Oil Liposome using composite phospholipid liposome technology and studies its best preparation process and prescription;Liu Yu
And using alcohol injection large unilamellar vesicle is made in rcumenol by Xiao Han et al..
Galactosylated acceptor is present in mammalian liver parenchyma towards on the cell membrane of sinusoid side, also known as goes saliva
Liquid acid glycoprotein receptor(Asialoglyco protein receptor, ASGPR), it is one of expressed in abundance on liver plasma membrane
Kind endocytosis receptor.ASGPR contains two types subunit H1And H2, H1It is the major subunits that ASGPR is functioned, can identifies end
Sugar chain of the end with galactose residue or N- acetyl galactose amidos, and can specifically bind therewith, cause receptoe mediated endocytosis
Effect, can carry it in liver cell by lysosomal degradation.The spy of heterologous compound can be selectively swallowed using ASGPR
Property, using this receptor as target spot, it is sugar-modified or be wrapped in by the sugar-modified liposome of gala and then special that drug can be carried out to gala
The opposite sex imports liver cell therapy liver cancer, the diseases such as hepatitis and hepatic sclerosis.The result of study of Luo Yan et al. is shown with glycosyl galactose courage
Sterol (- 3 β of 5- cholestene-oxygroup) 4- oxos -4- [2- lactose amide bases ethylamino] butyrate(CHS-ED-LA)It is auxiliary to target
Expect that the galactolipin modified liposome prepared can be selectively targeted in HepG2 cells, and grain size increases or addition PEG can be reduced
The targeting of liposome;Wu Wei et al. has studied the polyene taxol liposome after galactolipin is ligand modified(Gal-DOC-L)
Tissue distribution in Mice Body, drug has certain targeting effect after liposomal encapsulated to liver, and liposome passes through
The modification for crossing galactolipin ligand further enhances the targeting of its double of Lactose-modified Curcumol liposome.
However it is not reported using the liver active targeting liposome of the sugar-modified rcumenol of gala.
Invention content
The purpose of the invention is to high, the Small side effects that overcome the deficiencies of the prior art and provide a kind of bioavilability, and
The sugar-modified Curcumol liposome of gala of active targeting liver.
The first purpose of the invention is to provide a kind of sugar-modified Curcumol liposomes of gala.
Second object of the present invention is to provide a kind of preparation method of the sugar-modified Curcumol liposome of gala.
Third object of the present invention is to provide the preparation methods of the sugar-modified Curcumol liposome of the gala to be prepared
The sugar-modified Curcumol liposome of gala.
Fourth object of the present invention is to provide the sugar-modified Curcumol liposome of the gala in the medicine for preparing targeting liver
Application in object.
To achieve the goals above, the present invention is achieved by the following technical programs:
A kind of sugar-modified Curcumol liposome of gala, by rcumenol, carrier material, olein and galactolipin stearic acid
Ester forms, and galactolipin stearate is as galactolipin trim, using rcumenol as inclusion compound.
The preparation method of the sugar-modified Curcumol liposome of gala, includes the following steps:
S1. carrier material, galactolipin stearate, olein and rcumenol bulk pharmaceutical chemicals are dissolved in ether and are obtained
To total fat-soluble system;
S2. add account for total volume 25% phosphate buffer it is slow, and ultrasonication, to formation colostrum;
S3. colostrum is injected in tween-phosphate buffer, while homogenization, until removing all ether;
S4. the product of S3 is pressed through miillpore filter to get uniform liposome.
Preferably, in step S1, a concentration of 4 gL-1 of rcumenol in preparation system.
Preferably, in step S1, a concentration of 1gL-1 of olein in preparation system.
Preferably, in step S2, the volume of ether is prepare total volume 25~40%.
It is highly preferred that in step S1, the volume of ether is prepare total volume 40%.
Preferably, in step S1, the mass ratio of galactolipin stearate and carrier material is 15~25%.
It is highly preferred that in step S1, the mass ratio of galactolipin stearate and carrier material is 20%.
Preferably, in step S1, the mass ratio of rcumenol and carrier material is 1:1.5~2.5.
It is highly preferred that in step S1, the mass ratio of rcumenol and carrier material is 1:2.
Preferably, in step S1, the carrier material is the mixture of phosphatide, cholesterol.
Preferably, in step S1, the phosphatide is egg yolk lecithin.
Preferably, in step S1, the mass ratio of phosphatide and cholesterol is 1.5~2.5:1.
It is highly preferred that in step S1, the mass ratio of phosphatide and cholesterol is 2:1.
Preferably, in step S2, the pH value of the phosphate buffer is 5.8~8.0.
It is highly preferred that in step S2, the pH value of the phosphate buffer is 6.5.
Preferably, in step S2, the ultrasonication, 100 W of ultrasonic power.
Preferably, in step S2, the ultrasonication, ultrasonic time is no less than 15 min.
It is highly preferred that in step S2, the ultrasonication, ultrasonic time is 15 min.
Preferably, in step S3, the tween is Tween 80.
Preferably, in step S3, a concentration of 1.6 g L-1 of tween in the tween-phosphate buffer, pH be 5.8~
8.0。
Preferably, in step S3,20 min of homogenization homogenizing time.
Preferably, in step S4, be pressed through successively each 3 times of 0.45,0.22 μm of miillpore filter uniform liposome.
Most preferably, the preparation method of the sugar-modified Curcumol liposome of the gala, includes the following steps:
S1. carrier material, galactolipin stearate, olein and rcumenol bulk pharmaceutical chemicals are dissolved in ether and are obtained
To total preparation system, wherein a concentration of 4 gL of rcumenol in preparation system-1, olein is dense in preparation system
Degree is 1gL-1, the volume of ether is prepare total volume 40%, and the mass ratio of galactolipin stearate and carrier material is 20%,
The mass ratio of rcumenol and carrier material is 1:2, carrier material is phosphatide and cholesterol, mass ratio 2:1;
S2. add that account for the phosphate buffer that the pH value of total volume 25% is 6.5 slow, while ultrasonication, ultrasonic wave work(
100 W of rate, sonication times are 15 min, until forming colostrum;
S3. colostrum is injected in Tween 80-phosphate buffer, while homogenization, until removing all ether, wherein tween
A concentration of 1.6 g L-1, the pH of phosphate buffer is 6.5,20 min of homogenizing time;
S4. by the product of S3 be pressed through successively each 3 times of 0.45,0.22 μm of miillpore filter uniform liposome to get equal
Even liposome.
The sugar-modified Curcumol liposome of gala that the preparation method of the sugar-modified Curcumol liposome of gala is prepared,
Also belong to protection scope of the present invention.
Application of the above-described sugar-modified Curcumol liposome of gala in the drug for preparing targeting liver, also belongs to this
The protection domain of invention.
Compared with prior art, the present invention has the advantages that:
(1)Dosage of surfactant is reduced, the adverse reaction of drug is reduced.(2)The liver enriching quantity of drug is improved, drug is improved
Anti-liver cancer efficacy.
Rcumenol is developed into galactolipin modified liposome by the present invention, so that it is largely enriched in liver to improve curative effect,
The gap of itself and modern antineoplastic chemotherapy medicine is greatly shortened, new research and development can be provided for the research of rcumenol Liver targeting preparation and thought
Road.
Description of the drawings
Fig. 1 is the thin-layer chromatogram of the reaction mixture of stearate containing galactolipin;Wherein 1 is stearic acid vinyl ester;2 are
By-product;3 be target product, and solvent is:Hexamethylene:Ethyl acetate:Methanol=6:3:2.
Specific implementation mode
The present invention is made with specific embodiment with reference to the accompanying drawings of the specification and further being elaborated, the embodiment
It is served only for explaining the present invention, be not intended to limit the scope of the present invention.Test method used in following embodiments is such as without spy
Different explanation, is conventional method;Used material, reagent etc., unless otherwise specified, for the reagent commercially obtained
And material.
The preparation of the sugar-modified Curcumol liposome of 1 gala of embodiment
S1. it is 0.27 by mass ratio:2:7 D- galactolipins, stearic acid vinyl ester, the mixing of 4A type molecular sieves are placed in round-bottomed flask,
Tetrahydrofuran is added, and the round-bottomed flask is placed in constant temperature oscillator, 45 DEG C, 180 rpm, shakes 24 hours and removes reactant
Moisture;
S2. addition 435 immobilized lipase enzyme powders of Novozym in product one step up, constant temperature oscillator, 45 DEG C, 180
Rpm, concussion are sufficiently mixed to get the reaction mixture of stearate containing galactolipin for 24 hours;
S3. anti-galactolipin stearate reaction mixture is placed in centrifuge tube centrifugation, takes supernatant, THF is used in combination to wash 4A molecules
3 times, 2500 rpm, the 15 min centrifugations of sieve and enzyme powder, merge supernatant;
S4. silica white is added to supernatant, and rotary evaporation removes tetrahydrofuran;
S5. it is 1 to use volume ratio:The silica white of 1 carbon tetrachloride-petroleum ether adsorbed product(Column chromatography silica gel powder 200~
300 mesh), 2500 rpm, 15 min centrifugation, and liquid is discarded supernatant, it is repeated several times, until the stearic acid second in adsorbed product silica white
Enester is washed clean(Thin-layer chromatography detects);
S6. by silicagel column on the silica white of the adsorbed product without stearic acid vinyl ester(80 cm of pillar height, 3 cm of diameter), carry out
Column chromatography for separation collects the eluent containing target product, removes solvent to get galactolipin stearate, wherein column chromatography point
From the step of be:It is 6 first to use volume ratio:3:0.5 hexamethylene, ethyl acetate and methanol elution, thin-layer chromatography detection, until going out
Existing by-product spot;It is 6 to replace volume ratio:3:0.67 hexamethylene, ethyl acetate, methanol elution, thin-layer chromatography detection, until
By-product spot unobvious, it is 6 to replace volume ratio:3:2 petroleum ethers, ethyl acetate, methanol elution, thin-layer chromatography detection, until
There is target product(Galactolipin stearate)Spot.
S7. a certain amount of egg yolk lecithin is weighed according to aforementioned proportion precision(Injection stage), cholesterol(Injection stage), half
Lactose stearate, olein and rcumenol bulk pharmaceutical chemicals, wherein state the egg yolk lecithin of liposome(Injection stage):
Cholesterol(Injection stage)It is 2:1, ether volume is prepare total volume 40%, medicine fat ratio(The matter of rcumenol and phosphatide and cholesterol
Amount ratio)It is 1:2, a concentration of 1 gL of olein-1, the mass ratio of galactolipin stearate and carrier material is
20%.A concentration of 4 gL of rcumenol in liposome-1。
S8. the phosphate buffer of 25 % of total volume will be accounted for(pH=6.5)It is slowly injected into ether mixed liquor, while ice water
Bath ultrasound, injection, which finishes, continues 15 min of ultrasound,(100 W of ultrasonic power)Form colostrum.
S9. above-mentioned colostrum is slowly injected in Tween 80-PBS solution, while homogenization, injection finishes continuation homogeneous
A concentration of 1.6 g L of 20 min, wherein tween-1, the pH of phosphate buffer is 6.5.
S10. the product after homogeneous 0.45,0.22 μm of miillpore filter is pressed through successively to repair to get galactolipin for each 3 times
Adorn Curcumol liposome.
Fig. 1 is the thin-layer chromatogram of the reaction mixture of stearate containing galactolipin.Wherein 1 is stearic acid vinyl ester;2 are
By-product;3 be target product, and solvent is:Hexamethylene:Ethyl acetate:Methanol=6:3:2.
Claims (10)
1. a kind of sugar-modified Curcumol liposome of gala, which is characterized in that by rcumenol, carrier material, olein with
And galactolipin stearate composition, galactolipin stearate is as galactolipin trim, using rcumenol as inclusion compound.
2. a kind of preparation method of the sugar-modified Curcumol liposome of gala, which is characterized in that include the following steps:
S1. carrier material, galactolipin stearate, olein and rcumenol bulk pharmaceutical chemicals are dissolved in ether and are obtained
To total fat-soluble system;
S2. add account for total preparation system 25% phosphate buffer it is slow, while ultrasonication, to formation colostrum;
S3. colostrum is injected in tween-phosphate buffer, while homogenization, until removing all ether;
S4. the product of S3 is pressed through miillpore filter to get uniform liposome.
3. preparation method according to claim 2, which is characterized in that in step S1, the mass ratio of rcumenol and carrier material
It is 1:1.5~2.5.
4. preparation method according to claim 2, which is characterized in that in step S1, galactolipin stearate and carrier material
Mass ratio be 15~25%.
5. preparation method according to claim 2, which is characterized in that in step S1, the volume of ether is to prepare total volume
25~40%.
6. preparation method according to claim 2, which is characterized in that in step S1, carrier material be phosphatide and cholesterol,
Its mass ratio is 1.5~2.5:1.
7. preparation method according to claim 2, which is characterized in that the pH value of phosphate buffer described in step S2 is
5.8~8.0.
8. preparation method according to claim 2, which is characterized in that spat in tween-phosphate buffer described in step S3
A concentration of 1.6 g L of temperature-1。
9. the sugar-modified rcumenol of gala that the preparation method of the sugar-modified Curcumol liposome of gala described in claim 2 is prepared
Liposome.
10. application of the sugar-modified Curcumol liposome of the gala of claim 1 or 9 in the drug for preparing targeting liver.
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Citations (1)
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CN101569606A (en) * | 2009-06-09 | 2009-11-04 | 沈阳药科大学 | Curcumol liposome and preparation method thereof |
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CN101569606A (en) * | 2009-06-09 | 2009-11-04 | 沈阳药科大学 | Curcumol liposome and preparation method thereof |
Non-Patent Citations (1)
Title |
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李文杰: "莪术醇肝靶向脂质体的制备及其抗肿瘤研究", 《万方数据知识服务平台》 * |
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