CN109549926A - A kind of preparation method of pH sensitive liposome - Google Patents
A kind of preparation method of pH sensitive liposome Download PDFInfo
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- CN109549926A CN109549926A CN201811550654.6A CN201811550654A CN109549926A CN 109549926 A CN109549926 A CN 109549926A CN 201811550654 A CN201811550654 A CN 201811550654A CN 109549926 A CN109549926 A CN 109549926A
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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
- A61K9/1277—Processes for preparing; Proliposomes
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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
- A61K31/12—Ketones
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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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The present invention relates to a kind of preparation methods of pH sensitive liposome, belong to pharmaceutical field, the preparation method comprises the following steps: weighing lecithin, cholesterol and Fmoc-His first in glass container, ethyl alcohol dissolution is added into glass container, obtains mixed liquor;Then curcumin ethanol solution is added into mixed liquor, mixes, is evaporated under reduced pressure and removes organic solvent to dry film forming;Then phosphate buffered saline solution dissolution is added, ultrasonic 3-5 min is mixed them thoroughly, and obtains yellow turbid solution, as pH sensitive liposome after mixing.There is pH sensibility by liposome prepared by this method, while solving the problems, such as that fat-soluble medicine is not readily dissolved in water, while can also reduce the toxicity of encapsulated drug.
Description
Technical field
The invention belongs to pharmaceutical fields, and in particular, to a kind of preparation method of pH sensitive liposome.
Background technique
Liposome refers to drug encapsulation in the miniature vesicular body formed in lipoids bilayer.Because it has targeting
The features such as property, stability, slow-release and hypotoxicity and play an important role in drug delivery system.Tumor region has
The special microenvironment compared with normal tissue, if pH is relatively low, temperature drift (pH < 6.0, about 39-42 DEG C) and part enzyme are excessive
The features such as expression, causes the drug release in liposome limited, it is difficult to play the therapeutic effect of drug.PH sensitive liposome structure
In the stability of lipid bilayer change with environment pH and change, while acid-sensitive polymer liposome can also be called.It can not only
Enough improve the targeting of liposome, additionally it is possible to promote the expression of drug effect given full play to and improve gene.
Curcumin (CUR) is a kind of phenolic compound extracted from zingiberaceous plant turmeric, is the main work of Turmeric
Property ingredient.Studies have shown that CUR is a kind of safely and effectively with the drug of a variety of effects such as anticancer, anti-inflammatory, anti-oxidant, wherein
Curcumin all has inhibiting effect to the generation of kinds of tumor cells, proliferation, transfer for preventing and treating tumour.But
CUR is not soluble in water, and aqueous solution is unstable under neutrality to alkaline pH, stores three days at 4 DEG C of aqueous solution, external anticancer
Activity is decreased obviously.Therefore, for this fat-soluble therapeutic agent, how the excellent pH sensitive liposome of processability is antitumor
The key issues of research field.
Summary of the invention
For above situation, the purpose of the present invention is to provide a kind of preparation methods of pH sensitive liposome.Pass through the party
The liposome of method preparation has pH sensibility, while solving the problems, such as that fat-soluble medicine is not readily dissolved in water, improves biological utilisation
Degree, while can also reduce the toxicity of encapsulated drug.
To achieve the goals above, the present invention use the specific scheme is that
A kind of preparation method of pH sensitive liposome, comprising the following steps:
Step 1: weighing lecithin, cholesterol and Fmoc-His in glass container, ethyl alcohol dissolution is added into glass container,
Obtain mixed liquor;
Step 2: curcumin ethanol solution is added into mixed liquor, mix, is evaporated under reduced pressure and removes organic solvent to doing into
Film;Then phosphate buffered saline solution dissolution is added, ultrasonic 3-5min is mixed them thoroughly, and it is molten to obtain yellow muddiness after mixing
Liquid, as pH sensitive liposome.
It is advanced optimized as to above scheme, it is molten using ultrasonic wave added in the ethyl alcohol course of dissolution described in step 1
Solution.
It is advanced optimized as to above scheme, the frequency of the ultrasound is 30KHZ, and temperature is 30 DEG C, and the time is
5min。
It is advanced optimized as to above scheme, the content of curcumin is in CUR ethanol solution described in step 2
0.05~0.15mg.
It is advanced optimized as to above scheme, the relative pressure of reduction vaporization described in step 2 is -0.01MPa, temperature
Degree is 35-50 DEG C.
It is advanced optimized as to above scheme, lecithin described in step 1 is soybean lecithin.
It is advanced optimized as to above scheme, the mass ratio of lecithin and cholesterol is 3:1~8:1;Fmoc-His
Content be 3.5~12.5mg;Turmeric cellulose content is 0.1~0.3mg;The additional amount of phosphate buffered saline solution is 15~30mL.
As the further optimization to above scheme, the quality of the lecithin is 0.08g, and the quality of cholesterol is
0.01g;The content of Fmoc-His is 12.5mg;The content of curcumin is 0.1mg;The additional amount of phosphate buffered saline solution is
30mL。
It is advanced optimized as to above scheme, the pH of the phosphate buffered saline solution is 7.4.
The utility model has the advantages that
1, the liposome of the pH responsive type of the method preparation, the pH sensibility of liposome pass through insertion rouge through the invention
The protonation of Fmoc-His in plastid is realized.Due to tumour cell environment slant acidity, and the imidazole radicals in Fmoc-His exists
It is protonated in the environment of pH < 6.0, Fmoc-His shape is caused to change, finally affect the structure change of liposome, then
Drug can be released from liposome bilayers.
2, the method for the invention, the pH sensitive liposome of preparation encapsulate curcumin, play safely and effectively anticancer, anti-inflammatory
With it is anti-oxidant and other effects, using liposome technology, solve the problems, such as that fat-soluble medicine is not readily dissolved in water, while can also reduce and be wrapped
Seal the toxicity of drug.Last liposomal particle size obtained is evenly distributed, and has the characteristics that apparent pH sensitivity drug release;Liposome compares
Stablize, is not susceptible to leak.The liposome of preparation has biggish application prospect as pharmaceutical carrier.
Detailed description of the invention
Fig. 1 is the structural formula figure of Fmoc-His;
Fig. 2 is the grain size distribution of pH sensitive liposome;
Fig. 3 is Fmoc-His when being 12.5mg pH is sensitive and conventional liposome Release Performance figure;
Fig. 4 is cytotoxicity comparison diagram of the conventional liposome of various concentration with pH sensitive liposome to C6 cell.
Specific embodiment
Below in conjunction with the embodiment of the present invention and its attached drawing, technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description.
Embodiment 1
1, experimental procedure
Prepare liposome using film dispersion method: precision weighs lecithin, cholesterol and Fmoc-His in right amount in 500mL's
In round-bottomed flask, ethyl alcohol 10mL dissolution (dissolving using ultrasonic wave added) is added, the CUR ethanol solution for adding 1mL is appropriate,
It mixing, the phosphate buffered saline solution (PBS) that suitable pH is 7.4 is added in 45 DEG C of reduction vaporization removing organic solvents to dry film forming,
Then ultrasound 3-5min, mixes them thoroughly, and obtains yellow turbid solution after mixing.
The frequency of the ultrasound is 30KHZ, and temperature is 30 DEG C;The relative pressure of the reduction vaporization is -0.01MPa, phase
When being 0 in absolute pressure, carry out under vacuum conditions, temperature is 35-50 DEG C, preferably 45 DEG C.
The concentration of CUR is 0.05~0.15mg/mL in the CUR ethanol solution;The lecithin is preferably soybean
Lecithin.
2, the optimum material proportion of liposome preparation is studied
Optimum proportioning is found using orthogonal test, it is final to determine most using the encapsulation rate of liposome as the index investigated
Excellent prescription.The test method of reasonable arrangement and analysis many factors, has finally chosen three principal elements and is analyzed, is i.e. lecithin
Rouge and cholesterol ratio A, curcumin dosage are B, PBS dosage C, and each factor determines three levels, and each number of levels of A factor is successively
For 3:1,5:1,8:1;Each number of levels of B factor is followed successively by 0.1,0.2,0.3;Each number of levels of C factor is followed successively by 15,20,30,
L9 (33) orthogonal array is selected, as a result as shown in table 1 below.
1 Orthogonal Experiment and Design of table optimizes liposome prescription and the experimental design and result of preparation process
Measurement result: with the increase of the ratio of lecithin and cholesterol, encapsulation rate increases;That is the optimal level of ratio is
8:1.With the increase of turmeric cellulose content, encapsulation rate reduces;When the content of curcumin is 0.1mg, encapsulation rate is maximum, i.e. turmeric
The optimal level of cellulose content is 0.1mg.With the increase of PBS dosage, encapsulation rate increases;I.e. the optimal level of PBS is 30mL.Institute
To show that optimal level group is combined into A3 B1 C3, i.e. lecithin and cholesterol ratio is 8:1, wherein lecithin 0.08g, cholesterol
0.01g;Turmeric cellulose content is 0.1mg;PBS dosage 30mL.
3, formulation optimization
The optimum combination that conventional liposome is determined through above-mentioned orthogonal test is A3 B1 C3.PH sensitive liposome is influenced at this time
The principal element of encapsulation rate is that the content of Fmoc-His is added.
By aforementioned preparation process, only change Fmoc-His throwing amount, remaining operation is identical, prepares the liposome of 3 parts of pH sensitivities
Solution.It using encapsulation rate as inspection target, investigates 3.5mg is added respectively, the Fmoc-His of 7.5mg, 12.5mg form liposome
Encapsulation rate, the results are shown in Table 2:
The encapsulation rate of 2 different content Fmoc-His liposome of table is investigated
Measurement result: with the increase of the dosage of Fmoc-His, encapsulation rate amplitude of variation is little, but stability obviously increases
By force, and respectively it is that 7.5mg and 12.5mg carries out tablets in vitro observation pH sensibility to Fmoc-His content, comprehensively considers and determine most
Good prescription are as follows: lecithin is 8:1 with cholesterol ratio, and curcumin concentration is 0.1mg, PBS dosage 30mL, Fmoc-His content
12.5mg。
4, the particle diameter distribution of pH sensitive liposome
At 25 DEG C, proper amount of fresh is prepared after resulting liposome turbid liquor dilutes ten times with secondary distilled water through dynamic
Light scatter luminosity survey instrument ZETA-SIZERN anoSeriesNano-ZSZEN3600 (MalvernInstrumentsLtd, UK) into
Row measurement, measurement is repeated 3 times every time.As a result as shown in Figure 2.Measurement result are as follows: average grain diameter is the 89.99nm (coefficient of dispersion
PDI is that 0.413), particle diameter distribution is uniform.
5, tablets in vitro is tested
Precision draws two parts of separated each 1mL of Fmoc-His liposome, is respectively charged into the bag filter handled well,
Both ends tighten closing.In then beaker that bag filter is invaded to the 10mL PBS buffer solution equipped with pH7.4 and 5.0 respectively.It burns
Cup is sealed with preservative film, in order to avoid evaporating, with 100rpm magnetic agitation in 37 DEG C of water-baths, is spaced, is taken at regular intervals
10mL in dissolution medium, while the fresh PBS buffer solution of 10mL is added.With fluorescent spectrophotometer measuring F value, then calculate each time
The cumulative release total amount of point curcumin.
According to above-mentioned method, conventional liposome equally does the extracorporeal releasing experiment that dialysis medium is pH7.4 and 5.0.Knot
Fruit is as shown in Figure 3.From the figure 3, it may be seen that the Fmoc-His liposome release curcumin of 12.5mg is added compared with conventional liposome
The significant pH sensibility having, i.e., in the environment that pH is apparently higher than pH7.4 for rate of release and percentage in 5.0 PBS, especially
, in 30h, the two Cumulative release amount reaches maximum for it, 110h Cumulative release amount close to equal.It is last total
When Fmoc-His content is 12.5mg known to knot, the drug release of pH sensitivity is more obvious.
6, stability experiment
At 4 DEG C, different several imidazoles liposome turbid liquors standings will be formed and be kept in dark place, and respectively at the 0th, 2,
The corresponding encapsulation rate of these types liposomal samples liquid of measurement in 5,7 days.Using percolation ratio as metrics evaluation stability.As a result such as 3 institute of table
Show:
Table 3: permeability is investigated
Measurement result: under identical experiment condition, conventional liposome permeability is big, then Fmoc-His liposome is more steady
Determine, not easy to leak.
7, the in vitro toxicity test of liposome
Non- drug-loaded liposome selects C6 cell to carry out in vitro toxicity test by mtt assay..C6 cell is by 6000/hole
Concentration kind is in 96 orifice plates.After DMEM (200 hole the μ L/) culture for 24 hours containing 10%FBS, 200 μ L of change contain certain concentration
The fresh culture of liposome continues to cultivate 48h.Portalled after middle solution with 200 μ L fresh culture mediums, 20 μ are added to every hole
L MTT solution (5mg/mL) cultivates 4h.Culture medium is removed, and 150 μ L DMSO are added in each hole.At 570nm, through enzyme
Mark instrument (Bio-Rad, Model 550, USA) measurement absorbance value (OD).Versus cell activity is calculated by following formula: cell is living
Property (%)=[OD570 (sample)/OD570 (control)] × 100.Wherein, OD570 (control) indicates to be free of the measurement of liposome
Value, and OD570 (sample) indicates the measured value containing liposome.As a result as shown in Figure 4.As a result known to: when the concentration of liposome
When reaching 200 μ g/mL, the relative survival rate of C6 cell shows the materials lecithin for preparing liposome and gallbladder all 80% or more
Sterol and the pH sensitive material imidazoles of addition for cell, toxicity be it is very small, can ignore substantially, meet pharmaceutical carrier
The requirement of low toxicity, can be used as pharmaceutical carrier.
The above content is interpreted as illustrative, to be not intended to limit the present invention protection scope.Protection scope of the present invention with
It is to those skilled in the art, right under the premise of without departing substantially from spirit and scope of the present invention subject to the content of claims
Some nonessential modifications and adaptations that the present invention makes still fall within protection scope of the present invention.
Claims (9)
1. a kind of preparation method of pH sensitive liposome, it is characterised in that: the following steps are included:
Step 1: weighing lecithin, cholesterol and Fmoc-His in glass container, ethyl alcohol dissolution is added into glass container,
Obtain mixed liquor;
Step 2: curcumin ethanol solution is added into mixed liquor, mix, is evaporated under reduced pressure and removes organic solvent to doing into
Film;Then phosphate buffered saline solution dissolution is added, ultrasonic 3-5 min is mixed them thoroughly, and obtains yellow muddiness after mixing
Solution, as pH sensitive liposome.
2. a kind of preparation method of pH sensitive liposome as described in claim 1, it is characterised in that: the ethyl alcohol described in step 1
In course of dissolution, dissolved using ultrasonic wave added.
3. a kind of preparation method of pH sensitive liposome as claimed in claim 2, it is characterised in that: the frequency of the ultrasound is
30KHZ, temperature are 30 DEG C, time 5min.
4. a kind of preparation method of pH sensitive liposome as described in claim 1, it is characterised in that: CUR described in step 2 without
The content of curcumin is 0.05 ~ 0.15 mg in hydrous ethanol solution.
5. a kind of preparation method of pH sensitive liposome as described in claim 1, it is characterised in that: depressurize and steam described in step 2
The relative pressure of hair is -0.01MPa, and temperature is 35-50 DEG C.
6. a kind of preparation method of pH sensitive liposome as described in claim 1, it is characterised in that: lecithin described in step 1
For soybean lecithin.
7. a kind of preparation method of pH sensitive liposome as described in claim 1, it is characterised in that: lecithin and cholesterol
Mass ratio is 3:1 ~ 8:1;The content of Fmoc-His is 3.5 ~ 12.5mg;Turmeric cellulose content is 0.1 ~ 0.3mg;Phosphate-buffered salt is molten
The additional amount of liquid is 15 ~ 30mL.
8. a kind of preparation method of pH sensitive liposome as claimed in claim 7, it is characterised in that: the quality of the lecithin
For 0.08g, the quality of cholesterol is 0.01g;The content of Fmoc-His is 12.5mg;The content of curcumin is 0.1mg;Phosphoric acid is slow
The additional amount for rushing salting liquid is 30mL.
9. a kind of preparation method of pH sensitive liposome as claimed in claim 1 or 7, it is characterised in that: the phosphoric acid buffer
The pH of salting liquid is 7.4.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114532535A (en) * | 2022-01-05 | 2022-05-27 | 齐鲁工业大学 | Preparation method of curcumin nano-liposome |
CN114652682A (en) * | 2022-03-07 | 2022-06-24 | 河南省医药科学研究院 | New houttuynin sodium and cisplatin co-loading acidic sensitive liposome preparation and preparation method thereof |
Citations (2)
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US20050070721A1 (en) * | 2002-05-19 | 2005-03-31 | University Of Utah Research Foundation | PH-sensitive polymeric micelles for drug delivery |
CN103599069A (en) * | 2013-11-06 | 2014-02-26 | 四川大学 | Targeted lipidosome decorated by pH sensitive polypeptide |
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2018
- 2018-12-18 CN CN201811550654.6A patent/CN109549926A/en active Pending
Patent Citations (2)
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US20050070721A1 (en) * | 2002-05-19 | 2005-03-31 | University Of Utah Research Foundation | PH-sensitive polymeric micelles for drug delivery |
CN103599069A (en) * | 2013-11-06 | 2014-02-26 | 四川大学 | Targeted lipidosome decorated by pH sensitive polypeptide |
Non-Patent Citations (2)
Title |
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JU L,ET AL: "Preparation and properties evaluation of a novel pH-sensitive liposomes based on imidazole-modified cholesterol derivatives", 《INT J PHARM》 * |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114532535A (en) * | 2022-01-05 | 2022-05-27 | 齐鲁工业大学 | Preparation method of curcumin nano-liposome |
CN114652682A (en) * | 2022-03-07 | 2022-06-24 | 河南省医药科学研究院 | New houttuynin sodium and cisplatin co-loading acidic sensitive liposome preparation and preparation method thereof |
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