CN105796497A - Preparation method of coix seed oil temperature-sensitive lipidosome with high storage stability - Google Patents
Preparation method of coix seed oil temperature-sensitive lipidosome with high storage stability Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
The invention provides a preparation method of coix seed oil temperature-sensitive lipidosome with high storage stability. The method comprises the following steps: dissolving DPPC, cholesterol, lycopene and coix seed oil into absolute ether, and then preparing the coix seed oil temperature-sensitive lipidosome through the processes of injection, hydration, low-temperature ultrahigh pressure closed crushing and the like. The preparation conditions are mild; the problem of thermosensitive liposome inactivation caused by over-high temperature in the homogenization process can be effectively solved, so that the chemical stability and the physical uniformity of the thermosensitive liposome are improved. On this basis, a proper amount of lycopene is added to an embedded substance; oxidation of the DPPC and the coix seed oil can be effectively delayed; and the storage stability of the liposome is improved. The phase-transition temperature of the prepared temperature-sensitive lipidosome is 42+/-0.5 DEG C; the average particle size is 70-130nm; the embedding rate is 83%+/-3.8%; the sample is free of aggregation or stratification phenomenon after being stored for 18 months; and the leakage rate of the coix seed oil is smaller than 9%.
Description
Technical field
The present invention relates to medicine controlled releasing technical field, further to the preparation of thermal sensitive liposome, be specifically related to one
Kind there is high storage-stable, thermal sensitive liposome preparation method with Semen Coicis oil as effective ingredient.
Background technology
Medicine controlled releasing technology refers to control medicine released strip in vivo by modes such as dosage form improvement, chemical modifications
Part and rate of release, thus stabilised blood concentration or the realization targeted delivery of drugs to certain organs, for extending drug effect,
Promote medicine specific aim and there is vital effect.The controlled-release function of prior art Chinese medicine mainly passes through tripartite
Face means realize: 1, activating solvent controlled drug delivery systems；Medicine is typically dissolved or is dispersed in polymer
In carrier, medicine indiffusion during beginning, and when, after solvent penetration to polymer, polymer starts swelling, high
Strand relaxes, and medicine just spreads out from polymer support, therefore can be according to the solvent environment residing for medicine
Control its emission levels.2, Chemical Control drug delivery system；Medicine is tied with macromolecule carrier by chemical bond
Closing, gained complex does not have pharmaceutically active, and chemical bond can be interrupted by hydrolysis or mode of action in vivo,
Thus discharge active medicine, therefore can control its emission levels according to the chemical reaction condition residing for medicine.3、
Diffusion controlled drug delivery systems；Pharmaceutical pack is embedded in polymer support, reduces its release by embedding effect
Speed, thus realize medicine and change in constant release.
Thermal sensitive liposome (the most temperature sensitive liposome, lower same) is a kind of targeted drug carrier of rising in recent years,
Belong to a kind of novel form of targeting drug delivery system.Before reaching phase transition temperature, liposome membrane is pycnomorphous
Glue crystalline state, is embedded in hydrophilic medicament therein and is difficult to diffuse out through liposome membrane；When liposome reaches
After phase transition temperature, marshalling, fine and close glue crystalline state phospholipid bilayer become loose chaotic liquid crystal state originally,
The mobility of film and permeability increase, and are embedded in active component therein and discharge rapidly, therefore can be according to temperature
Condition Drug controlled release level.Above-mentioned character based on temperature sensitive liposome, can be by adding the local of target organ
Heat realizes targeted delivery of drugs effect: medicine is concentrated with blood circulation release through heated target organ, active component
Put, and in other organs, tissue, due to not up to phase transition temperature, active component burst size is minimum, thus
Promote the specific aim for the treatment of, reduce toxic and side effects.
Thermal sensitive liposome is many to be dispersed in by amphipathic Thermo-sensitive material and prepares through certain energy input after aqueous phase
Thermodynamic unstable system.In order to reduce system free energy, in preparation link generally by long ultrasonic shake
Swing or repeatedly circulate HIGH PRESSURE TREATMENT to realize the stable, homogeneous of liposomal particle size.Regardless of whether ultrasonic or HIGH PRESSURE TREATMENT
System will be caused to heat up, and this is totally unfavorable for heat sensitive material.DPPC, phosphatidylcholine etc. in addition
Routine is prepared raw material and is easily aoxidized, and produces the harmful substances such as lysophosphatide, is not only harmful to health, and easily causes
Embedded object seepage, produces phenomena impair Liposome and the controlled-release effects such as gathering, layering.
Semen Coicis oil is with grass family (Gramineae) Coix (Coix L.) plant Semen Coicis (Coix
Lachryma-jobi Linn) the oils and fats that extracted by raw material of mature seed kernel.Demonstrate,prove through a large amount of animals and clinical experiment
There is the physiological actions such as lowering blood pressure and blood fat, antiinflammatory, analgesia and there is stronger anti-tumor activity, especially in fact
Hepatocarcinoma, nasopharyngeal carcinoma, breast carcinoma, esophageal carcinoma etc. had preferable curative effect.
But, in Semen Coicis oil, unsaturated fatty acid is more than 70%, easily aoxidizes.Add substantial amounts of antioxidant
Being to ensure that the key of its safe edible, the chemical addition agent that multiple antioxidant activity is stronger, such as TBHQ, BHA
Etc. being commonly used to add in functional grease improve its storage-stable, but it generally has gastrointestinal tract mucous
Zest, some synthetized oxidation preventive agent is even prohibited from using in some countries.Therefore, for realizing Semen Coicis oil
Clinical practice, ensure composition safety on the basis of promote medicine stability be important technology premise.
Summary of the invention
It is contemplated that for the technological deficiency of prior art, it is provided that a kind of high storage-stable Semen Coicis oil is temperature sensitive
The preparation method of liposome, with solve the temperature sensitive method for preparing lipidosome of prior art affect liposome microstructure,
And then affect its technical problem to medicine embedding effect.
Another that the invention solves the problems that technical problem is that the temperature sensitive method for preparing lipidosome of prior art is easily generated poison
Property material.
The temperature sensitive method for preparing lipidosome of the Semen Coicis oil that further technical problem is that prior art that the invention solves the problems that,
The chemical stability of products therefrom is undesirable.
The another cancer that technical problem is that in prior art with Semen Coicis oil as effective ingredient that the invention solves the problems that
Medicine, its anticancer effect has to be hoisted.
For realizing above technical purpose, the present invention by the following technical solutions:
The preparation method of a kind of high temperature sensitive liposome of storage-stable Semen Coicis oil, the raw material of this preparation method includes
First raw material group, described first raw material group is grouped into by the one-tenth of following mass percent: Semen Coicis oil
0.01～3.0%, DPPC 0.05～5.0%, lycopene 0.0001～0.0025%, cholesterol 0.01～1.6%,
Surplus be concentration be the phosphate buffer of 0.02～0.2M/L；
Described preparation method comprises the following steps:
1) take the DPPC of formula ratio, Semen Coicis oil, lycopene and cholesterol, be dissolved in absolute ether,
Wherein DPPC is 1:(150～250 with the amount ratio of absolute ether) (g/mL)；
2) phosphate buffer that concentration is 0.02～0.2M/L of formula ratio is taken, by step 1) gained solution adds
Entering wherein, stirring obtains emulsion；
3) step 2 is taken) gained emulsion, ether is evaporated off, obtains the temperature sensitive liposome turbid liquor of Semen Coicis oil；
4) step 3 is taken) the temperature sensitive liposome turbid liquor of gained Semen Coicis oil, utilize cell crushing instrument to process, behaviour
As pressure be 10000～27000bar, operation temperature less than 20 DEG C, i.e. obtain described high storage-stable Semen Coicis
The quick liposome of core oil temperature.
As preferably, step 2) under described phosphate buffer is in stirring condition by step 1) gained
Solution is added thereto.
As preferably, step 2) described in phosphate buffer be in 34～38 DEG C under the conditions of by step 1) institute
Obtain solution to be added thereto.
As preferably, step 2) described in persistent period of stirring be 20～40min.
As preferably, step 2) described in stir and realized by magnetic stirring apparatus.
As preferably, step 3) in ether utilize vacuum rotation to steam instrument to be evaporated off；The most excellent
Choosing, it is 32～38 DEG C that the bath temperature of instrument is steamed in rotation.
As preferably, step 4) described in cell crushing instrument be low-temperature ultrahigh-pressure cell crushing instrument.
As preferably, step 4) in utilize cell crushing instrument to process number of times be 1 time.
In above technical scheme, the temperature sensitive liposome of described Semen Coicis oil, refer to utilize thermal sensitive liposome to embed the heart of a lotus seed
Semen Coicis oil products therefrom.Described DPPC is dipalmitoyl phosphatidyl choline.
In above technical scheme, described first raw material group refers to raw material used in preparation method of the present invention
The aggregation that a portion is formed, wherein said " first " is not offered as it and adds order or importance, and
Be only used for proposing described aggregation as entirety, therefore described " first " be not intended that this aggregation technology special
The restriction effect levied.It is to say, have in the aggregation formed due to part material in preparation method of the present invention
There is certain usage ratio relation, therefore proposing so that clearly describing the present invention as entirety.
In above technical scheme, step 4) the middle temperature maintaining less than 20 DEG C can be by with cooling
The crushing head of chuck realizes；In processing procedure, sample sucks high pressure sleeve due to action of gravity, treats that sample enters
After entering high pressure chest, high speed piston accelerates to close inlet valve, and makes sample at a high speed by fixed nozzle, thus real
Existing homogenization；In processing procedure, pressure is accurately controlled by fluid control systems, it is ensured that the reproduction of pressure size
Property and good crushing effect.
The invention provides the preparation method of a kind of high temperature sensitive liposome of storage-stable Semen Coicis oil.This technical side
First case has carried out innovative design to embedded object composition, and the problem for the oxidizable inactivation of Semen Coicis oil introduces
Lycopene composition, the antioxidation of lycopene self contributes to promoting Semen Coicis oil chemical stability, with
Time autoxidation, the photooxidation phenomenon of thermal sensitive liposome raw material DPPC are also had remission effect.Even more important,
Lycopene itself has definite defying age, promotes the effects such as immunity human body, it is joined with Semen Coicis oil
With contributing to lifting antineoplaston effect.
Additionally, present invention improves over the customary preparation methods of thermal sensitive liposome, in the link reducing system free energy
Use low-temperature ultrahigh-pressure crush method to process sample, make sample in confined conditions at a high speed by with cooling jacket
Crushing head, it is achieved while high pressure is broken, sample temperature quickly cools down, and can effectively prevent HIGH PRESSURE TREATMENT to cause
Thermal injury, its processing pressure is accurately controlled by fluid control systems simultaneously, it is ensured that the repeatability of pressure size and
Good crushing effect, gained liposome size is more homogeneous, and mean diameter in about 100nm, major part is
Big single cell structure, has more superior physical stability.
Under the guide of above technical thought, the present invention is to Semen Coicis oil, DPPC, lycopene, cholesterol
And the concrete consumption of solvent for use is optimized design, on the basis of ensureing embedding effect, improve storage
Stability and therapeutic effect, 4 DEG C of refrigerator cold-storages placements have not yet to see layering clustering phenomena for 18 months, and percolation ratio is less than
9%.In addition, its phase transition temperature of the thermal sensitive liposome prepared by the inventive method is just at 41～46 DEG C
Scope, this agrees with mutually with the ordinary temperature of tumor thermotherapy, therefore can simultaneously work as swelling during target administration
The effect of tumor thermotherapy, has positive effect for oncotherapy.
Accompanying drawing explanation
Fig. 1 is the schematic flow sheet of preparation method of the present invention.
Fig. 2 is the transmission electron microscope picture of the temperature sensitive liposome of the Semen Coicis oil prepared by the embodiment of the present invention 1.
Detailed description of the invention
The detailed description of the invention of the present invention will be described in detail below.In order to avoid the most unnecessary details,
In the examples below to belonging to known structure or function will not be described in detail.
Approximating language used in following example can be used for quantitative expression, shows do not changing basic function
In the case of quantity can be allowed to have certain variation.Therefore, the number revised with the language such as " about ", " left and right "
Value is not limited to this exact value itself.In certain embodiments, " about " represent that the numerical value allowing its correction is just
Change in the range of negative 10 (10%), such as, what " about 100 " represented can be 90 to 110 it
Between any numerical value.Additionally, in the statement of " the about first numerical value is to second value ", at about revise
One and two numerical value of second value.In some cases, approximating language may be relevant with the precision of measuring instrument.
In addition to being defined, technology used in following example and scientific terminology have and art skill of the present invention
The identical meanings that art personnel are commonly understood by.
Test reagent consumptive material used in following example, if no special instructions, is routine biochemistry reagent；Institute
State experimental technique, if no special instructions, be conventional method；Quantitative test in following example, is respectively provided with
Repeat experiment, results averaged for three times；% in following example, if no special instructions, is quality hundred
Divide content.
Embodiment 1
Weigh 0.1g Semen Coicis oil, 0.5g DPPC, 0.1g cholesterol, 2.5mg lycopene are dissolved completely in
In 50ml absolute ether, diethyl ether solution is slowly injected into 500ml pH7.0, concentration is the phosphoric acid of 0.02M
In salt buffer solution, under the conditions of 37 DEG C, magnetic agitation 30min obtains liposome turbid liquor, transfers it to
In round-bottomed bottle, under 35 DEG C of water bath condition, vacuum rotating removes absolute ether, forms uniform Semen Coicis oil
Temperature sensitive liposome turbid liquor, adds it in low-temperature ultrahigh-pressure cell crushing instrument, under the conditions of 14000bar
Cryogenic high pressure processes 1 time, i.e. prepares the temperature sensitive liposome of uniform Semen Coicis oil.The temperature sensitive liposome prepared
For relatively transparent milky white solution, envelop rate is 81.3%, and mean diameter is 90.4nm, and breadth coefficient is 0.312,
4 DEG C of cold preservations have no that lamination, Semen Coicis oil percolation ratio are 8.6% for 18 months.
Embodiment 2
Weigh 0.03g Semen Coicis oil, 0.1g DPPC, 0.02g cholesterol, 0.5mg lycopene are completely dissolved
In 20ml absolute ether, diethyl ether solution is slowly injected into 100ml pH7.0, concentration is the phosphorus of 0.02M
In hydrochlorate buffer solution, under the conditions of 36 DEG C, magnetic agitation 30min obtains liposome turbid liquor, is then shifted
To in round-bottomed bottle, under 34 DEG C of water bath condition, vacuum rotating removes absolute ether, forms uniform Semen Coicis
The quick liposome turbid liquor of oil temperature, adds it in low-temperature ultrahigh-pressure cell crushing instrument, in 25000bar condition
Lower cryogenic high pressure processes 1 time, i.e. prepares the temperature sensitive liposome of uniform Semen Coicis oil.The temperature sensitive fat prepared
Plastid is relatively transparent milky white solution, and phase transition temperature is 41.2 DEG C, and envelop rate is 85.1%, and mean diameter is
80.8nm, breadth coefficient is that 0.312,4 DEG C of cold preservations have no that lamination, Semen Coicis oil percolation ratio are for 18 months
7.1%.
Embodiment 3
A kind of preparation method of the high temperature sensitive liposome of storage-stable Semen Coicis oil, the raw material bag of this preparation method
Including the first raw material group, described first raw material group is grouped into by the one-tenth of following mass percent: Semen Coicis oil 0.01%,
DPPC 0.05%, lycopene 0.0001%, cholesterol 0.01%, surplus be concentration be the phosphorus of 0.02M/L
Phthalate buffer；
Described preparation method comprises the following steps:
1) take the DPPC of formula ratio, Semen Coicis oil, lycopene and cholesterol, be dissolved in absolute ether,
Wherein DPPC is 1:150 (g/mL) with the amount ratio of absolute ether；
2) phosphate buffer that concentration is 0.02M/L of formula ratio is taken, by step 1) addition of gained solution
Wherein, stirring obtains emulsion；
3) step 2 is taken) gained emulsion, ether is evaporated off, obtains the temperature sensitive liposome turbid liquor of Semen Coicis oil；
4) step 3 is taken) the temperature sensitive liposome turbid liquor of gained Semen Coicis oil, utilize cell crushing instrument to process, behaviour
As pressure be 10000bar, operation temperature be 5 DEG C, i.e. obtain the described high temperature sensitive fat of storage-stable Semen Coicis oil
Plastid.
On the basis of above technical scheme, meet following condition:
Step 2) under described phosphate buffer is in stirring condition by step 1) gained solution adds it
In.
Step 2) described in phosphate buffer be in 34 DEG C under the conditions of by step 1) gained solution is added thereto.
Step 2) described in stirring persistent period be 20min.
Step 2) described in stir and realized by magnetic stirring apparatus.
Step 3) in ether utilize vacuum rotation steam instrument be evaporated off, rotation steam instrument bath temperature be 32 DEG C.
Step 4) in utilize cell crushing instrument to process number of times be 1 time.
Embodiment 4
A kind of preparation method of the high temperature sensitive liposome of storage-stable Semen Coicis oil, the raw material bag of this preparation method
Including the first raw material group, described first raw material group is grouped into by the one-tenth of following mass percent: Semen Coicis oil 3.0%,
DPPC 5.0%, lycopene 0.0025%, cholesterol 1.6%, surplus be concentration be the phosphate of 0.2M/L
Buffer；
Described preparation method comprises the following steps:
1) take the DPPC of formula ratio, Semen Coicis oil, lycopene and cholesterol, be dissolved in absolute ether,
Wherein DPPC is 1:250 (g/mL) with the amount ratio of absolute ether；
2) phosphate buffer that concentration is 0.2M/L of formula ratio is taken, by step 1) gained solution adds it
In, stirring obtains emulsion；
3) step 2 is taken) gained emulsion, ether is evaporated off, obtains the temperature sensitive liposome turbid liquor of Semen Coicis oil；
4) step 3 is taken) the temperature sensitive liposome turbid liquor of gained Semen Coicis oil, utilize cell crushing instrument to process, behaviour
As pressure be 27000bar, operation temperature be 10 DEG C, i.e. obtain described high storage-stable Semen Coicis oil temperature sensitive
Liposome.
On the basis of above technical scheme, meet following condition:
Step 2) described in phosphate buffer be in 38 DEG C under the conditions of by step 1) gained solution is added thereto.
Step 2) described in stirring persistent period be 40min.
Step 3) in ether utilize vacuum rotation steam instrument be evaporated off, rotation steam instrument bath temperature be 38 DEG C.
Embodiment 5
The preparation method of a kind of high temperature sensitive liposome of storage-stable Semen Coicis oil, the raw material of this preparation method includes
First raw material group, described first raw material group is grouped into by the one-tenth of following mass percent: Semen Coicis oil 1.5%,
DPPC 3.0%, lycopene 0.001%, cholesterol 0.8%, surplus be concentration be the phosphate of 1.1M/L
Buffer；
Described preparation method comprises the following steps:
1) take the DPPC of formula ratio, Semen Coicis oil, lycopene and cholesterol, be dissolved in absolute ether,
Wherein DPPC is 1:200 (g/mL) with the amount ratio of absolute ether；
2) phosphate buffer that concentration is 1.1M/L of formula ratio is taken, by step 1) gained solution adds it
In, stirring obtains emulsion；
3) step 2 is taken) gained emulsion, ether is evaporated off, obtains the temperature sensitive liposome turbid liquor of Semen Coicis oil；
4) step 3 is taken) the temperature sensitive liposome turbid liquor of gained Semen Coicis oil, utilize cell crushing instrument to process, behaviour
As pressure be 18000bar, operation temperature be 20 DEG C, i.e. obtain described high storage-stable Semen Coicis oil temperature sensitive
Liposome.
Above embodiments of the invention are described in detail, but described content has been only the preferable enforcement of the present invention
Example, not in order to limit the present invention.All made in the application range of the present invention any amendment, equivalent
With improvement etc., should be included within the scope of the present invention.
Claims (8)
1. the preparation method of the one kind high temperature sensitive liposome of storage-stable Semen Coicis oil, it is characterised in that this system
The raw material of Preparation Method includes that the first raw material group, described first raw material group are grouped into by the one-tenth of following mass percent:
Semen Coicis oil 0.01～3.0%, DPPC 0.05～5.0%, lycopene 0.0001～0.0025%, cholesterol
0.01～1.6%, surplus be concentration be the phosphate buffer of 0.02～0.2M/L；
Described preparation method comprises the following steps:
1) take the DPPC of formula ratio, Semen Coicis oil, lycopene and cholesterol, be dissolved in absolute ether,
Wherein DPPC is 1:(150～250 with the amount ratio of absolute ether) (g/mL)；
2) phosphate buffer that concentration is 0.02～0.2M/L of formula ratio is taken, by step 1) gained solution adds
Entering wherein, stirring obtains emulsion；
3) step 2 is taken) gained emulsion, ether is evaporated off, obtains the temperature sensitive liposome turbid liquor of Semen Coicis oil；
4) step 3 is taken) the temperature sensitive liposome turbid liquor of gained Semen Coicis oil, utilize cell crushing instrument to process, behaviour
As pressure be 10000～27000bar, operation temperature less than 20 DEG C, i.e. obtain described high storage-stable Semen Coicis
The quick liposome of core oil temperature.
Preparation method the most according to claim 1, it is characterised in that step 2) at described phosphate
Buffer is in step 1 under stirring condition) gained solution is added thereto.
Preparation method the most according to claim 1, it is characterised in that step 2) described in phosphate delay
Rushing step 1 under the conditions of liquid is in 34～38 DEG C) gained solution is added thereto.
Preparation method the most according to claim 1, it is characterised in that step 2) described in stirring hold
The continuous time is 20～40min.
Preparation method the most according to claim 1, it is characterised in that step 2) described in stirring be logical
Cross what magnetic stirring apparatus realized.
Preparation method the most according to claim 1, it is characterised in that step 3) in ether be utilize true
Empty rotation steams what instrument was evaporated off.
Preparation method the most according to claim 6, it is characterised in that step 3) the middle water-bath revolving steaming instrument
Temperature is 32～38 DEG C.
Preparation method the most according to claim 1, it is characterised in that step 4) in utilize cell breakage
The number of times that instrument processes is 1 time.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108619097A (en) * | 2018-06-06 | 2018-10-09 | 江西科技师范大学 | A kind of anti-oxidant complex liposome of efficient anticancer |
| CN112831077A (en) * | 2021-02-08 | 2021-05-25 | 江南大学 | Intelligent gas-phase antioxidant film containing rosemary temperature-sensitive liposome and preparation method thereof |
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| CN108619097A (en) * | 2018-06-06 | 2018-10-09 | 江西科技师范大学 | A kind of anti-oxidant complex liposome of efficient anticancer |
| CN108619097B (en) * | 2018-06-06 | 2020-11-17 | 江西科技师范大学 | Efficient anticancer and antioxidant composite liposome |
| CN112831077A (en) * | 2021-02-08 | 2021-05-25 | 江南大学 | Intelligent gas-phase antioxidant film containing rosemary temperature-sensitive liposome and preparation method thereof |
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| CN105796497B (en) | 2018-09-11 |
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