CN109821056A - Suppository and its preparation method and application - Google Patents
Suppository and its preparation method and application Download PDFInfo
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- CN109821056A CN109821056A CN201910128594.7A CN201910128594A CN109821056A CN 109821056 A CN109821056 A CN 109821056A CN 201910128594 A CN201910128594 A CN 201910128594A CN 109821056 A CN109821056 A CN 109821056A
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Abstract
The present invention relates to a kind of suppositories and its preparation method and application.The suppository is particle aspherical and with regular shape, and the draw ratio of suppository is 1.1~100.Above-mentioned suppository surface is smooth, uniform particle diameter, compared to ball tap agent, can penetrate into smaller blood vessel, while it is bigger with vascular wall contact area, can be more stable at target blood.
Description
Technical field
The present invention relates to high molecular materials and biomedical engineering field, more particularly to a kind of suppository and its preparation side
Method and application.
Background technique
Suppository is a kind of conventional medical device generally used, and it is a variety of to be usually used in transcatheter arterial em-bolization of cancer etc.
In interventional therapy.Classify by physical behavior, suppository can be divided into embolic agent and liquid embolizing agent at present.Embolic agent master
It to be graininess suppository, including embolic particles and embolism microball.Embolic agent common are gelfoam particle/microballoon,
PVA particle/microballoon, sodium alginate micro ball, bletilla striata microballoon, curcuma zedoary microballoon etc..Part microsphere embolization agent has medicament slow release ability
(referred to as medicament elution microballoon).Liquid embolizing agent is currently used dehydrated alcohol, lipiodol, adhesive of medical (such as isobutyl group-
2- cyanoacrylate, normal-butyl -2- cyanoacrylate etc.).
The embolic particles shape clinically used at present is irregular, rough, holds during interventional therapy operation
Easily aggregation blocking microtubular, simultaneously because its partial size differs greatly, being easily accessible non-targeted blood vessel leads to accidentally bolt, and embolism depth
It is difficult to predict；The problem of then surface is smooth, partial size is more uniform for embolism microball, avoids aggregation obstruction conduit, while its partial size is big
It is small more accurate, therefore can predict its embolism depth, but because microsphere surface and vascular wall contact area are small, exist in embolic processes
Microballoon reflux drifting problem, is also easy to cause non-targeted blood vessel by accidentally bolt.So current suppository either embolic agent
Or the bad problem of the generally existing blood vessel embolism performance of liquid embolizing agent.
Summary of the invention
Based on this, it is necessary to provide a kind of suppository that embolism performance is good.
A kind of suppository, the suppository are particle aspherical and with regular shape, the draw ratio of the suppository
It is 1.1~100.
The characteristics of above-mentioned suppository is suppository aspherical and with ordered structure, combines ball tap agent, surface
Smooth, uniform particle diameter can penetrate into smaller blood vessel, while itself and vascular wall contact area compared to ball tap agent
It is bigger, it can be more stable at target blood.
The shape of the suppository is ellipsoidal particle, rod-shpaed particle or shuttle shape particle in one of the embodiments,.
The glass transition temperature of the material of the suppository is 20 DEG C~120 DEG C in one of the embodiments,；Or it is described
The melting temperature of the material of suppository is 20 DEG C~120 DEG C.
The draw ratio of the suppository can become smaller under environmental stimuli in one of the embodiments,.
The material of the suppository includes polylactic acid, polylactic acid-based copolymer, modified poly- cream in one of the embodiments,
Acid, polydactyl acid analog copolymer, polyglycolic acid, polyglycolic acid analog copolymer, modified polyglycolic acid, modified polyethanol acids are total
Polymers, polycaprolactone analog copolymer, modified polycaprolactone, modified polycaprolactone analog copolymer, polyethylene glycol, gathers polycaprolactone
Glycols copolymer, modified poly (ethylene glycol) analog copolymer, polyvinyl alcohol, polyvinyl alcohol analog copolymer, changes modified poly (ethylene glycol)
Property polyvinyl alcohol, modified polyvinylalcohol analog copolymer, polyacrylic acid, polyacrylic acid analog copolymer, modified polyacrylic acid and modification
At least one of polyacrylic acid analog copolymer.
A kind of preparation method of suppository, comprising the following steps:
It is 1.1~100 by the draw ratio that body to be tensioned is stretched to the body to be tensioned, obtains the suppository.
The material of the body to be tensioned includes polylactic acid, polylactic acid-based copolymer, is modified and gathers in one of the embodiments,
Lactic acid, polydactyl acid analog copolymer, polyglycolic acid, polyglycolic acid analog copolymer, modified polyglycolic acid, modified polyethanol acids
Copolymer, polycaprolactone, polycaprolactone analog copolymer, modified polycaprolactone, modified polycaprolactone analog copolymer, polyethylene glycol,
Polyethylene glycol analog copolymer, modified poly (ethylene glycol), modified poly (ethylene glycol) analog copolymer, polyvinyl alcohol, polyvinyl alcohol analog copolymer,
Modified polyvinylalcohol, modified polyvinylalcohol analog copolymer, polyacrylic acid, polyacrylic acid analog copolymer, modified polyacrylic acid and change
At least one of property polyacrylic acid analog copolymer.
The draw ratio that body to be tensioned is stretched to the body to be tensioned is 1.1~100 in one of the embodiments,
The step of include:
The body to be tensioned is mixed with preparation liquid, obtains mixed liquor, wherein the preparation liquid includes solvent；
The mixture is tiled, and the solvent is made to volatilize and form film to be tensioned；And
The film to be tensioned is stretched under conditions of 20 DEG C~250 DEG C, until the draw ratio of the body to be tensioned
It is 1.1~100.
The material of the body to be tensioned includes polylactic acid, polylactic acid-based copolymer, is modified and gathers in one of the embodiments,
Lactic acid, polydactyl acid analog copolymer, polyglycolic acid, polyglycolic acid analog copolymer, modified polyglycolic acid, modified polyethanol acids
Copolymer, polycaprolactone, polycaprolactone analog copolymer, modified polycaprolactone, modified polycaprolactone analog copolymer, polyethylene glycol,
Polyethylene glycol analog copolymer, modified poly (ethylene glycol), modified poly (ethylene glycol) analog copolymer, polyvinyl alcohol, polyvinyl alcohol analog copolymer,
Modified polyvinylalcohol, modified polyvinylalcohol analog copolymer, polyacrylic acid, polyacrylic acid analog copolymer, modified polyacrylic acid and change
Property at least one of polyacrylic acid analog copolymer, the preparation liquid further includes film forming matter, and the film forming matter is selected from poly- second
At least one of enol and modified polyvinylalcohol, in described the step of mixing the body to be tensioned with preparation liquid, it is described to
The quality of extrusion and the mass ratio of the film forming matter are 1:10~100000.
Instrument or Jie of the suppository made from the preparation method of above-mentioned suppository or above-mentioned suppository in preparation interventional therapy
Enter the application in the drug for the treatment of.
A kind of drug, including carrier and load active constituent on the carrier, the carrier be above-mentioned suppository or
The suppository that the preparation method of above-mentioned suppository obtains.
Detailed description of the invention
Fig. 1 is the spherical shape body to be tensioned before the partial size screening of embodiment 1；
Fig. 2 is the spherical shape body to be tensioned after the partial size screening of embodiment 1；
Fig. 3 is the elliposoidal suppository that spherical body to be tensioned obtains under elongation strain 100%；
Fig. 4 is the elliposoidal suppository that spherical body to be tensioned obtains under elongation strain 200% in Fig. 2；
Fig. 5 is situation of change of the suppository of the elliposoidal of embodiment 1 in the liver of decellularization after thermostimulation；
Fig. 6 is the elliposoidal suppository that the spherical shape body to be tensioned of embodiment 3 obtains under elongation strain 300%.
Specific embodiment
To facilitate the understanding of the present invention, a more comprehensive description of the invention is given in the following sections with reference to the relevant attached drawings.In attached drawing
Give section Example of the invention.But the invention can be realized in many different forms, however it is not limited to this paper institute
The embodiment of description.On the contrary, purpose of providing these embodiments is keeps the disclosure of invention more thorough and comprehensive.
Unless otherwise defined, all technical and scientific terms used herein and belong to technical field of the invention
The normally understood meaning of technical staff is identical.Term as used herein in the specification of the present invention is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.
The suppository of one embodiment, suppository are particle aspherical and with regular shape, the draw ratio of suppository
It is 1.1~100.
The shape of above-mentioned suppository is regular and is aspherical.Compared with traditional ball tap agent, under same volume, on
The cross-sectional area for stating suppository is smaller, and cross-sectional diameter is shorter, and can be delivered to vascular system deeper inside (can reach thinner blood
At pipe), and due to its it is regular it is aspherical be not likely to produce drift and accidentally bolt, there is better delivery performance；In identical embolism energy
Under power, above-mentioned suppository has bigger contact area than ball tap agent and blood vessel, and has bigger drugloading rate.Specifically
Ground, the shape of above-mentioned suppository are ellipsoidal particle, rod-shpaed particle or fusiform particle.It is understood that above-mentioned suppository
Shape is not limited to ellipsoidal particle, rod-shpaed particle or fusiform particle, can also be that other draw ratios are 1.1~100 regular shape
Shape.It should be noted that draw ratio refers to longest diameter and the longest diameter the ratio between perpendicular with it inside by suppository.It is regular
Refer to well-behaved neat.
The surface roughness of above-mentioned suppository is 1 nanometer~1 micron in one of the embodiments,.Further, above-mentioned
The surface roughness of suppository is 10 nanometers~200 nanometers.Smooth suppository is more conducive to suppository walking in the blood vessel.
The glass transition temperature of the material of above-mentioned suppository is 20 DEG C~120 DEG C in one of the embodiments,.Another
In a embodiment, the melting temperature of the material of above-mentioned suppository is 20 DEG C~120 DEG C.
Further, the draw ratio of above-mentioned suppository can be in environmental stimuli (such as hot, light, magnetic field, microwave etc.) in table
Become smaller under face tension or Entropy Changes effect.
There are high molecular polymer most molecule segments after orientation to be directed toward the same direction, in that direction, macromolecule
The macro property of polymer has differences with other directions, and in optical property, it is double that there is high molecular polymer orientation can generate
Refractiveness.The same orientation of the inherent strand of above-mentioned suppository can be in polarized light microscopy in one of the embodiments,
Birefringent phenomenon is presented under mirror, that is, there is birefringence.Above-mentioned suppository also has shape control performance, and glass transition temperature
Or melting temperature is 20 DEG C~120 DEG C, it can be (such as light, magnetic field, micro- in 30 DEG C~80 DEG C of direct thermostimulation or indirect stimulation
Wave etc.) under the action of be sized and/or shape is to adapt to the thickness of target blood so that embolism is thorough, embolism performance is more preferably.
The raw material of above-mentioned suppository, which can be, processed under the conditions of 20 DEG C~250 DEG C to have required draw ratio afterwards
Medical material.Specifically, the raw material of above-mentioned suppository includes polylactic acid, polylactic acid-based copolymer, polydactyl acid, modified poly- cream
Acid copolymer, polyglycolic acid analog copolymer, modified polyglycolic acid, modified polyglycolic acid analog copolymer, gathers in oneself polyglycolic acid
Ester, polycaprolactone analog copolymer, modified polycaprolactone, modified polycaprolactone analog copolymer, polyethylene glycol, polyethylene glycols copolymerization
Object, modified poly (ethylene glycol), modified poly (ethylene glycol) analog copolymer, polyvinyl alcohol, polyvinyl alcohol analog copolymer, modified polyvinylalcohol,
Modified polyvinylalcohol analog copolymer, polyacrylic acid, polyacrylic acid analog copolymer, modified polyacrylic acid and modified polypropene acids are total
At least one of polymers.Polylactic acid-based copolymer refers to that participating in the monomer of polymerization reaction includes other lists in addition to lactic acid monomer
Body, such as poly lactide-glycolide acid, polylactic acid-caprolactone copolymer, polylactic acid-caprolactone-co-glycolic acid
Etc..Polyglycolic acid analog copolymer, polycaprolactone analog copolymer, polyethylene glycol analog copolymer, polyethylene glycol analog copolymer, poly- second
The definition of enol analog copolymer and polyacrylic acid analog copolymer is similar with the definition of polylactic acid-based copolymer.Polydactyl acid refers to
To polylactic acid carry out the improved material of a step, such as in polylactic acid add other materials (such as physics addition polyethylene glycol,
Cellulose etc.), or functional groups modification (such as chemistry addition carbamate groups, cage are carried out to the strand of polylactic acid
Type polysilsesquioxane etc.).Modified polyglycolic acid, modified poly (ethylene glycol), modified polyvinylalcohol, is modified and gathers modified polycaprolactone
Acrylic acid is similar with the definition of polydactyl acid.Polydactyl acid analog copolymer, which refers to, carries out further polylactic acid-based copolymer
Improved material.Modified polyglycolic acid analog copolymer, modified polycaprolactone analog copolymer, modified poly (ethylene glycol) analog copolymer,
Modified polyvinylalcohol analog copolymer, modified polypropene acid copolymer are similar with the definition of polydactyl acid analog copolymer.
Further, the raw material of above-mentioned suppository be polymer, the monomer of polymer include lactic acid, glycolic, caprolactone,
At least one of ethylene glycol, vinyl alcohol and acrylic acid.
The raw material of above-mentioned suppository includes in polylactic acid, polyvinyl alcohol and polyacrylic acid in one of the embodiments,
It is at least one.
The raw material of above-mentioned suppository includes poly-dl-lactide or poly lactic-co-glycolic acid in one of the embodiments,
Copolymer.At this point, above-mentioned suppository has good biodegradability, it can be used for preparing short-term or mid-term embolotherapy
Drug.
The raw material of above-mentioned suppository includes polyvinyl alcohol or polyacrylic acid in one of the embodiments,.At this point, above-mentioned bolt
The biodegradability of suppository is poor, can be used for preparing the drug of permanent embolotherapy.
Above-mentioned suppository has at least the following advantages:
(1) above-mentioned surface is smooth, uniform particle diameter, and under same volume, the cross-sectional area of above-mentioned suppository is smaller, cross section
Diameter is shorter, can be delivered to vascular system deeper inside (can reach at thinner blood vessel), and due to its it is regular it is aspherical not
It is also easy to produce drift and accidentally bolt, there is better delivery performance；Under identical embolism ability, above-mentioned suppository than ball tap agent with
Blood vessel has bigger contact area, and has bigger drugloading rate.
(2) above-mentioned suppository also has shape control performance, can 30 DEG C~80 DEG C direct thermostimulation or indirectly thorn
Swash and be sized under the action of (such as light, magnetic field, microwave etc.) and/or shape is to adapt to the thickness of target blood, so that embolism
Thoroughly, embolism performance is more preferably.
The preparation method of above-mentioned suppository, comprising the following steps:
S10, body to be tensioned is prepared.
Body to be tensioned refers to that the draw ratio for being stretched to body to be tensioned is 1.1~100, obtains suppository.Body to be tensioned can be with
It is single compound, such as high polymer；It is also possible to mixture, such as the mixing of several high polymers.
Specifically, the raw material of body to be tensioned includes polylactic acid, polylactic acid-based copolymer, polydactyl acid, polydactyl acid
Analog copolymer, polyglycolic acid analog copolymer, modified polyglycolic acid, modified polyglycolic acid analog copolymer, gathers in oneself polyglycolic acid
Ester, polycaprolactone analog copolymer, modified polycaprolactone, modified polycaprolactone analog copolymer, polyethylene glycol, polyethylene glycols copolymerization
Object, modified poly (ethylene glycol), modified poly (ethylene glycol) analog copolymer, polyvinyl alcohol, polyvinyl alcohol analog copolymer, modified polyvinylalcohol,
Modified polyvinylalcohol analog copolymer, polyacrylic acid, polyacrylic acid analog copolymer, modified polyacrylic acid and modified polypropene acids are total
At least one of polymers.Polylactic acid-based copolymer, polyglycolic acid analog copolymer, polycaprolactone analog copolymer, polyethylene glycols
Copolymer, polyethylene glycol analog copolymer, polyvinyl alcohol analog copolymer, polyacrylic acid analog copolymer, polydactyl acid, modified poly- second
Alkyd, modified polycaprolactone, modified poly (ethylene glycol), modified polyvinylalcohol, modified polyacrylic acid, polydactyl acid analog copolymer,
Modified polyglycolic acid analog copolymer, modified polycaprolactone analog copolymer, modified poly (ethylene glycol) analog copolymer, modified poly ethylene alcohols
Copolymer and modified polypropene acid copolymer are as defined above.
Body to be tensioned is that spherical body to be tensioned, rodlike body to be tensioned or threadiness are to be tensioned in one of the embodiments,
Body.
Body to be tensioned is spherical body to be tensioned in one of the embodiments,.Wherein, the surface light of spherical body to be tensioned
Cunning, size are uniform.Specifically, spherical body to be tensioned can be prepared by a variety of conventional methods for preparing ball tap agent.Such as
There are commonly emulsification-evaporation method, phase separation method and spray drying processes etc..Further, it is prepared into using conventional method
Further include the steps that screening after to spherical body to be tensioned.By sieving, the microballoon that particle size range is narrower, more uniform is obtained.
The partial size of spherical body to be tensioned is 10 microns~500 microns in one of the embodiments,.Spherical body to be tensioned
Surface roughness is 1 nanometer~1 micron.Further, the partial size of spherical body to be tensioned is 100 microns~300 microns.Spherical shape to
The surface roughness of extrusion is 10 nanometers~200 nanometers.
Specifically, the operation of the spherical body to be tensioned of preparation is as follows: polylactic acid dissolution is made into 1% in methylene chloride~
PLA solution, is then dispersed in the polyethanol solution of 1%~10% (w/w) by 10% (w/w) solution, 100rp~
3h~72h is stirred under 1000rpm revolving speed, is then centrifuged for collecting microballoon, is obtained spherical body to be tensioned.Pass through different size the screen to filtrates
The spherical shape body to be tensioned of target grain size range can be obtained in screening.Further, polylactic acid dissolution is made into methylene chloride
PLA solution, is then dispersed in 5% polyethanol solution by 3% (w/w) solution, and 3h is stirred under 250rpm revolving speed, centrifugation
Microballoon is collected, spherical body to be tensioned is obtained, filtering screening obtains the spherical body to be tensioned of target grain size range.
In one embodiment, body to be tensioned is threadiness body to be tensioned.Specifically, threadiness body to be tensioned can be by melting
The conventional method that electrostatic spinning or solution-polymerized SBR etc. prepare macromolecular fibre is made.
The raw material of fibrous body to be tensioned includes polylactic acid in one of the embodiments,.Specifically, preparation threadiness to
The operation of extrusion is as follows: by polylactic acid dissolution be made into 10%~15% (w/w) solution in methylene chloride, then 2kV~
20kV acts on PLA solution 10min~for 24 hours, collects on 100rpm~500rpm reel, then air-dries, obtain it is fibrous to
Extrusion.Further, polylactic acid dissolution is made into 12% (w/w) solution in methylene chloride, is then acted on 3.78kV
It on molten mass, collects 6 hours, air-dries, secure satisfactory grades subbundle on 200rpm reel.
It is understood that in some embodiments, step S10 can be omitted, body to be tensioned is commercially available at this time.
S30, under conditions of 20 DEG C~120 DEG C, body to be tensioned is stretched until required draw ratio, suppository is obtained.
Body to be tensioned is spherical body to be tensioned in one of the embodiments, and body to be tensioned is stretched until required major diameter
The operation of ratio includes S310~S350.
S310, body to be tensioned is mixed with preparation liquid, obtains mixed liquor, wherein preparation liquid includes solvent.
Specifically, body to be tensioned is mixed with preparation liquid, obtains mixed liquor.
The shape of body to be tensioned is spherical shape in one of the embodiments, and body to be tensioned is water-insoluble, at this point, being film-made
Liquid is aqueous solution.It that is to say, the solvent of preparation liquid is water.Preparation liquid further includes film forming matter, and film forming matter is selected from polyvinyl alcohol
And at least one of modified polyvinylalcohol.In the step of body to be tensioned is mixed with preparation liquid, the quality of body to be tensioned at
The mass ratio of membrane substance is 1:10~100000.Further, the raw material of body to be tensioned includes polylactic acid, and preparation liquid includes poly-
Ethylene alcohol and water.Polyvinyl alcohol facilitates the dispersion of body to be tensioned in water pair, is conducive to body to be tensioned and forms a film.The matter of body to be tensioned
Amount and the mass ratio of the polyvinyl alcohol in preparation liquid are 1:100~500.Further, the quality and system of spherical body to be tensioned
The mass ratio of polyvinyl alcohol in film liquid is 1:150,1:200 or 1:250.
It in one of the embodiments, further include glycerol in preparation liquid.Glycerol makes stretched film have toughness, convenient for wait draw
It stretches uncovering for film and is hardly damaged, is easily molded.Further, the mass fraction of glycerol is 0.1%~20% in preparation liquid.Into one
Step, the mass fraction of glycerol is 1.5%, 2%, 2.5% or 3.5% in preparation liquid.
Carrier when preparation liquid is stretched as spherical body to be tensioned, body to be tensioned do not dissolve in preparation liquid, convenient for be tensioned
Body is covered by film after preparation liquid is dry.It is, of course, understood that in some other embodiment, it is spherical to be tensioned
Body is water solubility, at this point, the also corresponding replacement of the solvent of preparation liquid.
S330, mixed liquor is tiled, and solvent is made to volatilize and form film to be tensioned.
Mixed liquor tiling is made to the liquid film of 1 millimeter~20 millimeters thicks, the solvent in liquid film is then removed, obtains to be tensioned
Film.Further, liquid film with a thickness of 3 millimeters, 5 millimeters, 7 millimeters or 10 millimeters.
S350, film to be tensioned is stretched under conditions of 20 DEG C~250 DEG C, obtains suppository.
Specifically, film to be tensioned is stretched under conditions of 20 DEG C~250 DEG C, keeps its elongation strain and is cooled to
Lower than draft temperature, the suppository of elliposoidal is obtained.It is possible to further be cooled to room temperature.Room temperature refers to 4 DEG C~30 DEG C.Its
In, the rate of stretching is 0.1cm/min~100cm/min, and elongation strain range is between 100% to 1000%.
The raw material of body to be tensioned includes polylactic acid in one of the embodiments, at this point, being stretching in 50 DEG C~150 DEG C items
It is carried out under part, rate of extension is 0.5~20cm/min, and elongation strain range is between 100% to 1000%.Further, it stretches
It is carried out under the conditions of 60 DEG C, 70 DEG C, 80 DEG C or 90 DEG C, rate of extension 1cm/min, 2cm/min, 5cm/min or 10cm/min,
Elongation strain range is 150%, 200%, 400% or 800%.
Further, after the step of being cooled to room temperature, further include the steps that purifying.Specifically, the step of purifying is wrapped
It includes: film to be tensioned being stretched under conditions of 20 DEG C~250 DEG C, its elongation strain is kept and is cooled to room temperature, and post-tensioning
It stretches film to mix with water, so that the nonaqueous component of preparation liquid is dissolved in water, obtain to centrifugate；And will be centrifuged to centrifugate, is dry,
Obtain suppository.Preparation liquid can be removed by centrifugation, enrichment suppository is then centrifuged for, is then freeze-dried, obtains after purification
Elliposoidal suppository.It is, of course, understood that the solvent of preparation liquid is then when spherical body to be tensioned is water-soluble
Nonaqueous solvents, the solvent of preparation liquid can be the organic solvent that cannot be dissolved each other with spherical body to be tensioned, then remove preparation liquid at this time
Other components when also corresponding change, as long as component remaining in preparation liquid can be removed without influencing spherical body to be tensioned.
In another embodiment, body to be tensioned is threadiness body to be tensioned.Embolism is prepared by the body to be tensioned of threadiness
The step of agent includes: that body to be tensioned is stretched to required draw ratio, then cuts molding, obtains suppository.
Specifically, the condition by body to be tensioned at 20 DEG C~250 DEG C stretches, and then through film drawing process, cuts, obtains
Suppository.Wherein, heating temperature is higher than the high molecular phase transition temperature of body to be tensioned (glass transition temperature or melting temperature
Degree), the high molecular phase transition temperature of body to be tensioned can be determined according to the raw material of body to be tensioned.The rate of stretching depends on heating temperature
Degree, elongation strain range is between 100% to 1000%.It is understood that the shape of the suppository after cutting can be bar-like,
It is also possible to other shapes.
As polymer fiber material when stretching, extensograph parameter can be identical as spherical body to be tensioned.Macromolecular fibre material
Material can also directly cut out molding, obtain the suppository with required draw ratio.
In one embodiment, body to be tensioned is threadiness body to be tensioned, and the raw material of body to be tensioned includes polylactic acid, this
When, it is carried out under the conditions of being stretching in 20 DEG C~250 DEG C, rate of extension is 0.1~100cm/min, and elongation strain range is between 100%
To 1000%.Further, it is carried out under the conditions of being stretching in 50 DEG C~150 DEG C, rate of extension is 0.5~20cm/min, and stretching is answered
Become range between 150% to 1000%.Further, it is carried out under the conditions of being stretching in 60 DEG C, 70 DEG C, 80 DEG C or 90 DEG C, stretches speed
Rate is 1cm/min, 2cm/min, 5cm/min or 10cm/min, and elongation strain range is 150%, 200%, 400% or 800%.
In one embodiment, body to be tensioned is threadiness body to be tensioned, and the raw material of body to be tensioned includes polylactic acid-glycolic
Acetic acid copolymer, at this point, carrying out under the conditions of being stretching in 20 DEG C~250 DEG C, rate of extension is 0.1~100cm/min, and stretching is answered
Become range between 100% to 1000%.Further, carried out under the conditions of being stretching in 50 DEG C~150 DEG C, rate of extension be 0.5~
20cm/min, elongation strain range is between 150% to 1000%.Further, 60 DEG C, 70 DEG C, 80 DEG C or 90 DEG C items are stretching in
Carried out under part, rate of extension 1cm/min, 2cm/min, 5cm/min or 10cm/min, elongation strain range be 150%,
200%, 400% or 800%.
In another embodiment, suppository by by rodlike body to be tensioned be stretched to draw ratio to be tensioned be 1.1~
100, obtain suppository.
Specifically, rodlike body to be tensioned is stretched body to be tensioned until body to be tensioned under conditions of 20 DEG C~260 DEG C
Draw ratio be 1.1~100, obtain rodlike suppository.Wherein, heating temperature is that the vitrifying higher than rodlike body to be tensioned turns
The glass transition temperature of temperature, rodlike body to be tensioned can be determined according to the raw material of rodlike body to be tensioned.The rate of stretching takes
Certainly in heating temperature, elongation strain range is between 100% to 1000%.
For rodlike body to be tensioned when stretching, extensograph parameter is identical as spherical body to be tensioned.
The preparation method of above-mentioned suppository is easy to operate, is easy to large-scale production.
Application of the above-mentioned suppository in the instrument of preparation interventional therapy or the drug of interventional therapy.
Specifically, application of the above-mentioned suppository in the drug of preparation interventional therapy.Such as in preparation liver cancer, lung cancer, kidney
In the drug or instrument of the interventional therapy of a variety of diseases such as cancer, fibroid, hyperplasia of prostate, tumor of prostate, breast cancer
Using.Further, above-mentioned suppository can be as the carrier for carrying drug.For example carry the drugs such as taxol, adriamycin.
A kind of drug, including carrier and the active constituent being supported on carrier.
Specifically, carrier is above-mentioned suppository.Further, active constituent can be taxol, adriamycin etc..
Said medicine using suppository as carrier, can be delivered to blood vessel depths, and the medicine that the suppository can carry
Object amount is bigger, the depth of interaction and better effect of drug.
Specific embodiment
It is described in detail below in conjunction with specific embodiment.In embodiment if not otherwise indicated using drug and instrument,
For this field conventional selection.Test method without specific conditions in embodiment, according to normal conditions, such as document, books
Described in condition or manufacturer recommend method realize.
Embodiment 1
Prepare the suppository of elliposoidal
(1) the spherical body to be tensioned of preparation:
Polylactic acid dissolution is made into 2.9% (w/w) solution in methylene chloride, PLA solution is then dispersed in 5%
In polyethanol solution, 3h is stirred under 250rpm revolving speed, is then centrifuged for collecting microballoon, obtains spherical body to be tensioned.By 107 μm and
87 μm of the screen to filtrate screenings, the spherical shape body to be tensioned after being screened (partial size is 87 μm~107 μm).The partial size being prepared
Spherical shape body to be tensioned before screening is as shown in Figure 1, the spherical shape body to be tensioned after partial size screening is as shown in Figure 2.
(2) spherical shape body to be tensioned made from 0.03g step (1) is added to 40mL preparation liquid, wherein preparation liquid is poly- second
The mixed liquor of enol, glycerol and water, water is as solvent, and the mass percentage of polyvinyl alcohol is 10% in preparation liquid, preparation liquid
The mass percentage of middle glycerol is 4%.Rectangular culture dish (9cm x is arrived into the fully dispersed rear tiling of above-mentioned spherical shape body to be tensioned
In 9cm), the liquid film of 7mm is formed, is volatilized to the water in liquid film and obtains film to be tensioned.
(3) film to be tensioned is cut into the film to be tensioned (the wide 0.5~5cm of film, the long 3~20cm of film) of multiple strips, it will
The film to be tensioned of multiple strips is stretched under the conditions of 90 DEG C with 2.4cm/min rate, elongation strain be 100%~
300%.Then it keeps its elongation strain and is cooled to 25 DEG C, obtain stretched film.
(4) stretched film is mixed with deionized water, so that polyvinyl alcohol is soluble in water, is then centrifuged for abandoning supernatant, is enriched with, is cold
It is lyophilized dry, obtains the suppository of elliposoidal.The elliposoidal embolism of different draw ratios is obtained under elongation strain 100% and 200%
Agent.Elliposoidal suppository after stretching is respectively as shown in Fig. 3 (elongation strain 100%) and Fig. 4 (elongation strain 200%).
Embodiment 2
(1) by the suppository for the elliposoidal of step embodiment 1 prepared under conditions of elongation strain is 200% using note
The method injection penetrated is gone in the blood vessel of cell liver (by being formed after in vitro liver decellularization), and is being gone outside cell liver to ellipse
After spherical suppository carries out 42 DEG C of stimulation 15min, the variation of the suppository of elliposoidal in the blood vessel is observed and recorded.Record knot
Fruit is as shown in Figure 5.Wherein, the first row in Fig. 5 be respectively 42 DEG C stimulate 15min after 0min, 2min09s, 2min42s,
5min12s, 6min28s, 7min06s, 13min 40s blood vessel in ellipsoid suppository situation of change.
(2) aspherical polylactic acid suppository (preparing according to the preparation method of embodiment 1) and spherical polylactic acid suppository exist
The comparison of depth is delivered in liver vessel.The ball tap agent (suppository 1) that diameter is 100 microns, with 400 microns of minor axis of major diameter
50 microns ellipsoid suppository (suppository 2) volume is identical.Suppository 1 can enter the blood vessel of diameter >=100 micron, and androgynous
Long-pending suppository 2 can then enter the blood vessel of diameter >=50 micron, the size depending on suppository minor axis.Therefore, with same volume
Ball tap agent compare, the aspherical suppository with smaller minor axis has deeper delivering depth in the blood vessel.
(3) embolism of the aspherical polylactic acid suppository with thermostimulation (preparing according to the preparation method of embodiment 1) is imitated
Fruit.The ellipsoid suppository draw ratio of 400 microns of major diameter, 50 microns of minor axis be 8, in the blood vessel for being delivered to 50 micron diameters after,
Major diameter shorten to 200 microns after 42 DEG C of thermostimulations, and minor axis is increased to 71 microns, at this time deformation of the diameter of blood vessel due to suppository
And increase accordingly, so that suppository can be stablized reduces the stream of suppository in the blood vessel in the blood vessel strongerly
Dynamic property, reduce suppository as flowing and caused by uncertainty.
Embodiment 3
The preparation of the elliposoidal suppository of embodiment 3 is roughly the same with embodiment 1, and difference is, preparation embodiment 3
The raw material of spherical body to be tensioned is poly lactide-glycolide acid.
The suppository of the elliposoidal for the embodiment 3 being prepared under elongation strain 300% is as shown in Figure 6.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality
It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (11)
1. a kind of suppository, which is characterized in that the suppository is particle aspherical and with regular shape, the suppository
Draw ratio be 1.1~100.
2. suppository according to claim 1, which is characterized in that the shape of the suppository is ellipsoidal particle, rodlike
Particle or shuttle shape particle.
3. suppository according to claim 1, which is characterized in that the glass transition temperature of the material of the suppository is 20
DEG C~120 DEG C；Or
The melting temperature of the material of the suppository is 20 DEG C~120 DEG C.
4. suppository according to claim 1, which is characterized in that the draw ratio of the suppository can be under environmental stimuli
Become smaller.
5. suppository according to any one of claims 1 to 4, which is characterized in that the material of the suppository includes poly- cream
Sour, polylactic acid-based copolymer, polydactyl acid analog copolymer, polyglycolic acid, polyglycolic acid analog copolymer, changes polydactyl acid
Property polyglycolic acid, modified polyglycolic acid analog copolymer, polycaprolactone, polycaprolactone analog copolymer, modified polycaprolactone, modified poly-
Caprolactone analog copolymer, polyethylene glycol analog copolymer, modified poly (ethylene glycol), modified poly (ethylene glycol) analog copolymer, gathers polyethylene glycol
Vinyl alcohol, polyvinyl alcohol analog copolymer, modified polyvinylalcohol, modified polyvinylalcohol analog copolymer, polyacrylic acid, polyacrylic
At least one of copolymer, modified polyacrylic acid and modified polypropene acid copolymer.
6. a kind of preparation method of suppository, which comprises the following steps:
It is 1.1~100 by the draw ratio that body to be tensioned is stretched to the body to be tensioned, obtains the suppository.
7. the preparation method of suppository according to claim 6, which is characterized in that the material of the body to be tensioned includes poly-
Lactic acid, polylactic acid-based copolymer, polydactyl acid, polydactyl acid analog copolymer, polyglycolic acid, polyglycolic acid analog copolymer,
Modified polyglycolic acid, modified polyglycolic acid analog copolymer, polycaprolactone, polycaprolactone analog copolymer, modified polycaprolactone, modification
Polycaprolactone analog copolymer, polyethylene glycol, polyethylene glycol analog copolymer, modified poly (ethylene glycol), modified poly (ethylene glycol) analog copolymer,
Polyvinyl alcohol, polyvinyl alcohol analog copolymer, modified polyvinylalcohol, modified polyvinylalcohol analog copolymer, polyacrylic acid, polyacrylic acid
At least one of analog copolymer, modified polyacrylic acid and modified polypropene acid copolymer.
8. the preparation method of suppository according to claim 6 or 7, which is characterized in that described to be stretched to body to be tensioned
The draw ratio of the body to be tensioned be 1.1~100 the step of include:
The body to be tensioned is mixed with preparation liquid, obtains mixed liquor, wherein the preparation liquid includes solvent；
The mixture is tiled, and the solvent is made to volatilize and form film to be tensioned；And
The film to be tensioned is stretched under conditions of 20 DEG C~250 DEG C, until the draw ratio of the body to be tensioned is 1.1
~100.
9. the preparation method of suppository according to claim 8, which is characterized in that the material of the body to be tensioned includes poly-
Lactic acid, polylactic acid-based copolymer, polydactyl acid, polydactyl acid analog copolymer, polyglycolic acid, polyglycolic acid analog copolymer,
Modified polyglycolic acid, modified polyglycolic acid analog copolymer, polycaprolactone, polycaprolactone analog copolymer, modified polycaprolactone, modification
Polycaprolactone analog copolymer, polyethylene glycol, polyethylene glycol analog copolymer, modified poly (ethylene glycol), modified poly (ethylene glycol) analog copolymer,
Polyvinyl alcohol, polyvinyl alcohol analog copolymer, modified polyvinylalcohol, modified polyvinylalcohol analog copolymer, polyacrylic acid, polyacrylic acid
At least one of analog copolymer, modified polyacrylic acid and modified polypropene acid copolymer, the preparation liquid further include film forming
Substance, the film forming matter be selected from least one of polyvinyl alcohol and modified polyvinylalcohol, it is described will the body to be tensioned and
In the step of preparation liquid mixes, the quality of the body to be tensioned and the mass ratio of the film forming matter are 1:10~100000.
10. the preparation side of the described in any item suppositories of Claims 1 to 5 or the described in any item suppositories of claim 6~8
Application of the suppository made from method in the instrument of preparation interventional therapy or the drug of interventional therapy.
11. a kind of drug, which is characterized in that including the active constituent of carrier and load on the carrier, the carrier is power
Benefit requires the preparation method of 1~5 described in any item suppositories or the described in any item suppositories of claim 6~8 to obtain
Suppository.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110585476A (en) * | 2019-08-02 | 2019-12-20 | 南方科技大学 | Preparation method of non-spherical hydrogel microparticle embolic agent |
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