CN108721684A - Hud typed prepackage chemotherapeutics embolism microball of one kind and preparation method thereof - Google Patents
Hud typed prepackage chemotherapeutics embolism microball of one kind and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/08—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/104—Gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices
Abstract
The present invention provides the hud typed prepackage chemotherapeutics embolism microball of one kind and preparation method.This method emulsifies microlayer model as template using water/oil/water (W/O/W) emulsion type or oil/water/oil (O/W/O) emulsion type, fine droplet containing drug is wrapped up into outer layer drop, the high molecular polymer in inside and outside layer drop converts the shell of the core and outer layer to form internal layer by means such as physics, chemistry.It is formed by nucleocapsid medicine microspheres to be made of the polymer of double-layer structure, kernel contains drug, and shell helps to maintain kernel pharmaceutical activity, stablizes drug release, prevents burst release, increases safety.Drug bearing microsphere particle size range prepared by the present invention is at 10-1000 microns, good sphericity, uniform particle diameter (dimensional discrepancy<5%), entrapment efficiency is high, structure/load medicine is controllable.Meanwhile prepackage chemotherapeutics embolism microball preparation method of the invention, new approaches can be provided for the clinical application research of transcatheter arterial em-bolization.
Description
Technical field
The present invention relates to a kind of preparation processes of hud typed prepackage chemotherapeutics microsphere embolization agent, belong to biological medicine neck
Domain.
Background technology
Percutaneous angiographic embolization (Transarterial embolization, TAE) is by suppository Selective implantation
Diseased region target vessel blocks blood supply, to reach the mesh for inhibiting tumour growth, eliminating vascular lesions organ dysfunction and hemostasis
's.Kato in 1981 proposes chemoembolization method or Transcaheter cloure (Transarterial first
Chemoembolization, TACE), this method is to be combined drug with suppository, has embolism concurrently and medicament dual is made
With more efficient.Traditional TACE often adds adriamycin, cis-platinum or the mixing administration of other chemotherapeutics with lipiodol.But this side
There are 2 major defects for method：1. the local deposits of lipiodol Emulsion cannot obtain satisfactory effect sometimes, with prolonging for time
Long, chemotherapeutics also declines the cellulotoxic effect of tumor tissues therewith；2. traditional pharmaceutical carrier is lipid, and chemotherapeutics
It is water-soluble, this tradition emulsion can cause chemotherapeutics to discharge rapidly in blood flow, to rapidly enter systemic circulation system
System, increases the adverse reaction of whole body and reduces local efficiency.
Recently as Prefilled embolism microball preparation-drug bearing microsphere or medicament elution microballoon (drug-
Elutingbead, DEB) appearance, this microball preparation adds the plain mode of suppository more effective compared to chemotherapeutics, drug
Also can long-acting slow-release, and reduce the injury to other organs.Such as the drug embolism microball DC bead being commercialized, state
Interior trade name " up to celestial ball ", and the drug embolism microball in the preclinical study stage, including 5 FU 5 fluorouracil polylactic acid are micro-
Ball, adriamycin sodium alginate micro ball, ion-exchange type microballoon, cisplatin Microspheres and the answering containing traditional Chinese medicine ingredients for carrying bleomycin A5
Square oil of zedoary turmeric microballoon etc..However either commercialization is in the drug embolism microball of experimental stage, all there is grain size
Distribution is wide (such as DC Bead points are 100~300 μm, 300~500 μm, multiple ranges such as 500~700 μm), and drugloading rate is low and not
Uniformly, easily by the problems such as environment and human factor are influenced, Release Performance is unstable, therefore safety allows of no optimist.Due to TACE
The super-selective of art, size is inhomogenous to easily cause non-targeted embolism, causes severe complication, only dimensional homogeneity good micro-
Ball just can ensure that the blood vessel of embolism specific dimensions.Further for drug bearing microsphere, the size uniformity rule that then releases the drug is consistent, contributes to
The follow-up embolism process of accurate judgement.Therefore, the uniform microballoon for only selecting suitable size, could more preferably reach therapeutic effect.
The existing inhomogenous reason of stype plug microspherulite diameter size that carries is the mode that preparation method is large scale, such as
Emulsion dispersion method, spray drying process, phase separation method etc. lack the strong control to Microsphere Size, structure etc..Obtained microballoon
Product cut size Size Distribution is wide, is difficult to realize the uniform particle diameter of microballoon.Existing load medicine embolism microball drugloading rate is low and uneven,
The unstable reason of Release Performance is made other than grain size caused by large scale preparation method is inhomogenous with Electrostatic Absorption
For carrying medicine or directly being mixed with high molecular polymer to carry medicine be also to cause to carry medicine is incomplete, Release Performance is unstable reason
One of.
Therefore, it is micro- to improve existing load stype plug that size uniformity, the novel load medicine embolism microball of load medicine/drug release controllably are prepared
The problems of ball is particularly important.
Chinese patent CN106729951A discloses a kind of chemoembolization porous microsphere with microwave enhanced sensitivity function and is preparing
The adsorbate of the drug for treating tumour or the application in preparation, the microballoon is inorganic salts and chemotherapeutics, the bone of the microballoon
Frame is polylactic-co-glycolic acid；The microsphere diameter is 20-700 μm, and specific surface is more than 10m2/g.The present invention also provides above-mentioned
The preparation method of chemoembolization porous microsphere.Chemoembolization porous microsphere of the present invention has the heating of good microwave enhanced sensitivity and tumour
Blood vessel embolism function, in the spherical shape of rule, porosity is high, and particle diameter distribution is narrow, and granularity is controllable；In addition, the present invention is for the first time by poly- breast
Sour hydroxyacetic acid is prepared into the treatment that the chemoembolization microballoon with microwave enhanced sensitivity is applied to cancer, achieves excellent tumour suppression
It makes and uses, there is good clinical value.The load medicine mechanism of microballoon described in the patent of invention is that physical absorption carries medicine.Absorption
Carry medicine be Drug absorbability on the surface of porous media, Drug absorbability process is influenced by specific surface area, and drugloading rate is restricted；Together
When, the release process of drug is uncontrolled, it is possible to create burst drug release phenomenon is detrimental to health.In addition, the grain of the microballoon
Diameter distribution is wider, is unfavorable for the blood vessel of embolism specific dimensions, it is also possible to block the blood vessel for being not required to embolism.
Chinese patent CN101099725 discloses a kind of preparation method of the multifunctional arterial embolic agent of composite interstitial substance, will
Doxorubicin hydrochloride solution is dispersed in oil contrast media, under the action of surfactant, micro emulsion and Submicron Emulsion is formed, as first
Newborn phase E1；Colostrum is mutually dropped evenly to the W of the sodium alginate soln containing surfactant and calcium carbonate or calcium phosphate micro mist
Xiang Zhong forms secondary lotion E2；Secondary breast E2 is added dropwise in atoleine again, whole grade lotion E3 is formed, in lasting stirring
Under the conditions of be added organic acid, complete crosslinking and balling-up reaction, through precipitation, remove supernatant liquid, it is good while containing to obtain sphericity
There is the microsphere embolization agent of chemotherapeutics and radiography agent.The present invention can be controlled by adjusting preparation parameter (mechanical agitation power etc.)
The distribution of microspherulite diameter processed obtains composite interstitial substance, arterial embolism microball preparation with diagnosing and treating function.The invention is special
Profit prepares microsphere embolization agent using mechanical agitation, and the method lacks effective control to microspherulite diameter, obtained microballoon
Particle size distribution range is wider, pessimistic to the embolization effect of specific dimensions blood vessel, it is also possible to block the blood vessel for being not required to embolism.This
Outside, drug is added in the process of preparation in a manner of being added dropwise, and drug loss rate is higher.
Invention content
In order to make up for the deficiencies of the prior art, the present invention provides a kind of uniform particle diameter, structure/load medicine controllable hud typed pre-
Fill the preparation method of chemotherapeutics embolism microball.
Prefilled microball preparation is that the high molecular polymer of drug and biocompatibility is made by miniature technique for packing
Grain size be tens to hundreds of microns of microballoon.The factors affects such as microspherulite diameter, drugloading rate and rate of releasing drug the treatment of microballoon
Effect.
Using the blood supply arteriole for the microball preparation occluded lesions tissue for being loaded with drug, embolism position can be constantly to lesion target
Area's targeted release drug makes drug have targeting and controlled-release function, changes drug and be distributed in vivo and dynamics, raising medicine
The bioavilability of object, therapeutic effect is notable, reduces toxic side effect.
From preparation method angle, the present invention is based on Microfluidic droplet technologies, and stream is utilized in micron to nanoscale channel
Dispersed phase fluid is divided into nanoliter level and nanoliter level size one below by the interaction between body shearing force and surface tension
The drop of cause.Droplet is wrapped into big drop, forms the drop with double-layer structure, the size and outer layer of internal droplet
The size of big drop can be adjusted by parameters such as flow velocity/property of fluid, channel sizes.Internal droplet contains medicine
Object is completely wrapped into the big drop of outer layer, carry medicine completely, without drug loss.Contained high molecular polymer passes through object in fluid
After the solidification of reason/chemical means, the core-shell microspheres with double-layer structure are formed, grain size is uniform, structure/load to prepare with this
The controllable Prefilled embolism microball (dimensional discrepancy of medicine<5%).Further, the present invention can prepare particle size range 10~
1000 microns of core-shell microspheres, while by changing property, the nucleocapsid ratio of core and shell material, it can be achieved that microspheres product grain
Diameter/structure/load medicine/drug release is controllable.
From microspheres product angle, the present invention provides a kind of novel forms carrying medicine embolism microball.It is micro- to be different from tradition load medicine
Ball is carrying out load medicine using preceding by being mixed with drug, and the drug of the novel form is to feed into microballoon in advance in preparation process.
The novel form is made of the polymer of double-layer structure, has nucleocapsid, and drug is pre-installed in kernel, can pre-install hydrophilic or oleophylic
Property drug, the shell of core-shell microspheres help to maintain kernel pharmaceutical activity.The novel form grain size is uniform, can stablize load
Medicine/drug release prevents from being released, and increases safety.
The present invention solve grain size/structure in current drug embolism microball preparation process it is uncontrollable, carry medicine not exclusively, drug release
The problems such as uncontrollable.
The technical solution adopted by the present invention is as follows：
A kind of hud typed prepackage chemotherapeutics embolism microball, is made of the polymer of double-layer structure, has nucleocapsid, medicine
Object is pre-installed in kernel, and hydrophilic or lipophilic medicament can be pre-installed, and the shell of core-shell microspheres helps to maintain kernel pharmaceutical activity；
Preparation methods steps are as follows：
(1) solution system is determined
According to the property and formulation requirements of required preloaded medication, solution system be divided into water/oil/water (W/O/W) emulsion type and
Two kinds of oil/water/oil (O/W/O) emulsion type.
For water soluble drug, W/O/W emulsion type solution systems are applicable in, the solution system is by inner aqueous phase fluid, centre
Oil phase fluid and outer aqueous phase fluid collectively constitute.Relative to intermediate oil phase, inner aqueous phase is dispersed phase, and intermediate oil phase is mobile phase；
Relative to outer aqueous phase, intermediate oil phase is dispersed phase, and outer aqueous phase is then mobile phase.
The inner aqueous phase fluid is the aqueous solution containing biocompatibility macromolecule polymer, the high molecular polymer choosing
Take cellulose, chitosan, sodium alginate, glucan, soluble starch, gelatin, polyethylene glycol (PEG), gamma-polyglutamic acid (γ-
PGA), the mass fraction of macromolecule polymer solution is 0.1-40%, and drug is dissolved in inner aqueous phase；
The middle oil phase fluid is the oil solution containing biocompatibility macromolecule polymer, the high molecular polymer
Choose polylactic acid (PLA), polylactic acid/hydroxy acetate multipolymer (PLGA), polyethylene glycol PEG, the matter of macromolecule polymer solution
Amount score is 0.1-40%, and the solvent of high molecular polymer oil solution selects dichloromethane, dimethyl carbonate etc.；Intermediate oil phase stream
Body contains the molten surfactant of oil, chooses EM90, Span-80；
The outer aqueous phase fluid is the aqueous solution containing surfactant.
For oil-soluble medicine, it is applicable in oil/water/oil (O/W/O) emulsion type solution system, the solution system is by interior oil phase
Fluid, intermediate water phase fluid and outer oil phase fluid collectively constitute.Relative to intermediate water phase, interior oil phase is dispersed phase, intermediate water phase
For mobile phase；Relative to outer oil phase, intermediate water phase is dispersed phase, and outer oil phase is then mobile phase.
The interior oil phase fluid is the oil solution containing biocompatibility macromolecule polymer solution, the high molecular polymerization
Object chooses polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA), polyethylene glycol (PEG), macromolecule polymer solution
Mass fraction be 0.1-40%；The solvent of macromolecule polymer solution is dichloromethane, acetone, dimethyl carbonate, dimethyl
Formamide；Drug is dissolved in interior oil phase；
The intermediate water phase fluid is the aqueous solution containing biocompatibility macromolecule polymer, the high molecular polymer
Choose cellulose, chitosan, sodium alginate, polyvinyl alcohol, glucan, starch, gelatin, polyethylene glycol (PEG), γ-polyglutamic
The mass fraction of sour (γ-PGA) etc., macromolecule polymer solution are 0.1-40%；Intermediate water phase fluid contains soluble surface
Activating agent；
The outer oil phase fluid is to contain oil soluble surfactant with the immiscible organic solvent of water, outer oil phase；It is described
Organic solvent is selected from one of C12-18 alkane, silicone oil, paraffin or combination；Or natural edible oil, preferably soybean oil, castor oil；
(2) prepared by W/O/W emulsions type or O/W/O emulsion type drops
The interior phase, interphase and external fluid phase are entered with respective constant-flow pump in microscale channel respectively, in micro- ruler
In degree channel W/O/W emulsions type or O/W/O emulsion type liquid are formed using the interaction between hydrodynamic shear and surface tension
Drop；
The interior phase, interphase and external fluid phase control flow, external fluid phase flow velocity by respective channel by syringe pump>
Interphase fluid flow rate>Internal phase fluid flow velocity；The range of flow of the internal phase fluid is 0.1-5.0mL/h, the interphase stream
The range of flow of body is 0.5-15.0mL/h, and the range of flow of the external fluid phase is 2.0-20.0mL/h.
(3) drop solidification process
Drop solidification process can choose physics or chemical method is cured, solidification process at a temperature of 20-80 DEG C into
Row stands 24 hours so that completion of cure later；
The physical solidification method is：Cured by the method for illumination (such as UV), heating.Based on microchannel to light
Well transmitance or the good conductivity to heat, physical solidification can carry out online.It is micro- logical collecting after the double-deck microlayer model is formed
The nearly exit solidification in road.
The chemical curing processes are to carry out cured method using crosslinking agent, catalyst.The crosslinking agent can choose penta
The mass fraction of dialdehyde, glyoxal, formaldehyde, epoxychloropropane or aqueous metallic ions, cross-linking agent solution is 0.1-80%,
The preferred 0.1-10% of mass fraction of middle aqueous metallic ions.The catalyst is Bronsted acid or biological enzyme aqueous solution, institute
The Bronsted acid stated is preferably organic acid or inorganic acid, and the pH value of Bronsted acid is preferably pH=1-5；The biological enzyme is preferably able to
Between catalytic proteins molecule or within crosslinking, the enzyme that is connected between protein and amino acid, most preferably glutamine turns amine
The mass fraction of enzyme, biological enzyme aqueous solution is 0.1-10%, preferably 0.1-2.0%.
The addition of crosslinking agent and catalyst is related to selected system and method in chemical curing processes, preferably following several solid
Change mode：
Polyvinyl alcohol cures：It is crosslinking agent to select glutaraldehyde or formaldehyde, and Bronsted acid is catalyst, and curing reaction is polyvinyl alcohol
Mixed with crosslinking agent it is latter with enter reaction system i.e. microscale channel in, formed microlayer model, after collection under Protic Acid Catalyzed
Solidification；
Sodium alginate cures：The microlayer model that step (2) is formed, is collected in container, metallic-ion crosslinking agent is then added
Cured；
Starch cures：It need to be latter same into reaction system, that is, microscale channel by starch and crosslinking agent epoxychloropropane premix
In, preparation forms microlayer model and then is cured；
Gelatin cures：It need to be latter same into reaction system, that is, microscale channel by gelatin and glutamine transaminage premix
In, preparation forms microlayer model and then is cured.
(4) it washs, is dry
Reaction solution filtering after step (3) is cured, collects solid particle, is washed respectively with organic solvent, deionized water,
It obtains carrying medicine embolism microball after drying.
Load stype plug microspherulite diameter prepared by the present invention is uniform, surface is smooth, nucleocapsid/load medicine is controllable, microspherulite diameter
Controllable in 10~1000 μ ms, deviation is less than 5%；It is further preferred that grain size is 110~950 μm, deviation is less than 4%.
According to currently preferred, step (1) described water soluble drug is one kind in water-soluble antitumor chemotherapeutics,
Antineoplastic chemotherapy medicine is selected from that adriamycin class (adriamycin, Epi-ADM, than soft adriamycin), (liquor epinephrinae bitartratis ophthalmicus Changchun is auspicious for Noviburn
Shore injection), mustargen (cyclophosphamide), cis-platinum (carboplatin), daunorubicin, methopterin, fluorouracil, cytarabine, mitogen
Mycin, phosphinothioylidynetrisaziridine, vincristine.
According to currently preferred, step (1) described oil-soluble medicine is one kind in oil-soluble antineoplastic chemotherapy medicine,
Selected from taxanes (taxol, taxol, docetaxel, Paclitaxe), ginsenoside.
When containing surfactant in water phase fluid according to currently preferred, in step (1), the surfactant choosing
From the one or more of water soluble surfactant active, it is further preferred that the surfactant be Tween-20 (polysorbas20),
PVA (polyvinyl alcohol), Triton X-100 (Triton X-100), mass fraction 0.05-5%.
When containing surfactant in oil phase fluid according to currently preferred, in step (1), the surfactant choosing
From the one or more of oil soluble surfactant, it is further preferred that the surfactant is EM90 (the poly- second of cetyl two
- 10/1 dimethyl siloxane of alcohol/polypropylene glycol), DC749 (cyclomethicone and trimethyl silica hydrochlorate), the 80 (mountains Span
Pears alcohol acid anhydride monoleate), mass fraction 0.5-5%.
According to currently preferred, the range of flow of internal phase fluid described in step (2) is 0.3-3.0mL/h, in described
Between the range of flow of phase fluid be 2.0-8.0mL/h, the range of flow of the external fluid phase is 2.0-15.0mL/h.
According to currently preferred, the formation of drop is to utilize the shearing force of fluid in microscale channel in step (2)
And dispersed phase fluid is divided into nanoliter level and nanoliter level drop below by the interaction between surface tension.Micro- ruler
Spend ranging from 20-2000 microns of channel diameter.
According to currently preferred, the organic solvent of washing described in step (4) is selected from boiling point in 80 DEG C of liquid below
One or more combinations in alkane, 60-90 DEG C of petroleum ether, ethyl acetate, ethyl alcohol, deionized water.Wash time is that 0.5-3 is small
When.The drying refers to vacuum drying, freeze-drying or spray drying.
According to currently preferred, the one kind of microscale channel in following microchannel described in step (2)：
(A) microscale channel is flowed altogether, is connected in series by the total stream microscale channel of two groups of coaxial connections；Internal phase fluid is micro- logical
Angle between road and interphase flow microchannel is θ 1,0<θ1≤90°；Internal phase fluid microchannel and external fluid phase microchannel it
Between angle be θ 2,0<θ2≤90°；
(B) flow focusing type microscale channel；
Microscale channel material according to the present invention is quartz glass, dimethyl silicone polymer (PDMS) or poly- methyl-prop
E pioic acid methyl ester (PMMA) etc..
The present invention emulsifies microlayer model as template using water/oil/water (W/O/W) emulsion type or oil/water/oil (O/W/O) emulsion type,
Fine droplet containing drug is wrapped up into outer layer drop, the high molecular polymer in inside and outside layer drop passes through physics, chemistry
Etc. means convert the shell of the core and outer layer to form internal layer.Nucleocapsid medicine microspheres are formed by by the poly- of two or more layers structure
It closes object to constitute, shell helps to maintain kernel pharmaceutical activity, stablizes drug release, prevents burst release, increases safety.
Beneficial effects of the present invention are as follows：
1, it is several that grain size, which is made, by miniature technique for packing in the high molecular polymer of prepackage chemotherapeutics and biocompatibility
Ten to hundreds of microns of hud typed drug bearing microsphere is formed by nucleocapsid medicine microspheres and is made of the polymer of double-layer structure,
Shell helps to maintain kernel pharmaceutical activity, stablizes drug release, prevents burst release, increases safety.
2, the present invention comes real by adjusting the property of fluid flow rate, microchannel size and core and shell material, nucleocapsid ratio
Existing grain size, nucleocapsid, it is controllable to carry medicine/drug release.
3, the present invention is based on Microfluidic droplet technologies, and the load stype plug microspherulite diameter of preparation is uniform, surface is smooth, nucleocapsid knot
Structure/load medicine is controllable, and microspherulite diameter is controllable in 10~1000 μ ms, and deviation is less than 5%；Preferable particle size is 110~950 μm,
Deviation is less than 4%.
4, the blood supply arteriole of the microball preparation occluded lesions tissue of present invention prepackage chemotherapeutics, embolism position can be continuous
To lesion target area targeted release drug, make drug that there is targeting and controlled-release function, changes drug and be distributed in vivo and power
It learns, improves the bioavilability of drug, therapeutic effect is notable, reduces toxic side effect.
5, the load stype plug method for preparing microsphere provided by the invention for being applied to drug prepackage and controlled release field of medicaments,
New approaches can be provided for the clinical application research of transcatheter arterial em-bolization.
Figure of description
Fig. 1 is microscale channel structural schematic diagram (channel dimension is micron order).In figure, arrow direction represents fluid flowing
Direction.
Fig. 1 (A) is the schematic three dimensional views for flowing microscale channel altogether, flows microscale channel altogether by two groups and forms；
Wherein, label represents as follows：1, internal phase fluid inlet microchannel；2, interphase fluid inlet microchannel；3, foreign minister
Fluid inlet microchannel；4, single layer emulsifies microlayer model collection channel；5, the double-deck emulsification microlayer model collection channel；6, physical solidification position
It sets, such as UV, heat source can be loaded；Wherein, the angle between microchannel 1 and 2 is θ 1,0<θ1≤90°；Between microchannel 1 and 3
Angle is θ 2,0<θ2≤90°；Emulsion type microlayer model is formed about in second group of microchannel 1 and 3 intersections.
Fig. 1 (B) is the schematic three dimensional views of the total focus type microscale channel of flowing；
Wherein, label represents as follows：7, internal phase fluid microchannel, 8, interphase flow microchannel, 9, external fluid phase it is micro- logical
Road, 10, drop collect microchannel；The connection coaxial with 10 of microchannel 7；11, physical solidification position can load such as UV, heat source.?
Under the driving of pump, internal phase fluid enters microchannel 7, under interphase and external fluid phase shearing force, in 10 entrance of microchannel
Place forms emulsion type microlayer model, and microlayer model is collected via microchannel 10 is collected.
Fig. 2,3,4,5 are the microscope of hud typed prepackage chemotherapeutics embolism microball made from embodiment 1,2,3,4 respectively
Photo.
Specific implementation mode
The present invention will be further described with reference to the accompanying drawings and examples, but the protection domain of this ° of invention is not limited to
This.
Percent concentration unit in embodiment is mass percent.
Embodiment 1：Hud typed prepackage taxol embolism microball and preparation
It selects Fig. 1 (A) to flow microscale channel altogether, prepares O/W/O emulsion type microlayer models, wherein θ 1=90 °, θ 2=90 °；
1 a diameter of 200 micron of interior oil phase fluid channel in microscale channel, 2 a diameter of 200 microns of intermediate water phase fluid channel are collected
4 a diameter of 250 microns of microchannel；3 a diameter of 250 microns of outer oil phase fluid channel collects 5 a diameter of 400 microns of microchannel.
Interior oil phase selects the dichloromethane solution containing 8%PLGA, the taxol of 400 μ g/mL to be dissolved in wherein；Intermediate water phase selects
With 1.5% sodium alginate and 2% polyvinyl alcohol aqueous solution, outer oil phase selects the saxol containing 2%EM90.Respectively will
Interior oil phase, intermediate water phase and outer oil phase are pumped into the constant flow rate of 0.8mL/h, 3.0mL/h, 5.0mL/h in channel 1,2,3.It is multiple
Newborn type microlayer model generates near microchannel 3 and 5 junctions.
Drop is collected, is added into 5% calcium chloride solution, is obtained after it is stood 24 hours under room temperature in 25 DEG C white
Color solid.Then it filters, collects product.After being washed three times with ethyl acetate, deionized water successively, obtained after 4 DEG C of dryings of vacuum
Drug bearing microsphere.Drug bearing microsphere kernel particle size is 128 microns, and shell grain size is 320 microns, and Microsphere Size deviation is 4%.
Embodiment 2：Hud typed prepackage ginsenoside embolism microball and preparation
The microscale channel is as described in Example 1, prepares O/W/O emulsion type microlayer models.Except that minute yardstick is logical
It is straight to collect microchannel 4 for 1 a diameter of 150 micron of interior oil phase fluid channel in road, 2 a diameter of 150 microns of intermediate water phase fluid channel
Diameter is 200 microns；3 a diameter of 200 microns of outer oil phase fluid channel collects 5 a diameter of 300 microns of microchannel.
Interior oil phase selects the dimethyl carbonate solution containing 6%PLGA, the ginsenoside of 30 μ g/ml to be dissolved in wherein；Intermediate water
Mutually select 12% gelatin (pre-add 1mL10% glutamine transaminages, mixing) and 2% polyvinyl alcohol aqueous solution, outer oil phase
Select the soybean oil containing 2%DC749.Respectively by interior oil phase, intermediate water phase and outer oil phase with 0.7mL/h, 3.0mL/h, 6.0mL/h
Constant flow rate be pumped into channel 1,2,3.Emulsion type drop generates near microchannel 3 and 5 junctions.
37 DEG C of online physical solidifications are heated to, drop is collected, are obtained after it is stood 24 hours under room temperature in 25 DEG C
White solid.Then it filters, collects product.After being washed three times with ethyl acetate, deionized water successively, after 4 DEG C of dryings of vacuum
To drug bearing microsphere.Drug bearing microsphere kernel particle size is 78 microns, and shell grain size is 250 microns, and Microsphere Size deviation is 3%.
Embodiment 3：Hud typed prepackage adriamycin embolism microball and preparation
The microscale channel of Fig. 1 (B) flow focusing structure is selected, W/O/W emulsion type drops are prepared.The microscale channel
The outlet diameter of inner aqueous phase fluid channel 7 is 50 microns, and the inlet diameter for collecting microchannel 10 is 120 microns.
Inner aqueous phase selects 20%PEG and 2% sodium alginate mixed aqueous solution, the adriamycin of 200 μ g/mL to be dissolved in wherein；In
Between oil phase select the dodecane containing 2%EM90, outer aqueous phase select 4% polyvinyl alcohol water solution.Respectively by inner aqueous phase, intermediate oil phase
It is pumped into channel 7,8,9 with the constant flow rate of 0.8mL/h, 2.0mL/h, 13.0mL/h with outer aqueous phase.Emulsion type microlayer model is logical
Road 7 and 10 intersections generate.
Drop is collected, is added into 5% calcium chloride solution.Place it in 25 DEG C under room temperature stand 24 hours after obtain
White solid.Then it filters, collects product.After being washed three times with ethyl alcohol, deionized water successively, carried after 4 DEG C of dryings of vacuum
Medicine microballoon.Drug bearing microsphere kernel particle size is 50 microns, and shell grain size is 90 microns, and Microsphere Size deviation is 4%.
Embodiment 4：It is prepared by hud typed prepackage cis-platinum embolism microball
The microscale channel of Fig. 1 (B) flow focusing structure is selected, W/O/W emulsion type drops are prepared.The microscale channel
7 a diameter of 80 microns of inner aqueous phase fluid channel inlet, a diameter of 150 microns of outlet 10.
It is water-soluble that inner aqueous phase selects 10% soluble starch (pre- that 2mL crosslinking agents epoxychloropropane is added) to be mixed with 20%PEG
The cis-platinum of liquid, 150 μ g/mL is dissolved in wherein；Intermediate oil phase selects the dichloromethane containing 3%Span80, outer aqueous phase to select 3% poly- second
Enol aqueous solution.Respectively by inner aqueous phase, intermediate oil phase and outer aqueous phase with the constant-flow pump of 0.4mL/h, 2.0mL/h, 12mL/h
Enter in channel 7,8,9.Emulsion type microlayer model generates in channel 7 and 10 intersections.
Drop is collected, white solid is obtained after it is stood 24 hours under room temperature in 25 DEG C.Then it filters, collects production
Product.After being washed three times with ethyl alcohol, deionized water successively, drug bearing microsphere is obtained after 4 DEG C of dryings of vacuum.Drug bearing microsphere kernel particle size is
88 microns, shell grain size is 116 microns, and Microsphere Size deviation is 4%.
Claims (10)
1. a kind of hud typed prepackage chemotherapeutics embolism microball, is made of the polymer of double-layer structure, has nucleocapsid, drug
It pre-installs in kernel, hydrophilic or lipophilic medicament can be pre-installed, the shell of core-shell microspheres helps to maintain kernel pharmaceutical activity；Its
Steps are as follows for preparation method：
(1) solution system is determined
According to the property and formulation requirements of required preloaded medication, solution system be divided into water/oil/water (W/O/W) emulsion type and oil/
Two kinds of water/oil (O/W/O) emulsion type；
For water soluble drug：W/O/W emulsion type solution systems are applicable in, the solution system is by inner aqueous phase fluid, intermediate oil phase
Fluid and outer aqueous phase fluid collectively constitute；Relative to intermediate oil phase, inner aqueous phase is dispersed phase, and intermediate oil phase is mobile phase；Relatively
In outer aqueous phase, intermediate oil phase is dispersed phase, and outer aqueous phase is then mobile phase；
The inner aqueous phase fluid is the aqueous solution containing biocompatibility macromolecule polymer, and the high molecular polymer is chosen fine
Tie up element, chitosan, sodium alginate, glucan, soluble starch, gelatin, polyethylene glycol (PEG), gamma-polyglutamic acid (γ-
PGA), the mass fraction of macromolecule polymer solution is 0.1-40%, and drug is dissolved in inner aqueous phase；
The middle oil phase fluid is the oil solution containing biocompatibility macromolecule polymer, and the high molecular polymer is chosen
Polylactic acid (PLA), polylactic acid/hydroxy acetate multipolymer (PLGA), polyethylene glycol PEG, the quality point of macromolecule polymer solution
Number is 0.1-40%, and the solvent of high molecular polymer oil solution selects dichloromethane, dimethyl carbonate etc.；Middle oil phase fluid contains
There is the molten surfactant of oil, chooses EM90, Span-80；
The outer aqueous phase fluid is the aqueous solution containing surfactant；
For oil-soluble medicine：It is applicable in oil/water/oil (O/W/O) emulsion type solution system, the solution system is by interior oil phase stream
Body, intermediate water phase fluid and outer oil phase fluid collectively constitute；Relative to intermediate water phase, interior oil phase is dispersed phase, and intermediate water phase is
Mobile phase；Relative to outer oil phase, intermediate water phase is dispersed phase, and outer oil phase is then mobile phase；
The interior oil phase fluid is the oil solution containing biocompatibility macromolecule polymer solution, the high molecular polymer choosing
Take polylactic acid (PLA), Poly(D,L-lactide-co-glycolide (PLGA), polyethylene glycol (PEG), the matter of macromolecule polymer solution
Amount score is 0.1-40%；The solvent of macromolecule polymer solution is dichloromethane, acetone, dimethyl carbonate, dimethyl formyl
Amine；Drug is dissolved in interior oil phase；
The intermediate water phase fluid is the aqueous solution containing biocompatibility macromolecule polymer, and the high molecular polymer is chosen
Cellulose, chitosan, sodium alginate, polyvinyl alcohol, glucan, starch, gelatin, polyethylene glycol (PEG), gamma-polyglutamic acid
The mass fraction of (γ-PGA) etc., macromolecule polymer solution are 0.1-40%；Intermediate water phase fluid contains soluble surface's work
Property agent；
The outer oil phase fluid is to contain oil soluble surfactant with the immiscible organic solvent of water, outer oil phase；It is described organic
Solvent is selected from one of C12-18 alkane, silicone oil, paraffin or combination；Or natural edible oil, preferably soybean oil, castor oil；
(2) prepared by W/O/W emulsions type or O/W/O emulsion type drops
The interior phase, interphase and external fluid phase are entered with respective constant-flow pump in microscale channel respectively, it is logical in minute yardstick
In road W/O/W emulsions type or O/W/O emulsion type drops are formed using the flow focusing principle of fluid；
The interior phase, interphase and external fluid phase control flow, external fluid phase flow velocity by respective channel by syringe pump>It is intermediate
Phase fluid flow velocity>Internal phase fluid flow velocity；The range of flow of the internal phase fluid is 0.1-5.0mL/h, the intermediate phase fluid
Range of flow is 0.5-15.0mL/h, and the range of flow of the external fluid phase is 2.0-20.0mL/h；
(3) drop solidification process
Drop solidification process can choose physics or chemical method is cured, and solidification process carries out at a temperature of 20-80 DEG C, it
Standing 24 hours afterwards makes completion of cure；
(4) it washs, is dry
Reaction solution filtering after step (3) is cured, collects solid particle, is washed respectively with organic solvent, deionized water, dry
After obtain carry medicine embolism microball.
2. a kind of preparation method of hud typed prepackage chemotherapeutics embolism microball as described in claim 1, which is characterized in that system
Standby load stype plug microspherulite diameter is uniform, surface is smooth, nucleocapsid/load medicine is controllable, and microspherulite diameter is in 10~1000 μ ms
Interior controllable, deviation is less than 5%；110~950 μm of preferable particle size, deviation are less than 4%.
3. a kind of preparation method of hud typed prepackage chemotherapeutics embolism microball as described in claim 1, which is characterized in that institute
State step (1) water soluble drug be water-soluble antitumor chemotherapeutics in one kind, selected from adriamycin class, Noviburn, mustargen,
Cis-platinum, daunorubicin, methopterin, fluorouracil, cytarabine, mitomycin, phosphinothioylidynetrisaziridine, vincristine；
The oil-soluble medicine of the step (1) is one kind in oil-soluble antineoplastic chemotherapy medicine, selected from taxanes, ginseng soap
Glycosides.
4. a kind of preparation method of hud typed prepackage chemotherapeutics embolism microball as described in claim 1, which is characterized in that institute
State in step (1) when containing surfactant in water phase fluid, surfactant be selected from water soluble surfactant active one kind or
It is a variety of, it is further preferred that the surfactant is Tween-20, polyvinyl alcohol, Triton X-100；It lives on surface
Property agent mass fraction be 0.05-5%；
When containing surfactant in the step (1) in oil phase fluid, surfactant is selected from oil soluble surfactant
It is one or more, it is further preferred that the surfactant is -10/1 diformazan of EM90 cetyls polyethylene/polypropylene glycol
Radical siloxane, DC749 cyclomethicones and trimethyl silica hydrochlorate, 80 sorbitan mono-oleic acid esters of Span；Surfactant
Mass fraction be 0.5-5%.
5. a kind of preparation method of hud typed prepackage chemotherapeutics embolism microball as described in claim 1, which is characterized in that institute
The range of flow for stating internal phase fluid in step (2) is 0.3-3.0mL/h, and the range of flow of the intermediate phase fluid is 2.0-
The range of flow of 8.0mL/h, the external fluid phase are 2.0-15.0mL/h.
6. a kind of preparation method of hud typed prepackage chemotherapeutics embolism microball as described in claim 1, which is characterized in that institute
The formation for stating drop in step (2) be in microscale channel, it is mutual using the shearing force of fluid and between surface tension
It is 20- that dispersed phase fluid is divided into nanoliter level and nanoliter level drop below, the microscale channel diameter range by effect
2000 microns.
7. a kind of preparation method of hud typed prepackage chemotherapeutics embolism microball as described in claim 1, which is characterized in that institute
Stating physical solidification method is：Cured by the method for illumination, heating；After the double-deck microlayer model is formed, microchannel is being collected
Nearly exit solidification；UV irradiations can be used in the illumination；
The chemical curing processes are to carry out cured method using crosslinking agent, catalyst, the crosslinking agent can choose glutaraldehyde,
The mass fraction of glyoxal, formaldehyde, epoxychloropropane or aqueous metallic ions, cross-linking agent solution is 0.1-80%；It is described to urge
Agent is Bronsted acid or biological enzyme aqueous solution, the preferred organic acid of the Bronsted acid or inorganic acid, and the pH value of Bronsted acid is pH=
1-5；The biological enzyme be preferably able between catalytic proteins molecule or within crosslinking, be crosslinked between protein and amino acid
Enzyme, most preferably glutamine transaminage；The mass fraction of biological enzyme aqueous solution is 0.1-10%；
The addition of crosslinking agent and catalyst is related to selected system and method in the chemical curing processes, preferably following several solid
Change mode：
Polyvinyl alcohol cures：It is crosslinking agent to select glutaraldehyde or formaldehyde, and Bronsted acid is catalyst, and curing reaction is polyvinyl alcohol and friendship
Join agent mixing it is latter with enter reaction system, that is, microscale channel in, formed microlayer model, collect drop after under Protic Acid Catalyzed
Solidification；
Sodium alginate cures：The microlayer model that step (2) is formed, is collected in container, and metallic-ion crosslinking agent is then added and carries out
Solidification；
Starch cures：Need to by starch and crosslinking agent epoxychloropropane premix it is latter with enter reaction system, that is, microscale channel in,
Preparation forms microlayer model, is then cured；
Gelatin cures：Need to be latter with entering in reaction system, that is, microscale channel by gelatin and glutamine transaminage premix, it makes
Then the standby microlayer model that formed is cured.
8. a kind of preparation method of hud typed prepackage chemotherapeutics embolism microball as claimed in claim 7, which is characterized in that institute
The mass fraction for stating crosslinking agent aqueous metallic ions is 0.1-10%；The mass fraction of catalyst biology enzyme aqueous solution is 0.1-
2.0%.
9. a kind of preparation method of hud typed prepackage chemotherapeutics embolism microball as described in claim 1, which is characterized in that institute
It states in step (4) washing organic solvent and is selected from boiling point in 80 DEG C of liquid alkanes below, 60-90 DEG C of petroleum ether of boiling point, acetic acid
One or more combinations in ethyl ester, ethyl alcohol, deionized water；Wash time is 0.5-3 hours；The drying refers to that vacuum is dried
Dry, freeze-drying or spray drying.
10. a kind of preparation method of hud typed prepackage chemotherapeutics embolism microball as claimed in claim 6, which is characterized in that
The one kind of the microscale channel in following microchannel：
(A) microscale channel is flowed altogether；It is connected in series by the total stream microscale channel of two groups of coaxial connections；Internal phase fluid microchannel and
Angle between interphase flow microchannel is θ 1,0<θ1≤90°；Between internal phase fluid microchannel and external fluid phase microchannel
Angle is θ 2,0<θ2≤90°；
(B) flow focusing type microscale channel；
Microscale channel material according to the present invention is quartz glass, polydimethylsiloxane or poly-methyl methacrylate
Ester PMMA.
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| CN114377191A (en) * | 2022-01-18 | 2022-04-22 | 上海方润介入器械有限公司 | Degradable embolism microsphere and preparation method thereof |
| CN114748674A (en) * | 2022-04-18 | 2022-07-15 | 上海方润介入器械有限公司 | Embolism microsphere preloaded with medicine and processing method thereof |
| CN115068669A (en) * | 2022-06-08 | 2022-09-20 | 湖南工业大学 | Triple-network porous embolism microsphere and preparation method thereof |
| CN115282322A (en) * | 2022-07-26 | 2022-11-04 | 杭州旸顺医疗科技有限公司 | Embolism microsphere and preparation method and application thereof |
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