CN106237338A - A kind of method preparing biostromal degraded macromolecular drug release material - Google Patents
A kind of method preparing biostromal degraded macromolecular drug release material Download PDFInfo
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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Abstract
The present invention is a kind of method preparing Biodegradable high molecular Thermosensitive Material Used for Controlled Releasing of Medicine, it to the effect that makes polymer-based drug loading layer and polymer-based barrier layer replace ordered arrangement by the way of melted coextrusion, utilize the shearing when repeatedly stratiform overlaps of the layer multiplexer, stretching action makes macromolecule deform in extrusion and be orientated, improve drug diffusion and release channel, the alternately stratiform Biodegradable high molecular drug release material obtained is made to possess rational initial release concentration and required long-term rate of release, realize the controlled the most effectively release of medicine, to meet different release demands.The form of the medicament slow release composite of the present invention is controlled, and formula is adjustable；Good mechanical performance；Can produce by continuous batch, the beneficially raising of production efficiency；Applied range, has wide industrialization and market prospect.
Description
Technical field
The present invention relates to that a kind of configuration can determine structure, performance can design, can be continuously produced, drug release behavior flexible
The preparation of controlled alternately stratiform Biodegradable high molecular Thermosensitive Material Used for Controlled Releasing of Medicine, belongs to functional composite material preparation field.
Background technology
Medicament slow release preparation is compared with convenient administration system, and they are not required to frequent drug administration, can remain internal in the long period
Effective drug level, reduces misery and inconvenience that frequent medication brings to patient, is greatly improved drug effect and reduces the secondary work of poison
With.Polymer Drug Delayed Release Materials typically divides not Biodegradable material and biodegradation material two class, and wherein biodegradation is high
Molecular material is due to its good biocompatibility, avirulence, it is not necessary to second operation takes out, and metabolite is free of a burden to human body
Etc. advantage, it has also become one of main direction of studying of medicament slow release.
Develop in recent years and the slow-release controlled-release type of preparation of clinical practice has: the cladding of the most chemically modified synthesis is water-soluble
The property collosol and gel of medicine, aqueous dispersion, latex etc..2. emulsion-solvent evaporation method, phase separation method, spray drying method, fusion method
Deng the sustained-release micro-spheres of preparation, microcapsule etc..3. through direct compression process, pill prepared by hot-melt extruded, tablet etc. [1].These pass
There is a lot of deficiencies in homogeneous slow releasing preparation of uniting: the drug release of part preparation method is non-linear；Dosage form is the most single,
Dosage and dosage regimen are difficult to flexible Effective Regulation, increase the difficulty of composite drug administration；Certain formulations poor stability, drug effect
Low.So, compounding medicine-feeding technology especially multilamellar slow-release material technology of preparing, the most increasingly by the attention of scholars.Research
Show, Thermosensitive Material Used for Controlled Releasing of Medicine is designed to multiple structure, the release behavior of the notable regulating medicine of energy.
Qiu et al. [2] have studied ibuprofen by the permeability after chitosan and sodium carboxymethyl cellulose encapsulation, sends out
Now can form by changing cyst wall and regulate wall thickness and control the release of medicine.Cuomo [3] et al. is with dye, rhodamine
B is model drug, have studied rhodamine B by the permeability after the chitosan of the different numbers of plies and alginate encapsulation, finds to compare
For 3 layers and 5 Rotating fields, the cyst wall structure of higher number (7 layers) makes the infiltration rate of dyestuff the slowest.Chen etc. [4] are by I type
Collagen and medicine rapamycin are the most alternately sprayed at metal support surface (type i collagen is for being close to metal surface), outermost layer
Spraying type i collagen layer is to reduce medicine initial release value, and by genipin (genipin), type i collagen is carried out crosslinking Treatment
Prevent it from dissolving.The number of plies of the multilayer medicine slow-release material of experiment preparation is up to 21 layers, and (11 layers of type i collagen, 10 layers of auspicious handkerchief are mould
Element), drug release behavior is characterized, finds that medicine is essentially constant release, without obvious phenomenon of burst release, drug release is lasting
Time is relevant to the number of plies.Paclitaxel, in the self assembling multilayer medicine-carried system of phospholipid and polyvinyl alcohol, is carried on by Choi etc. [5]
Phospholipid layer, by changing the relative position of medicine carrying phospholipid layer, drugs anticancer proliferation function.Research finds to work as medicine carrying
Layer is when top, and release incipient cell propagation is suppressed rapidly, when drug-loaded layer is hindered by barrier layer at bottom drug release,
Cell quantity held stationary.The regulation of this drug loading mode has obvious regulating and controlling effect for drug release behavior.
Though more than studying the dosage that conventional homogeneous medicine carrying material can be overcome to bring and dosage regimen being difficult to the most effectively
The problems such as regulation and control, but owing to its multiplex solwution method is prepared, there is solvent removing difficulty, matrix and medicament selection has relatively overall situation
Sex-limited, complex process, it is difficult to meet the demand of industrialization large-scale production.For solving these problems, to adding once melted
Multilayer medicine slow-release material is prepared, it is achieved the most effectively release of medicine is compounding with good, controls biodegradation high during work
The Rotating fields of molecular material is crucial.How material is made to possess rational initial release concentration and long-term release by structure design
Speed, reaches the most quick-acting but also long-acting purpose, increases dosage and the flexible adjustability of dosage regimen of Thermosensitive Material Used for Controlled Releasing of Medicine,
Meeting the difference needs of drug release is present stage problem in the urgent need to address.
List of references
[1] Zhu Xingnian. medicament slow release, the progress of controlled release preparation. pharmacy practice magazine, 2002,20 (3): 155-
157.
[2] Qiu X, Leporatti S, Donath E, et al. Studies on the drug release
properties of polysaccharide multilayers encapsulated ibuprofen
microparticles. Langmuir, 2001, 17(17): 5375-5380.
[3] Cuomo F, Lopez F, Piludu M, et al. Release of small hydrophilic
molecules from polyelectrolyte capsules: Effect of the wall thickness.
Journal of colloid and interface science, 2015, 447: 211-216.
[4] Chen M C, Liang H F, Chiu Y L, et al. A novel drug-eluting stent
spray-coated with multi-layers of collagen and sirolimus. Journal of
controlled release, 2005, 108(1): 178-189.
[5] Choi J, Konno T, Takai M, et al. Regulation of cell proliferation by
multi-layered phospholipid polymer hydrogel coatings through controlled
release of paclitaxel. Biomaterials, 2012, 33(3): 954-961。
Summary of the invention
Shortcoming and the deficiency of biostromal degraded macromolecular Thermosensitive Material Used for Controlled Releasing of Medicine is prepared for conventional solution method, the present invention's
Purpose be directed to a kind of melted coextrusion prepare that configuration can determine structure, performance can design, can be continuously produced, drug release
The method of the biostromal degraded macromolecular drug release material that behavior is the most controlled.The method can be designed by structure and regulate and control
Drug distribution makes material possess rational initial release concentration and required long-term rate of release, reaches the most quick-acting but also long-acting mesh
, increase dosage and the flexible adjustability of dosage regimen of Thermosensitive Material Used for Controlled Releasing of Medicine, meet the different needs to drug release；
By the design to different drug effect drug loading situations, the good compounding of different drug effect medicine can be realized；And medicine can be realized release
Put performance and mechanical property improves simultaneously.The method has that continuous production is strong, steady quality, suitable large-scale industry metaplasia simultaneously
The advantage produced.
The ultimate principle of the present invention is, obtains polymer-based drug loading layer material and polymer-based resistance by design of components
Interlayer material, makes polymer-based drug loading layer material and polymer-based barrier layer material alternately by the way of melted coextrusion
Ordered arrangement forms alternately stratiform Biodegradable high molecular drug release material, and is designed by alternating layer structure, flexible modulation
Polymer-based drug loading layer morphosis, optimizes medicine dispersity；Utilize layer multiplexer cutting when repeatedly stratiform overlaps
Cut, stretching action makes macromolecule be deformed in extrusion and be orientated, and regulates and controls polymer-based barrier layer matrix and dispersion phase
Morphosis, improve drug diffusion and release channel so as to get alternately stratiform Biodegradable high molecular drug release material
Possess rational initial release concentration and required long-term rate of release, reach the most quick-acting but also long-acting purpose.Simultaneously because not
With medicine, obtained release channel had different release responses, so can load in polymer-based drug loading layer simultaneously
Different pharmaceutical, is spread by regulating drug and release channel regulates and controls the release behavior of different pharmaceutical, it is achieved different drug effect medicines
Good compounding.The present invention, from this point, is devoted to realize the polymer-based medicine of different drug release behavior in processing method
Load layer and the good of polymer-based barrier layer alternately compound, and by the form of material monolayer structures and integral layer structure is adjusted
Control comes Drug controlled release cycle, thus regulating medicine release in alternately stratiform Biodegradable high molecular drug release material
Behavior.Specifically, the present invention is than changing medicine release behavior in polymer-based drug loading layer by component, uses
Melted coextrusion processes passes through dispersity and the macromolecule of shear tension effect regulating drug under layering superposed force field action
Orientation, and by regulating polymer-based drug loading layer and the single layer structure of polymer-based barrier layer, the number of plies and relative thickness
Change drug release passage regulating medicine deenergized period, the alternately stratiform Biodegradable high molecular medicine controlled releasing material finally given
The drug release behavior of material is the most adjustable, and mechanical property also obtains synchronizing to improve.
The present invention is based on above-mentioned principle, it is achieved foregoing invention purpose be the technical scheme is that by following polymer-based
Drug loading layer material and polymer-based barrier layer material extruded machine fusion plastification extrusion respectively is the most folded in junction station exit
After being combined the following initiating structure of formation, if then through the repeatedly stratiform overlapping work of the dried layer multiplexer that is connected with junction station
With, formed and there is the biphase extrudate being arranged alternately multiple structure:
(1) macromolecule in polymer-based drug loading layer described in is relatively indissoluble solution or the biodegradated polymer materal of degraded
(macromolecule matrix of drug loading layer) and be prone to dissolve or degraded the biodegradated polymer materal (high score of drug loading layer
Sub-dispersion phase) it is 50～99.99%:50～0.01% blends carrying out mixing by weight percentage；
(2) biodegradated polymer materal that macromolecule is relatively indissoluble solution or the degraded (resistance in the polymer-based barrier layer described in
The macromolecule matrix of interlayer) and be prone to dissolve or macromolecular material (the fractionated polymer dephasing of the barrier layer) percentage by weight of degraded
Ratio is 50～99%:50～1% blends carrying out mixing.
If above-mentioned during the repeatedly stratiform overlapping effect of the dried layer multiplexer being connected with junction station, preparation side
Method use disclosed in the Chinese patent CN101439576A that the applicant applies for by extruder (A, B), allotter (C), layer times
The microbedding co-extruder that increasing device (D) and outlet mold (E) are constituted, is characterized in preparing polymer-based drug loading layer material the most respectively
With polymer-based barrier layer material, then polymer-based drug loading layer material and polymer-based barrier layer material are put into respectively
In the two extruders (A, B) of microbedding co-extrusion device, after fusion plastification, make two strands of melts overlapping in allotter (C), through n
After the cutting of individual layer multiplexer (D) and superposition, flow out from outlet mold (E), then through the compacting of tri-roll press machine and traction machine
Traction, obtains 2(n+1)Layer is by the most alternatively distributed alternately biostromal of polymer-based drug loading layer and polymer-based barrier layer
Degraded macromolecular drug release material.
Thus can realize polymer-based drug loading layer and polymer-based barrier layer by multi-layer co-extruded method
Alternately superposition, and by building the morphosis of composite, it is achieved alternately stratiform Biodegradable high molecular medicine controlled releasing material
The structure optimization of material, makes material possess rational initial release concentration and required long-term rate of release, and makes medicine releasability
Can be improved with mechanical property simultaneously.The preparation method of this new bio degraded macromolecular Thermosensitive Material Used for Controlled Releasing of Medicine on the one hand energy
The morphosis of flexible modulation macromolecular material, thus the release behavior that regulating medicine is wherein, on the other hand can avoid solvent
Use, fundamentally solve solvent and be difficult to process, pollute the problem such as environment.
The alternately stratiform Biodegradable high molecular drug release material of above-mentioned gained is actual is that sheet type medicament slow release is combined
Material, can be cut into the medicament slow release composite of difformity and size, thus meet not further according to release and application demand
Same release demand.
The blend that macromolecule is biodegradated polymer materal in polymer-based drug loading layer described above, the most relatively
The macromolecular material of indissoluble solution or degraded is matrix (macromolecule matrix of the most polymer-based drug loading layer), selected from poly-own interior
One in ester, polylactic acid, poly-succinic fourth diester, hydroxypropyl cellulose, ethyl cellulose and cellulose acetate；It is prone to dissolve
Or the macromolecular material of degraded is dispersion phase (the fractionated polymer dephasing of the most polymer-based drug loading layer), selected from polyoxyethylene
One in alkene, Polyethylene Glycol, thermoplastic starch and thermoplastic polyvinyl alcohol.
Described above in polymer-based drug loading layer medicament contg is this floor height total molecular weight 0.01～
40%, in ibuprofen, ketoprofen, spectinomycin hydrochloride, chlorphenamine maleate, hydrochlorothiazide and diclofenac sodium
One or more.
The above-mentioned mode first preparing polymer-based drug loading layer material is at high mixer by macromolecule and medicine in this layer
In mix.
The above-mentioned mode first preparing polymer-based drug loading layer material can also be macromolecule and medicine in this layer to be existed
Extruder carries out melting mixing.
The above-mentioned mode first preparing polymer-based drug loading layer material can also be by first to macromolecule in this layer and medicine
High mixer mixes, then carries out melting mixing in an extruder.
The macromolecule matrix in polymer-based barrier layer described above is selected from polycaprolactone, polylactic acid, poly-succinic
One in fourth diester, hydroxypropyl cellulose, ethyl cellulose and cellulose acetate, the macromolecule dispersion of polymer-based barrier layer
One in polyethylene glycol oxide, Polyethylene Glycol, thermoplastic starch and thermoplastic polyvinyl alcohol mutually.
The above-mentioned mode first preparing polymer-based barrier layer material is to be entered in high mixer by polyblend in this layer
Row mixing.
The above-mentioned mode first preparing polymer-based barrier layer material can also be in extrusion by polyblend in this layer
Machine carries out melting mixing.
The above-mentioned mode first preparing polymer-based barrier layer material can also be first at height by polyblend in this layer
Mixed machine mixes, then carries out melting mixing in an extruder.
Extrudate described above is by two extruders (A, B), junction station (C) if dried layer multiplexer (D), outlet mold (E)
The multilayer extrusion system formed with cooling tractor (F) prepares by melt extruding, and its medicine controlled releasing performance can be passed through
Gross thickness, the thickness ratio of internal total number of plies, polymer-based drug loading layer and polymer-based barrier layer regulate and control, wherein:
The gross thickness of extrudate is 0.01-10mm；Total number of plies number within extrudate is 2-32769；Described polymer-based medicine is born
The thickness of carrier layer and polymer-based barrier layer is than for 1:99-99:1.
The number of plies of extrudate initiating structure described above can be entered by the switch convection current number of channels in described junction station (C)
Row regulation and control: the initiating structure that the initiating structure that 2 runners obtain is 2 layers, 3 runners obtain is 3 layers；The number of plies of extrudate can be led to
Cross the initiating structure number of plies and layer multiplexer number regulate and control in such a way:
(1) it is 2 layers when initiating structure, and when using n layer multiplexer, the number of plies of extrudate is 2(n+1)Layer, wherein: n is 0-
14。
(2) it is 3 layers when initiating structure, and when using n layer multiplexer, the number of plies of extrudate is 2(n+1)+ 1 layer, wherein: n
For 0-14.
The present invention compared with the method that the solwution method of prior art prepares biostromal degraded macromolecular Thermosensitive Material Used for Controlled Releasing of Medicine,
Sum up and there is advantage highlighted below:
1, alternately stratiform Biodegradable high molecular drug release material prepared by the present invention forms drug loading layer and barrier layer is handed over
For the layer structure of arrangement, the cuniform channel of combination layer multiplexer can refine dispersed phase size, improve phase morphology.Select different number
The layer multiplexer of amount, and can design level configuration and polymer-based drug loading layer and high score by regulation and control extruder rotating ratio
The thickness ratio of subbase barrier layer, and then determine the release channel needed for structure, and then the deenergized period of regulating medicine, processability is controlled
Material, while realizing the Intelligentized regulating and controlling of macromolecular structure, form and medicine-releasing performance synchronize improve the mechanics of materials
Performance.
2, the method can realize the selectivity dispersion of medicine, and can realize the good compounding of different pharmaceutical, thus obtains not
Controlled compound release behavior with drug effect medicine.
3, can accurately calculate and control drug loading, overcome the medicine forbidden due to drug loading metering and cause to release
High-volume it is difficult to the difficult problem accurately controlled.Medicine addition is the most adjustable simultaneously, and it accounts between 0.01～40% of polymer weight,
The shortcoming that when avoiding being typically prepared drug controlled release system, medicine addition limitation is big.
4, the method for melted coextrusion disclosed by the invention preparation alternately stratiform Biodegradable high molecular drug release material,
Preparation process one-shot forming, technique is simple, convenient operation and control；Biocompatibility is good, to human non-toxic's evil effect, is not required to add
Add other reagent that human body is had burden, it is adaptable to the great majority controllable release to hot insensitive medicine.By regulation and control
The extrusion rotating ratio of two extruders, can adjust the thickness of drug-loaded layer and barrier layer；By controlling the number of increase and decrease layer multiplexer
Amount, can the number of plies of flexible alternate multiple material, and then the release behavior of regulating medicine.
5, the method is the raising of a kind of continuous flow procedure, beneficially production efficiency；Technique is simple, between different batches
Product quality indicator stable, can large-scale industrial production, applied range, there is wide industrialization and market prospect；
Achieve polymeric articles high performance and functionalization is same, improve the surcharge of polymeric articles, widened polymer
The range of application of product, significant at aspects such as polymer composites theoretical research and application and developments.
Accompanying drawing explanation
Further illustrate the present invention below in conjunction with the accompanying drawings.
Fig. 1 is the structural representation of microbedding co-extruder involved in the present invention: A, B are extruder；C is allotter；D is
Layer multiplexer；E is cooling tractor.
Fig. 2 is the structure enlarged diagram of multi-layer biological degraded macromolecular Thermosensitive Material Used for Controlled Releasing of Medicine prepared by the present invention.At figure
In, F: drug-loaded layer, G: barrier layer.
Specific implementation method:
By the following examples the present invention is further described specifically.In following embodiment, the consumption of each component
It is quality consumption.Be necessary it is pointed out here that, the present invention is simply further illustrated by example below, it is impossible to be interpreted as this
The restriction of invention protection domain, person skilled in art can carry out some non-according to the invention described above content to the present invention
The improvement of matter and adjustment.
Embodiment 1
The first step, polymer-based drug loading layer (hereinafter referred to as drug-loaded layer) selects polycaprolactone to be drug-loaded layer matrix (molecular weight
It is 80000), polyethylene glycol oxide is drug-loaded layer dispersion phase (molecular weight is 100000), and with percentage by weight 90%:10% dispensing；
Spectinomycin hydrochloride is drug-loaded layer medicine, carries out dispensing by the 10% of drug-loaded layer macromolecule gross weight.By above-mentioned macromolecule and medicine
Thing mixes 5 minutes in height stirs machine, and its rotating speed is 100 revs/min, obtains polymer-based drug loading layer material.
Polymer-based barrier layer (hereinafter referred to as barrier layer) selects polycaprolactone to be that (molecular weight is barrier layer matrix
80000), polyethylene glycol oxide is barrier layer dispersion phase (molecular weight is 100000), and with percentage by weight 70%:30% dispensing.Will
Above-mentioned macromolecule mixes 5 minutes in height stirs machine, and its rotating speed is 100 revs/min, obtains polymer-based barrier layer material.
Second step, the polymer-based drug loading layer material first step prepared and polymer-based barrier layer material are thrown respectively
Enter the microbedding co-extrusion being made up of extruder A, B, distributor C, the layer multiplexer D dress disclosed in Chinese patent CN101439576A
In the extruder A put and extruder B (see Fig. 1), the rotating ratio of regulation drug-loaded layer and barrier layer extruder is 1:1, works as extruder
After interior material melts plasticizing, two strands of melts are made to overlap in distributor C, and when the repeatedly stratiform of 6 layer multiplexers overlaps
Shearing, stretching action, then through the compacting of tri-roll press machine and the traction of traction machine, the total number of plies that i.e. can obtain extrusion is
Wide 40mm, the composite of thick 1.8mm that 128 layers, wherein drug-loaded layer (totally 64 layers) and barrier layer (totally 64 layers) are arranged alternately (are joined
See Fig. 2), wherein, the Thickness ratio of drug-loaded layer and barrier layer is 1:1.Extruder A, B charge door, transportation section, melt zone, homogenizing zone,
Mouth die, junction station, the temperature of layer multiplexer are respectively 40 DEG C, 80 DEG C, 120 DEG C, 120 DEG C, 120 DEG C, 120 DEG C, 120 DEG C.
Alternately stratiform Biodegradable high molecular drug release material obtained above is carried out pelletizing, collection, and through not
The conventional extruder using microbedding co-extruder is extruded, then through the compacting of tri-roll press machine and the traction of traction machine,
To wide 40mm, the homogeneous Biodegradable high molecular drug release material of thick 1.8mm, wherein extruder charge door, transportation section, melted
Section, homogenizing zone, the temperature of mouth die are respectively 40 DEG C, 80 DEG C, 120 DEG C, 120 DEG C, 120 DEG C.Obtained homogeneous biodegradation is high
Molecular medicine releasable material has and the above-mentioned material proportion that alternately stratiform Biodegradable high molecular drug release material is identical, but
Its non-alternating laminated structure, but homogeneous composite construction.Obtained homogeneous Biodegradable high molecular drug release material is at phosphorus
Soaking 24 hours i.e. release in phthalate buffer (PBS) and reach the medicine of 50%, within 5 days, burst size reaches 85%, shows the most prominent releasing
Behavior.
And owing to the present embodiment have employed by 6 layer multiplexers, the drug metoprolol tartrate selectivity that it obtains divides
It is distributed in 128 layers of alternately stratiform Biodegradable high molecular drug release material release 15% in 24 hours of polymer-based drug loading layer
Medicine, 26 days release 93%, demonstrate the mildest controllable release behavior and excellent long-acting release performance.It draws simultaneously
Stretch intensity and also brought up to 14.9 MPa by 10.35 original MPa.Alternately stratiform Biodegradable high molecular medicine controlled releasing material is described
Drug release behavior and the hot strength of material are significantly improved, and are simultaneously achieved drug slow release function and improve and mechanical property
Lifting, make alternately stratiform Biodegradable high molecular drug release material functionalization and the height of carrying medicament spectinomycin hydrochloride
Performance-based is unified.This alternately existing mainly due to drug-loaded layer and barrier layer so that material in immersion process, medicine carrying
Layer is obstructed jacket space restriction effect, and initial release value reduces, and burst drug release disappears, and demonstrates good initial release behavior；
The iris action of barrier layer and layer structure are brought simultaneously layer thickness direction drug diffusion and the change of release channel make release
Cycle stretch-out, demonstrate good long-acting release behavior (owing to material thickness is much smaller than length and width, drug release rate
Determiner is the release behavior of thickness direction medicine).Be additionally, since layer multiplexer repeatedly stratiform overlapping time shearing, draw
Stretching effect, with the presence of becoming hundred bed boundarys in alternate multiple blend, the bed boundary compatibility is good, and cementability is strong, and interface interaction power is big,
So when by extraneous drawing force, according to the equivalent superposition that stratiform is in parallel, the existence of interface interaction imparts
The tensile property that alternate multiple blended compound material is more excellent.So material is while obtaining good release behavior, it is strong
Degree also gets a promotion.The formula of embodiment 1, Thickness ratio and the number of plies can be adjusted according to actual needs, and then obtain different dispersion phase
The alternately stratiform Biodegradable high molecular drug release material of content.
Embodiment 2
The first step, polymer-based drug loading layer (hereinafter referred to as drug-loaded layer) selects poly-succinic fourth diester to be drug-loaded layer matrix
(molecular weight is 100000), Polyethylene Glycol is drug-loaded layer dispersion phase (molecular weight is 6000), and joins with percentage by weight 90%:10%
Material；Ibuprofen is drug-loaded layer medicine, carries out dispensing by the 20% of drug-loaded layer macromolecule gross weight.Above-mentioned macromolecule and medicine are existed
Height stirs in machine and mixes 5 minutes, and its rotating speed is 100 revs/min, obtains polymer-based drug loading layer material.
Polymer-based barrier layer (hereinafter referred to as barrier layer) selects polycaprolactone to be that (molecular weight is barrier layer matrix
80000), polyethylene glycol oxide is barrier layer dispersion phase (molecular weight is 100000), and with percentage by weight 80%:20% dispensing.Will
Above-mentioned macromolecule mixes 5 minutes in height stirs machine, and its rotating speed is 100 revs/min, obtains polymer-based barrier layer material.
Second step, the polymer-based drug loading layer material first step prepared and polymer-based barrier layer material are thrown respectively
Enter the microbedding co-extrusion being made up of extruder A, B, distributor C, the layer multiplexer D dress disclosed in Chinese patent CN101439576A
In the extruder A put and extruder B (see Fig. 1), the rotating ratio of regulation drug-loaded layer and barrier layer extruder is 1:2, works as extruder
After interior material melts plasticizing, two strands of melts are made to overlap in distributor C, and when the repeatedly stratiform of 4 layer multiplexers overlaps
Shearing, stretching action, then through the compacting of tri-roll press machine and the traction of traction machine, the total number of plies that i.e. can obtain extrusion is 32
Layer, the wide 40mm that wherein drug-loaded layer (totally 16 layers) and barrier layer (totally 16 layers) are arranged alternately, the composite of thick 1.8mm (see
Fig. 2), wherein, the Thickness ratio of drug-loaded layer and barrier layer is 1:2.Extruder A, B charge door, transportation section, melt zone, homogenizing zone, mouth
Mould, junction station, the temperature of layer multiplexer are respectively 50 DEG C, 100 DEG C, 130 DEG C, 130 DEG C, 130 DEG C, 130 DEG C, 130 DEG C.
Alternately stratiform Biodegradable high molecular drug release material obtained above is carried out pelletizing, collection, and through not
The conventional extruder using microbedding co-extruder is extruded, then through the compacting of tri-roll press machine and the traction of traction machine,
To wide 40mm, the homogeneous Biodegradable high molecular drug release material of thick 1.8mm, wherein extruder charge door, transportation section, melted
Section, homogenizing zone, the temperature of mouth die are respectively 50 DEG C, 100 DEG C, 130 DEG C, 130 DEG C, 130 DEG C.Obtained homogeneous biodegradation is high
Molecular medicine releasable material has and the above-mentioned material proportion that alternately stratiform Biodegradable high molecular drug release material is identical, but
Its non-alternating laminated structure, but homogeneous composite construction.Obtained homogeneous Biodegradable high molecular drug release material is at phosphorus
Phthalate buffer (PBS) soaks the 24 hours i.e. release medicine more than 45%, demonstrates obvious phenomenon of burst release.
And owing to the present embodiment have employed by 4 layer multiplexers, its medicine ibuprofen obtained is selectively distributed in high score
The medicine of 32 layers of subbase drug loading layer alternately stratiform Biodegradable high molecular drug release material release 18% in 24 hours, 10
It discharges the medicine of 89% altogether, demonstrates the mildest controllable release behavior and excellent long-acting release performance.Its stretching simultaneously
Intensity is also brought up to 46.9 MPa by 35.4 original MPa.Illustrate to replace stratiform Biodegradable high molecular drug release material
Drug release behavior and hot strength are significantly improved, and are simultaneously achieved drug slow release function and improve and the carrying of mechanical property
Rise, make alternately stratiform Biodegradable high molecular drug release material functionalization and the high performance of carrying medicament ibuprofen be united
One.This is mainly due to drug-loaded layer and the alternately existence of barrier layer so that material is in immersion process, and drug-loaded layer is empty by barrier layer
Between restriction effect, initial release value reduce, burst drug release disappear, demonstrate good initial release behavior；Barrier layer simultaneously
Layer thickness direction drug diffusion and the change of release channel that iris action and layer structure are brought make extend deenergized period, display
(owing to material thickness is much smaller than length and width, the determiner of drug release rate is thick to go out good long-acting release behavior
The release behavior of degree direction medicine).Shearing when being additionally, since the repeatedly stratiform overlapping of layer multiplexer, stretching action are alternately the most
With the presence of becoming hundred bed boundarys in layer blend, the bed boundary compatibility is good, and cementability is strong, and interface interaction power is big, so by the external world
During drawing force, according to the equivalent superposition that stratiform is in parallel, the existence of interface interaction imparts alternate multiple and is blended
The tensile property that composite is more excellent.So material is while obtaining good release behavior, its intensity also gets a promotion.
The formula of embodiment 2, Thickness ratio and the number of plies can be adjusted according to actual needs, and then obtain the alternately stratiform of different content of dispersed phase
Biodegradable high molecular drug release material.
Embodiment 3
The first step, polymer-based drug loading layer (hereinafter referred to as drug-loaded layer) selects ethyl cellulose to be drug-loaded layer matrix (molecule
Amount is 130000), Polyethylene Glycol is drug-loaded layer dispersion phase (molecular weight is 6000), and with percentage by weight 80%:20% dispensing；Hydrogen
Chlorothiazide is drug-loaded layer medicine 1, and spectinomycin hydrochloride is drug-loaded layer medicine 2, presses the 20% of drug-loaded layer macromolecule gross weight respectively
Dispensing is carried out with 10%.Above-mentioned macromolecule and medicine being mixed in height stirs machine 5 minutes, its rotating speed is 100 revs/min, obtains
Polymer-based drug loading layer material.
Polymer-based barrier layer (hereinafter referred to as barrier layer) selects ethyl cellulose to be that (molecular weight is barrier layer matrix
80000), Polyethylene Glycol is barrier layer dispersion phase (molecular weight is 6000), and with percentage by weight 80%:20% dispensing.By above-mentioned
Macromolecule mixes 5 minutes in height stirs machine, and its rotating speed is 100 revs/min, obtains polymer-based barrier layer material.
Second step, the polymer-based drug loading layer material first step prepared and polymer-based barrier layer material are thrown respectively
Enter the microbedding co-extrusion being made up of extruder A, B, distributor C, the layer multiplexer D dress disclosed in Chinese patent CN101439576A
In the extruder A put and extruder B (see Fig. 1), the rotating ratio of regulation drug-loaded layer and barrier layer extruder is 1:1, works as extruder
After interior material melts plasticizing, two strands of melts are made to overlap in distributor C, and when the repeatedly stratiform of 3 layer multiplexers overlaps
Shearing, stretching action, then through the compacting of tri-roll press machine and the traction of traction machine, the total number of plies that i.e. can obtain extrusion is 16
Layer, the wide 40mm that wherein drug-loaded layer (totally 8 layers) and barrier layer (totally 8 layers) are arranged alternately, the composite of thick 1.8mm (see figure
2), wherein, the Thickness ratio of drug-loaded layer and barrier layer is 1:1.Extruder A, B charge door, transportation section, melt zone, homogenizing zone, mouth
Mould, junction station, the temperature of layer multiplexer are respectively 50 DEG C, 100 DEG C, 140 DEG C, 140 DEG C, 140 DEG C, 140 DEG C, 140 DEG C.
Alternately stratiform Biodegradable high molecular drug release material obtained above is carried out pelletizing, collection, and through not
The conventional extruder using microbedding co-extruder is extruded, then through the compacting of tri-roll press machine and the traction of traction machine,
To wide 40mm, the homogeneous Biodegradable high molecular drug release material of thick 1.8mm, wherein extruder charge door, transportation section, melted
Section, homogenizing zone, the temperature of mouth die are respectively 50 DEG C, 100 DEG C, 140 DEG C, 140 DEG C, 140 DEG C.Obtained homogeneous biodegradation is high
Molecular medicine releasable material has and the above-mentioned material proportion that alternately stratiform Biodegradable high molecular drug release material is identical, but
Its non-alternating laminated structure, but homogeneous composite construction.Obtained homogeneous Biodegradable high molecular drug release material is at phosphorus
Phthalate buffer (PBS) soaks 48 hours hydrochlorothiazide burst sizes and is about 45%, release 98% in 7 days, 24 hours tartaric acid U.S. torr
Luo Er burst size is 30%, release 95% in 9 days, all demonstrates obvious phenomenon of burst release.
And owing to the present embodiment have employed by 3 layer multiplexers, medicine hydrochlorothiazide that it obtains and tartaric acid Mei Tuoluo
You be selectively distributed in 16 layers of polymer-based drug loading layer alternately stratiform Biodegradable high molecular drug release material 48 little
Time release 25% hydrochlorothiazide, the drug release patterns of 27 days is substantially linear afterwards, and the tartaric acid of release 10% in 24 hours is beautiful
Tuo Luoer, the medicine discharging 94% altogether in 29 days, demonstrate the mildest controllable release behavior and excellent long-acting release performance.
Its hot strength is also brought up to 10.9 MPa by 5.4 original MPa simultaneously.Alternately stratiform Biodegradable high molecular medicine is described
The drug release behavior of controlled-release material and hot strength are significantly improved, and are simultaneously achieved drug slow release function and improve and power
Learn the lifting of performance, make the alternately stratiform Biodegradable high molecular medicine control of carrying medicament hydrochlorothiazide and spectinomycin hydrochloride
Release material functional and high performance is unified.This is mainly due to drug-loaded layer and the alternately existence of barrier layer so that material
In immersion process, drug-loaded layer is obstructed jacket space restriction effect, and initial release value reduces, and burst drug release disappears, and demonstrates good
Good initial release behavior；The iris action of barrier layer and layer structure are brought simultaneously layer thickness direction drug diffusion and release
The change of passage makes extend deenergized period, demonstrates that good long-acting release behavior is (owing to material thickness is much smaller than length and width
Degree, the determiner of drug release rate is the release behavior of thickness direction medicine).It is additionally, since many sublevels of layer multiplexer
Shearing during shape overlapping, stretching action, with the presence of becoming hundred bed boundarys in alternate multiple blend, the bed boundary compatibility is good, bonding
Property strong, interface interaction power is big, so when by extraneous drawing force, according to the equivalent superposition that stratiform is in parallel, boundary
The existence of face effect imparts the tensile property that alternate multiple blended compound material is more excellent.So material is well released in acquisition
While clearance is, its intensity also gets a promotion.The formula of embodiment 3, Thickness ratio and the number of plies can be adjusted according to actual needs, enter
And obtain the alternately stratiform Biodegradable high molecular drug release material of different content of dispersed phase.
Embodiment 4
The first step, polymer-based drug loading layer (hereinafter referred to as drug-loaded layer) selects polylactic acid to be that (molecular weight is drug-loaded layer matrix
180000), thermoplastic starch is drug-loaded layer dispersion phase (molecular weight is 50000), and with percentage by weight 85%:15% dispensing；Double
Chlorine sweet smell acid sodium is drug-loaded layer medicine, carries out dispensing by the 30% of drug-loaded layer macromolecule gross weight.By above-mentioned macromolecule and medicine at height
Stirring in machine and mix 5 minutes, its rotating speed is 100 revs/min, obtains polymer-based drug loading layer material.
Polymer-based barrier layer (hereinafter referred to as barrier layer) selects polylactic acid to be barrier layer matrix (molecular weight is 180000),
Polyethylene Glycol is barrier layer dispersion phase (molecular weight is 60000), and with percentage by weight 60%:40% dispensing.By above-mentioned macromolecule
Mixing 5 minutes in height stirs machine, its rotating speed is 100 revs/min, obtains polymer-based barrier layer material.
Second step, the polymer-based drug loading layer material first step prepared and polymer-based barrier layer material are thrown respectively
Enter the microbedding co-extrusion being made up of extruder A, B, distributor C, the layer multiplexer D dress disclosed in Chinese patent CN101439576A
In the extruder A put and extruder B (see Fig. 1), the rotating ratio of regulation drug-loaded layer and barrier layer extruder is 1:1, works as extruder
After interior material melts plasticizing, two strands of melts are made to overlap in distributor C, and when the repeatedly stratiform of 5 layer multiplexers overlaps
Shearing, stretching action, then through the compacting of tri-roll press machine and the traction of traction machine, the total number of plies that i.e. can obtain extrusion is 64
Layer, the wide 40mm that wherein drug-loaded layer (totally 32 layers) and barrier layer (totally 32 layers) are arranged alternately, the composite of thick 1.8mm (see
Fig. 2), wherein, the Thickness ratio of drug-loaded layer and barrier layer is 1:1.Extruder A, B charge door, transportation section, melt zone, homogenizing zone, mouth
Mould, junction station, the temperature of layer multiplexer are respectively 80 DEG C, 150 DEG C, 180 DEG C, 180 DEG C, 180 DEG C, 180 DEG C, 180 DEG C.
Alternately stratiform Biodegradable high molecular drug release material obtained above is carried out pelletizing, collection, and through not
The conventional extruder using microbedding co-extruder is extruded, then through the compacting of tri-roll press machine and the traction of traction machine,
To wide 40mm, the homogeneous Biodegradable high molecular drug release material of thick 1.8mm, wherein extruder charge door, transportation section, melted
Section, homogenizing zone, the temperature of mouth die are respectively 80 DEG C, 150 DEG C, 180 DEG C, 180 DEG C, 180 DEG C.Obtained homogeneous biodegradation is high
Molecular medicine releasable material has and the above-mentioned material proportion that alternately stratiform Biodegradable high molecular drug release material is identical, but
Its non-alternating laminated structure, but homogeneous composite construction.Obtained homogeneous Biodegradable high molecular drug release material is at phosphorus
Phthalate buffer (PBS) soaks the 24 hours i.e. release diclofenac sodium more than 50%, demonstrates obvious phenomenon of burst release.
And owing to the present embodiment have employed by 5 layer multiplexers, the medicine diclofenac sodium that it obtains is selectively distributed in
64 layers of polymer-based drug loading layer replace double chlorine of stratiform Biodegradable high molecular drug release material release 20% in 24 hours
Fragrant acid sodium, the drug release patterns of 11 days is substantially linear afterwards, demonstrates the mildest controllable release behavior and excellent
Long-acting release performance.Its hot strength is also brought up to 73.9 MPa by 40.4 original MPa simultaneously.Alternately biostromal is described
The drug release behavior of degraded macromolecular drug release material and hot strength are significantly improved, and are simultaneously achieved medicine and delay
Release function to improve and the lifting of mechanical property, make the alternately stratiform Biodegradable high molecular medicine control of carrying medicament diclofenac sodium
Release material functional and high performance is unified.This is mainly due to drug-loaded layer and the alternately existence of barrier layer so that material
In immersion process, drug-loaded layer is obstructed jacket space restriction effect, and initial release value reduces, and burst drug release disappears, and demonstrates good
Good initial release behavior；The iris action of barrier layer and layer structure are brought simultaneously layer thickness direction drug diffusion and release
The change of passage makes extend deenergized period, demonstrates that good long-acting release behavior is (owing to material thickness is much smaller than length and width
Degree, the determiner of drug release rate is the release behavior of thickness direction medicine).It is additionally, since many sublevels of layer multiplexer
Shearing during shape overlapping, stretching action, with the presence of becoming hundred bed boundarys in alternate multiple blend, the bed boundary compatibility is good, bonding
Property strong, interface interaction power is big, so when by extraneous drawing force, according to the equivalent superposition that stratiform is in parallel, boundary
The existence of face effect imparts the tensile property that alternate multiple blended compound material is more excellent.So material is well released in acquisition
While clearance is, its intensity also gets a promotion.The formula of embodiment 4, Thickness ratio and the number of plies can be adjusted according to actual needs, enter
And obtain the alternately stratiform Biodegradable high molecular drug release material of different content of dispersed phase.
Embodiment 5
The first step, polymer-based drug loading layer (hereinafter referred to as drug-loaded layer) selects hydroxypropyl cellulose to be that drug-loaded layer matrix (divides
Son amount is 1150000), Polyethylene Glycol is plasticizer (molecular weight is 400), and with percentage by weight 98%:2% dispensing；Maleic acid
Chlorphenamine is drug-loaded layer medicine, carries out dispensing by the 5% of drug-loaded layer macromolecule gross weight.By above-mentioned macromolecule and medicine at height
Stirring in machine and mix 5 minutes, its rotating speed is 100 revs/min, obtains polymer-based drug loading layer material.
Polymer-based barrier layer (hereinafter referred to as barrier layer) selects poly-succinic fourth diester to be barrier layer matrix, polyoxyethylene
Alkene is barrier layer dispersion phase (molecular weight is 1000000), and with percentage by weight 90%:10% dispensing.By above-mentioned macromolecule at height
Stirring in machine and mix 5 minutes, its rotating speed is 100 revs/min, obtains polymer-based barrier layer material.
Second step, the polymer-based drug loading layer material first step prepared and polymer-based barrier layer material are thrown respectively
Enter the microbedding co-extrusion being made up of extruder A, B, distributor C, the layer multiplexer D dress disclosed in Chinese patent CN101439576A
In the extruder A put and extruder B (see Fig. 1), the rotating ratio of regulation drug-loaded layer and barrier layer extruder is 1:1, works as extruder
After interior material melts plasticizing, two strands of melts are made to overlap in distributor C, and when the repeatedly stratiform of 2 layer multiplexers overlaps
Shearing, stretching action, then through the compacting of tri-roll press machine and the traction of traction machine, the total number of plies that i.e. can obtain extrusion is 8
Layer, the wide 40mm that wherein drug-loaded layer (totally 4 layers) and barrier layer (totally 4 layers) are arranged alternately, the composite of thick 1.8mm (see figure
2), wherein, the Thickness ratio of drug-loaded layer and barrier layer is 1:1.Extruder A, B charge door, transportation section, melt zone, homogenizing zone, mouth
Mould, junction station, the temperature of layer multiplexer are respectively 80 DEG C, 150 DEG C, 180 DEG C, 180 DEG C, 180 DEG C, 180 DEG C, 180 DEG C.
Alternately stratiform Biodegradable high molecular drug release material obtained above is carried out pelletizing, collection, and through not
The conventional extruder using microbedding co-extruder is extruded, then through the compacting of tri-roll press machine and the traction of traction machine,
To wide 40mm, the homogeneous Biodegradable high molecular drug release material of thick 1.8mm, wherein extruder charge door, transportation section, melted
Section, homogenizing zone, the temperature of mouth die are respectively 80 DEG C, 150 DEG C, 180 DEG C, 180 DEG C, 180 DEG C.Obtained homogeneous biodegradation is high
Molecular medicine releasable material has and the above-mentioned material proportion that alternately stratiform Biodegradable high molecular drug release material is identical, but
Its non-alternating laminated structure, but homogeneous composite construction.Obtained homogeneous Biodegradable high molecular drug release material is at phosphorus
Soaking the 24 hours i.e. release medicine more than 60% in phthalate buffer (PBS), within 3 days afterwards, release is close to completely, demonstrates release
There is the most prominent releasing at initial stage.
And owing to the present embodiment have employed by 2 layer multiplexers, the medicine chlorphenamine maleate selectivity that it obtains divides
8 layers that are distributed in polymer-based drug loading layer replace the release 20% in 48 hours of stratiform Biodegradable high molecular drug release material
Medicine, reaches 95% to the 17th day release amount of medicine, shows that the method that the present embodiment uses can significantly reduce the prominent of release initial stage and release row
For, demonstrate the mildest controllable release behavior and excellent long-acting release performance.Its hot strength is also by original simultaneously
25.68 MPa bring up to 37.89 MPa.The drug release behavior of alternately stratiform Biodegradable high molecular drug release material is described
It is significantly improved with hot strength, is simultaneously achieved drug slow release function and improves and the lifting of mechanical property, make load medicine
Alternately stratiform Biodegradable high molecular drug release material functionalization and the high performance of thing chlorphenamine maleate are unified.
This alternately existing mainly due to drug-loaded layer and barrier layer so that material is in immersion process, and drug-loaded layer is obstructed jacket space
Restriction effect, initial release value reduces, and burst drug release disappears, and demonstrates good initial release behavior；The resistance of barrier layer simultaneously
Change every effect and the layer thickness direction drug diffusion brought of layer structure and release channel makes extend deenergized period, demonstrates
(owing to material thickness is much smaller than length and width, the determiner of drug release rate is thickness to good long-acting release behavior
The release behavior of direction medicine).Be additionally, since layer multiplexer repeatedly stratiform overlapping time shearing, stretching action, alternate multiple
With the presence of becoming hundred bed boundarys in blend, the bed boundary compatibility is good, and cementability is strong, and interface interaction power is big, so being drawn by the external world
When stretching active force, according to the equivalent superposition that stratiform is in parallel, the existence of interface interaction imparts alternate multiple and is blended multiple
The tensile property that condensation material is more excellent.So material is while obtaining good release behavior, its intensity also gets a promotion.Can
Adjust the formula of embodiment 5, Thickness ratio and the number of plies according to actual needs, and then the alternately stratiform obtaining different content of dispersed phase is raw
Thing degraded macromolecular drug release material.
Claims (6)
1. the method preparing alternately stratiform Biodegradable high molecular drug release material, it is characterised in that this medicine controlled releasing material
Expect by polymer-based drug loading layer material and polymer-based barrier layer material extruded machine fusion plastification extrusion respectively and converging
Stream device exit is superimposed together after the following initiating structure of formation, if then through the dried layer multiplexer that is connected with described junction station
Repeatedly stratiform overlapping effect, formation there is polymer-based drug loading layer and multilamellar knot that polymer-based barrier layer is arranged alternately
Structure extrudate:
(1) macromolecule in polymer-based drug loading layer described in is relatively indissoluble solution or the biodegradated polymer materal of degraded
(macromolecule matrix of drug loading layer) and be prone to dissolve or degraded the biodegradated polymer materal (high score of drug loading layer
Sub-dispersion phase) it is 50～99.99%:50～0.01% blends carrying out mixing by weight percentage；
(2) the relatively indissoluble solution that the macromolecule in polymer-based barrier layer is melt-processable described in or the macromolecule material of degraded
Weight pressed by material (macromolecule matrix of barrier layer) and the macromolecular material (the fractionated polymer dephasing of barrier layer) being prone to dissolve or degrade
Amount percentage ratio is 50～99.99%:50～0.01% blends carrying out mixing.
Preparation the most according to claim 1 replaces the method for stratiform Biodegradable high molecular drug release material, its feature
It is that the macromolecule matrix of described polymer-based drug loading layer is selected from polycaprolactone, polylactic acid, poly-succinic fourth diester, hydroxyl
One in propyl cellulose, ethyl cellulose and cellulose acetate；The fractionated polymer dephasing of drug loading layer is selected from polyoxygenated
One in ethylene, Polyethylene Glycol, thermoplastic starch and thermoplastic polyvinyl alcohol.
3., according to the method for the alternately stratiform Biodegradable high molecular drug release material of the preparation described in claim 1 and 2, it is special
Levy medicament contg is this floor height total molecular weight 0.01～40% be in described polymer-based drug loading layer, be selected from
One or several in ibuprofen, ketoprofen, spectinomycin hydrochloride, chlorphenamine maleate, hydrochlorothiazide and diclofenac sodium
Kind.
Preparation the most according to claim 1 replaces the method for stratiform Biodegradable high molecular drug release material, its feature
The macromolecule matrix being in described polymer-based barrier layer is selected from polycaprolactone, polylactic acid, poly-succinic fourth diester, hydroxypropyl
One in base cellulose, ethyl cellulose and cellulose acetate, the fractionated polymer dephasing of polymer-based barrier layer is selected from polyoxy
Change the one in ethylene, Polyethylene Glycol, thermoplastic starch and thermoplastic polyvinyl alcohol.
Preparation the most according to claim 1 replaces the method for stratiform Biodegradable high molecular drug release material, its feature
It is that described extrudate is if dried layer multiplexer (D), outlet mold (E) and cooling are led by two extruders (A, B), junction station (C)
The multilayer extrusion system that leading-in device (F) forms prepares by melt extruding, and its medicine controlled releasing performance can pass through gross thickness, interior
The thickness ratio of total number of plies in portion, polymer-based drug loading layer and polymer-based barrier layer regulates and controls, wherein: extrudate total
Thickness is 0.01-10mm；Total number of plies number within extrudate is 2-32769；Described polymer-based drug loading layer and high score
The thickness of subbase medicine barrier layer is than for 1:99-99:1.
Preparation the most according to claim 1 replaces the method for stratiform Biodegradable high molecular drug release material, its feature
It is that the number of plies of described extrudate initiating structure can be regulated and controled by the switch convection current number of channels in described junction station (C): 2
The initiating structure that the initiating structure that individual runner obtains is 2 layers, 3 runners obtain is 3 layers；The number of plies of extrudate can be by initial knot
The structure number of plies and layer multiplexer number regulate and control in such a way:
(1) it is 2 layers when initiating structure, and when using n layer multiplexer, the number of plies of extrudate is 2(n+1)Layer, wherein: n is 0-
14；
(2) it is 3 layers when initiating structure, and when using n layer multiplexer, the number of plies of extrudate is 2(n+1)+ 1 layer, wherein: n is 0-
14。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107260654A (en) * | 2017-06-01 | 2017-10-20 | 四川大学 | It is a kind of to prepare the method that Thermo-sensitive replaces stratiform insoluble drug release composite |
| CN114623069A (en) * | 2022-05-17 | 2022-06-14 | 成都科建生物医药有限公司 | Pump and liposome preparation device with same |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85102106A (en) * | 1984-02-08 | 1987-01-31 | 美国辉瑞有限公司 | The laminated device of control and the environment thing release towards periphery of prolongation material |
| CN1407886A (en) * | 1999-11-11 | 2003-04-02 | 罗曼治疗系统股份公司 | Multi-layer preparation in film form, consisting of hydrophilic polymers, for rapid release of active ingredients |
| CN101439576A (en) * | 2008-12-18 | 2009-05-27 | 四川大学 | Method for preparing polymer-based damping composite material capable of being designed into alternate laminar structure |
| CN102482818A (en) * | 2009-07-07 | 2012-05-30 | 可乐丽可乐富丽世股份有限公司 | Laminated sheet, and process for production thereof |
-
2016
- 2016-09-05 CN CN201610801407.3A patent/CN106237338A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85102106A (en) * | 1984-02-08 | 1987-01-31 | 美国辉瑞有限公司 | The laminated device of control and the environment thing release towards periphery of prolongation material |
| CN1407886A (en) * | 1999-11-11 | 2003-04-02 | 罗曼治疗系统股份公司 | Multi-layer preparation in film form, consisting of hydrophilic polymers, for rapid release of active ingredients |
| CN101439576A (en) * | 2008-12-18 | 2009-05-27 | 四川大学 | Method for preparing polymer-based damping composite material capable of being designed into alternate laminar structure |
| CN102482818A (en) * | 2009-07-07 | 2012-05-30 | 可乐丽可乐富丽世股份有限公司 | Laminated sheet, and process for production thereof |
Non-Patent Citations (1)
| Title |
|---|
| X.JIN，ET AL.: "Tailored additive release rates in extruded plastic films produced with smart blending machines", 《JOURNAL OF PLASTIC FILM & SHEETING》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107260654A (en) * | 2017-06-01 | 2017-10-20 | 四川大学 | It is a kind of to prepare the method that Thermo-sensitive replaces stratiform insoluble drug release composite |
| CN114623069A (en) * | 2022-05-17 | 2022-06-14 | 成都科建生物医药有限公司 | Pump and liposome preparation device with same |
| CN114623069B (en) * | 2022-05-17 | 2022-08-09 | 成都科建生物医药有限公司 | Pump and liposome preparation device with same |
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