CN103735490A - Method for preparing medicament sustained-release material - Google Patents
Method for preparing medicament sustained-release material Download PDFInfo
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- CN103735490A CN103735490A CN201410004813.8A CN201410004813A CN103735490A CN 103735490 A CN103735490 A CN 103735490A CN 201410004813 A CN201410004813 A CN 201410004813A CN 103735490 A CN103735490 A CN 103735490A
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
- B29B7/00—Mixing; Kneading
- B29B7/30—Mixing; Kneading continuous, with mechanical mixing or kneading devices
- B29B7/34—Mixing; Kneading continuous, with mechanical mixing or kneading devices with movable mixing or kneading devices
- B29B7/38—Mixing; Kneading continuous, with mechanical mixing or kneading devices with movable mixing or kneading devices rotary
- B29B7/46—Mixing; Kneading continuous, with mechanical mixing or kneading devices with movable mixing or kneading devices rotary with more than one shaft
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
- B29B7/00—Mixing; Kneading
- B29B7/30—Mixing; Kneading continuous, with mechanical mixing or kneading devices
- B29B7/58—Component parts, details or accessories; Auxiliary operations
- B29B7/72—Measuring, controlling or regulating
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
- B29B7/00—Mixing; Kneading
- B29B7/74—Mixing; Kneading using other mixers or combinations of mixers, e.g. of dissimilar mixers ; Plant
- B29B7/7461—Combinations of dissimilar mixers
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
- B29B9/00—Making granules
- B29B9/12—Making granules characterised by structure or composition
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
- B29C48/25—Component parts, details or accessories; Auxiliary operations
- B29C48/36—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die
- B29C48/395—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die using screws surrounded by a cooperating barrel, e.g. single screw extruders
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
- B29C48/25—Component parts, details or accessories; Auxiliary operations
- B29C48/36—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die
- B29C48/395—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die using screws surrounded by a cooperating barrel, e.g. single screw extruders
- B29C48/397—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die using screws surrounded by a cooperating barrel, e.g. single screw extruders using a single screw
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
- B29C48/25—Component parts, details or accessories; Auxiliary operations
- B29C48/36—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die
- B29C48/50—Details of extruders
- B29C48/505—Screws
- B29C48/625—Screws characterised by the ratio of the threaded length of the screw to its outside diameter [L/D ratio]
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
- B29C48/25—Component parts, details or accessories; Auxiliary operations
- B29C48/92—Measuring, controlling or regulating
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29B—PREPARATION OR PRETREATMENT OF THE MATERIAL TO BE SHAPED; MAKING GRANULES OR PREFORMS; RECOVERY OF PLASTICS OR OTHER CONSTITUENTS OF WASTE MATERIAL CONTAINING PLASTICS
- B29B9/00—Making granules
- B29B9/02—Making granules by dividing preformed material
- B29B9/06—Making granules by dividing preformed material in the form of filamentary material, e.g. combined with extrusion
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C2948/00—Indexing scheme relating to extrusion moulding
- B29C2948/92—Measuring, controlling or regulating
- B29C2948/92504—Controlled parameter
- B29C2948/92704—Temperature
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C2948/00—Indexing scheme relating to extrusion moulding
- B29C2948/92—Measuring, controlling or regulating
- B29C2948/92819—Location or phase of control
- B29C2948/92828—Raw material handling or dosing, e.g. active hopper or feeding device
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C48/00—Extrusion moulding, i.e. expressing the moulding material through a die or nozzle which imparts the desired form; Apparatus therefor
- B29C48/25—Component parts, details or accessories; Auxiliary operations
- B29C48/36—Means for plasticising or homogenising the moulding material or forcing it through the nozzle or die
- B29C48/50—Details of extruders
- B29C48/505—Screws
- B29C48/52—Screws with an outer diameter varying along the longitudinal axis, e.g. for obtaining different thread clearance
- B29C48/525—Conical screws
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Abstract
The invention discloses a method for preparing a medicament sustained-release composite material. In the method, biodegradable high polymers are taken as a substrate and a dispersed phase, and 50-99 percent by weight of a biodegradable high polymer substrate, 50-1 percent by weight of a biodegradable high polymer dispersed phase, and a medicament of which the amount is 0.01-40 percent based on the total weight of a biodegradable high polymer mixture are fused and mixed by using an extruding machine of a multi-stage bilateral stretching, mixing and pelletizing integrated device, so that structuring of a drug-loading biodegradable high polymer blend is realized, a high polymer drug-loading substrate with flexibly-controllable releasing performance is prepared, and different medicament releasing demands are met. By adopting a continuous production process in the method, the production efficiency is increased, the process is simple, and the quality indexes of different batches of products are stable. The method can be applied to large-scale industrial production, is wide the application range, and has wide industrial and market prospects.
Description
Technical field
The present invention relates to a kind of preparation method of Biodegradable high molecular Thermosensitive Material Used for Controlled Releasing of Medicine, relate in particular that a kind of melt blending prepares that configuration can determine that structure, performance can design, can be continuously produced, the drug release behavior method of controlled Biodegradable high molecular Thermosensitive Material Used for Controlled Releasing of Medicine flexibly, belong to functional composite material technical field.
Background technology
Medicament slow release preparation claims again Atrigel (sustained release drug delivery system), compare with traditional drug-supplying system, they do not need frequent drug administration, can maintain effective drug level in body in the long period, can greatly improve drug effect and reduce toxic and side effects.Medicine carrying material generally divides not Biodegradable material and biodegradation material two classes, wherein biodegradated polymer materal as pharmaceutical carrier to control the slow release of medicine, due to its good biocompatibility, avirulence, do not need second operation to take out, metabolite, to the advantage such as human body is free of a burden, has become one of main direction of studying of medicament slow release.
Tradition is prepared the method for polymer drug slow releasing preparation and how in solution, to be carried out, such as Pitarresi etc., by graft reaction, prepare poly-[α, β-(N-2-second hydroxyl)-DL-agedoite] and copolymer of poly lactic acid (PHEA-PLA), it is 7.4 phosphate buffer that the dimethyl sulphoxide solution of PHEA-PLA is dropwise splashed into pH, adopt the synthetic PHEA-PLA copolymer gel of situ-gel method, that utilizes that the carboxyl of copolymer side chain and the strong ion pair effect of model drug leuprorelin amido slow down medicine prominently releases behavior, extends its release time [1].Polylactic acid-lysine copolymer (poly[L-lactic acid-co-l-lysine (Z)]) is prepared in the employing lysines such as Kidchob and lactide ring-opening polymerisation, and adopt w/o/w solvent evaporated method to prepare copolymer microcapsule, research lactide and the impact of lysine content on microcapsule release behavior.Result shows, along with lysine content increases, copolymer microcapsule is by the smooth roughening gradually of surfacing, in TRIS buffer (pH is 7.5), more easily degrade and form micropore, model drug dextran (FITC-dextran) is discharged and accelerate, thereby can control drug release rate [2] by controlling the content of lysine.Though these methods can obtain the pharmaceutical carrier of different release behaviors, there is solvent and remove difficulty, complex process, residual solvent easily to shortcomings such as human body generation toxic and side effects.So, adopt under non-solvent condition and prepare medicament slow release preparation, especially melting preparation method is just more and more subject to the attention of researcher.
The hydroxypropyl emthylcellulose that Ghosh etc. be take through different graft reactions is matrix, propylene glycol is plasticizer, NVS981 is that model drug adopts extrusion by melting to prepare medicine carrying material, through grinding to sieve, choose the sample that particle diameter is less than 0.8 mm and carry out Soak Test, find that the rate of release of medicine NVS981 is accelerated [3] with grafting group hydrophilic.Negrin etc. adopt polylactic acid/hydroxy acetate multipolymer (PLGA) or polylactic acid (PLA) and the blend of model drug methadone, and room temperature tabletting makes methadone embedded type tablet under 433 or 347 MPa pressure.In the research methadone phosphate buffer that is 7.4 at pH and the release behavior in animal body, find that prepared methadone tablet can keep standard at the uniform velocity to discharge [4] in one month.The Peppas in the Austin of Texas ,Usa university branch school, the people such as McGinity and professor Fukuda is engaged in the research that extrusion by melting is prepared Thermosensitive Material Used for Controlled Releasing of Medicine for a long time, mainly to adopt different Biodegradable high molecular (chitosans, microcrystalline Cellulose, polylactic acid etc.) as excipient or dispersant, carry out the load of medicine, the release behavior [5-8] of drugs in different buffer.
Though more than research can overcome solwution method and prepares the solvent that medicine carrying material brings and remove the problems such as difficulty, it mostly is homogeneous system, and dosage regimen is difficult to flexible Effective Regulation, is difficult to meet the release demand of different solubility property medicines.For addressing this problem, to realize effectively discharging with well composite flexibly of medicine in a melt-processed process, the morphosis of controlling biodegradated polymer materal is crucial.How in the Effective Regulation course of processing, the morphosis of decentralized photo is present stage problem in the urgent need to address to obtaining the complex carrier of diverse microcosmic structure.
list of references
[1]?Giovanna?Pitarresi,?Fabio?S.?Palumbo,?Antonella?Albanese,?Mariano?Licciardi,?Filippo?Calascibetta,?Gaetano?Giammona.?In?situ?gel?forming?graft?copolymers?of?a?polyaspartamide?and?polylactic?acid:?Preparation?and?characterization.?European?Polymer?Journal,?2008,?44:?3764-3775.
[2]?Tongjit?Kidchob,?Shunsaku?Kimura,?Yukio?Imanishi.?Degradation?and?release?profile?of?microcapsules?made?of?poly[L-lactic?acid-co-l-lysine(Z)].?Journal?of?Controlled?Release,?1998,?54:?283-292.
[3]?Indrajit?Ghosh,?Jennifer?Snyder,?Radha?Vippagunta,?Marilyn?Alvine,?Ronak?Vakil,?Wei-Qin?(Tony)?Tong,?Sudha?Vippagunta.?Comparison?of?HPMC?based?polymers?performance?as?carriers?for?manufacture?of?solid?dispersions?using?the?melt?extruder.?International?Journal?of?Pharmaceutics.?2011,?419:?12-19.
[4]?C.?M.?Negrin,?A.?Delgado,?M.?Llabres,?C.?Evora.?Methadone?implants?for?methadone?maintenance?treatment.?In?vitro?and?in?vivi?animal?studies.?Journal?of?Controlled?Release,?2004,?95:?413-421.
[5]?Michael?M.?Crowley,?Britta?Schroeder,?Anke?Fredersdorf,?Sakae?Obara,?Mark?Talarico,?Shawn?Kucera,?James?W.?McGinity.?Physicochemical?properties?and?mechanism?of?drug?release?from?ethyl?cellulose?matrix?tablets?prepared?by?direct?compression?and?hot-melt?extrusion.?International?Journal?of?Pharmaceutics.?2004,?269(2):?509-522.
[6]?Mamoru?Fukuda,?Nicholas?A.?Peppas,?James?W.?McGinity.?Floating?hot-melt?extruded?tablets?for?gastroretentive?controlled?drug?release?system.?Journal?of?Controlled?Release.?2006,?115(2):?121-129.
[7]?Mamoru?Fukuda,?Nicholas?A.?Peppas,?James?W.?McGinity.?Properties?of?sustained?release?hot-melt?extruded?tablets?containing?chitosan?and?xanthan?gum.?International?Journal?of?Pharmaceutics.?2006,?310:?90-100.
[8]?Michael?M.?Crowley,?Feng?Zhang,?Michael?A.?Repka,?Sridhar?Thumma,?Sampada?B.?Upadhye,?Sunil?Kumar?Battu,?James?W.?McGinity,?Charles?Martin.?Pharmaceutical?Applications?of?Hot-Melt?Extrusion:?Part?I.?2007,?33(9):?909-926。
Summary of the invention
For traditional solwution method, prepare the shortcoming of Biodegradable high molecular Thermosensitive Material Used for Controlled Releasing of Medicine and the deficiency of existing fusion preparation method, object of the present invention is intended to propose that a kind of melt blending prepares that configuration can determine that structure, performance can design, can be continuously produced, the drug release behavior method of controlled Biodegradable high molecular Thermosensitive Material Used for Controlled Releasing of Medicine flexibly, the method can be improved medicine and the deployment conditions of decentralized photo in macromolecule matrix, in simple process, realize medicine discharge flexibly effectively and well composite, and realize medicine-releasing performance and mechanical property improves simultaneously.The advantage that the method has that continuous production is strong simultaneously, steady quality, suitability for mass industrializedization are produced.
Ultimate principle of the present invention is, in view of the dispersity of medicine different with rate of dissolution larger on drug release behavior impact, so in Biodegradable polymer blended thing, if can regulate and control flexibly the rate of dissolution morphosis of decentralized photo faster, its dispersion and state of orientation are optimized, thereby the dispersion behavior of the fine regulating drug of energy in polyblend, improve drug diffusion and release channel, also the release behavior of regulating medicine flexibly just, and can when adding two or more medicines, realize the composite release of different pharmaceutical.Simultaneously medicine and Biodegradable high molecular matrix and decentralized photo mix and preparation technology's change also can change medicine deployment conditions therein, thereby obtain different drug release behaviors.The present invention, from this point, is devoted to improve the dispersity of medicine and decentralized photo, thus the release behavior of regulating medicine in processing method.Specifically, the present invention adopts the high mixed and/or dispersion of melting mixing process reform medicine in polymer in mixed process; In the course of processing, allow polymer melt shunt and biaxial tension deformation under the effect of biaxial tension stress field, improve medicine and the decentralized photo dispersity in polymeric matrix, the drug release behavior of the medicament slow release composite finally obtaining is adjustable flexibly, and mechanical property is also synchronously improved.
The present invention is based on above-mentioned principle, realize the technical scheme that foregoing invention object adopts and be: the present invention be take Biodegradable high molecular as matrix and decentralized photo, comprises the steps:
The first step, is 50～99%:50～1% by Biodegradable high molecular matrix, Biodegradable high molecular decentralized photo by weight percentage, and medicine is pressed 0.01～40% batching of Biodegradable high molecular matrix and decentralized photo gross weight;
Second step, carries out dried by said medicine;
The 3rd step, adopts high mixed and/or melting mixing technique to obtain corresponding pre-composition in the medicine after dried and Biodegradable high molecular matrix and decentralized photo;
The 4th step, the pre-composition that the 3rd step is obtained is put in the extruder (1) of the combined bidirectional stretching mixed-forming integrated apparatus consisting of extruder (1), adapter (2), single or combined bidirectional stretching blender (3) and chiller (4), wherein in the body shell of biaxial tension melt mixer, is provided with the wedge shape melt flow channel that 2～10 varying levels extend; Polymer melt flow through adapter and in the different cuniform channels of biaxial tension blender (3) shunting, biaxial tension deformation and superimposed after, cooling through apparatus for supercooling (4), can obtain medicament slow release composite.
In above-mentioned the 4th step, through extruder (1), the polymer melt that adapter (2) flows out is shunted at the charging aperture place of biaxial tension blender (3), flow into the wedge shape melt flow channel of 2～10 varying levels extensions and occur superimposed at cuniform channel end, when flowing through cuniform channel, can there is stretching ratio and be 2～10 times and (while being two such as cuniform channel, be 2 times in polymer melt, in the time of three, be 3 times, in the time of four, be 4 times, in the time of eight, be 8 times) biaxial tension deformation, it disperses and state of orientation is optimized, and every process biaxial tension melt mixer once disperses just to optimize once (when blender is combined bidirectional stretching blender) with state of orientation, so just can further improve dispersity in polymeric matrix of medicine and decentralized photo and build the planform of composite by the method for melt blending, realize the structure optimization of medicament slow release composite, medicine-releasing performance and mechanical property are improved simultaneously.Explanation, is provided with n cuniform channel in the housing of biaxial tension blender again, n can be between 2～10 value, that is: 10≤n≤2, n both desirable even numbers 2,4,6,8,10, again 3 of desirable odd number, 5,7,9; Biaxial tension blender (3) can consist of single biaxial tension blender, also can by two or more (such as: 2～20) form linear connection of biaxial tension blender; When biaxial tension blender (3) is combined bidirectional stretching blender, it is connected and form along melt flows direction is linear by the biaxial tension melt mixer of two or more (that is: n value is identical) of the same type and/or dissimilar (that is: n value is not identical or inconsistent), and whole entrance size and whole outlet size between adjacent blender match.This novel method of preparing Biodegradable high molecular Thermosensitive Material Used for Controlled Releasing of Medicine can regulate and control the morphosis of macromolecular material on the one hand flexibly, thereby regulating medicine release behavior therein, can avoid the use of solvent on the other hand, fundamentally solve solvent and be difficult to process, the problems such as contaminated environment.
Described in above-mentioned the 3rd step, high mixed and/or melting mixing technique is that medicine is mixed in high mixer with Biodegradable high molecular matrix and decentralized photo.
Described in above-mentioned the 3rd step, high mixed and/or melting mixing technique can be also the melting mixing that medicine and Biodegradable high molecular matrix and decentralized photo are carried out in extruder.
Described in above-mentioned the 3rd step high mixed and/or melting mixing technique can be also by medicine and Biodegradable high molecular matrix together with decentralized photo after high-speed mixer and mixing melting mixing in extruder again.
Described in above-mentioned the 3rd step high mixed and/or melting mixing technique can be also by medicine and Biodegradable high molecular matrix or decentralized photo elder generation after high mixer mixes in extruder melting mixing, the then melting mixing in extruder with Biodegradable high molecular decentralized photo or matrix.
Described in above-mentioned the 3rd step, the mixed and/or melting mixing technique of different height can obtain the pre-composition of different structure, obtain and there is the polymer/drug compound system that different drug selectivities disperses, thereby flexible regulating medicine release behavior, reaches the object of controllable release.
In above-mentioned the 4th step the medicament slow release composite of gained actual be sheet type medicament slow release composite, can according to release and application demand, be cut into the medicament slow release composite of difformity and size again, thereby meet different release demands.
Biodegradable high molecular matrix described in the above-mentioned first step is one or more in polycaprolactone, polylactic acid, poly-succinic fourth diester, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate.
Biodegradable high molecular decentralized photo described in the above-mentioned first step is one or more in polyethylene glycol oxide, Polyethylene Glycol, starch, polyacrylic acid, polyvinyl alcohol.
Medicine described in the above-mentioned first step is one or more in ibuprofen, cefalexin, vancomycin, theophylline, hydrochlorothiazide, diclofenac sodium, amoscanate.
In above-mentioned the 3rd step, the temperature of the charge door of melting mixing technique extruder used, transportation section, melt zone, homogenizing zone, mouthful mould is respectively 30～180 ℃, 50～220 ℃, 50～220 ℃, 50～220 ℃, 50～220 ℃.
The temperature of the charge door of the extruder (1) that above-mentioned the 4th step is used, transportation section, melt zone, homogenizing zone, adapter (2), biaxial tension melt mixer (3) is respectively 30～180 ℃, 50～220 ℃, 50～220 ℃, 50～220 ℃, 50～220 ℃, 50～220 ℃.
The present invention compares with the method that Biodegradable high molecular Thermosensitive Material Used for Controlled Releasing of Medicine is prepared in the melting of prior art, sum up have advantages of following outstanding:
1, the cuniform channel of combined bidirectional stretching blender can refinement dispersed phase size, improve phase morphology, the degree of orientation that changes strand is, the draw ratio that improves decentralized photo or slenderness ratio etc.Select different combined bidirectional stretching blenders, polymer-based melt is applied to the biaxial tension force field of varying strength, can design and determine the required configuration of structure, the material that processability is controlled can synchronously improve material mechanical performance in the Intelligentized regulating and controlling of realizing macromolecular structure, form and medicine-releasing performance.
2, energy accurate Calculation and control drug loading amount, overcome because the inaccurate release amount of medicine causing of drug loading amount metering is difficult to an accurately difficult problem for control.Simultaneously medicine addition is adjustable flexibly, its account for polymer weight 0.01～40% between, the large shortcoming of medicine addition limitation while avoiding generally preparing drug controlled release system.
3, the method for Biodegradable high molecular Thermosensitive Material Used for Controlled Releasing of Medicine is prepared in melting disclosed by the invention, not needing to add other has the reagent of burden to human body, technique is simple, and biocompatibility is good, to human body nonhazardous effect, be applicable to the controllable release of great majority to the insensitive medicine of heat.
4, the method is a kind of continuous flow procedure, is conducive to the raising of production efficiency; Technique is simple, and product quality indicator between different batches is stable, can large-scale industrial production, and applied range, has wide industrialization and market prospect; Realize polymeric articles high performance and functionalization same, improved the surcharge of polymeric articles, widened the range of application of polymeric articles, significant at aspects such as polymer composites theoretical research and application and developments.
Accompanying drawing explanation
Below in conjunction with accompanying drawing, further illustrate the present invention.
Fig. 1 is the biaxial tension mixed-forming integrated apparatus structural representation that the present invention uses
Fig. 2 is that adapter is along the profile of melt flows direction
Fig. 3 is the discharge port end structural representation of adapter
Fig. 4 is the entrance point structural representation of 1 minute 2 types (n=2) biaxial tension blender
Fig. 5 is the port of export structural representation of 1 minute 2 types (n=2) biaxial tension blender
Fig. 6 is that 1 minute 2 types (n=2) biaxial tension blender is along the profile of melt flows direction
Fig. 7 is the entrance point structural representation of 1 minute 4 types (n=4) biaxial tension blender
Fig. 8 is the port of export structural representation of 1 minute 4 types (n=4) biaxial tension blender
Fig. 9 is that 1 minute 4 types (n=4) biaxial tension blender is along the profile of melt flows direction
Figure 10 is the entrance point structural representation of 1 minute 8 types (n=8) biaxial tension blender
Figure 11 is the port of export structural representation of 1 minute 8 types (n=8) biaxial tension blender
Figure 12 is that 1 minute 8 types (n=8) biaxial tension blender is along the profile of melt flows direction
The sign object of the shown by reference numeral in above-mentioned accompanying drawing is:
In Fig. 1～3: 1 is extruder; 2 is adapter; 3 is combined bidirectional stretching blender; 4 is chiller; 5 is goods; 2-1 is adapter runner discharging opening.
In Fig. 4～6: 4-1,4-2 are rectangle entrance; 4-3 is mediastinum; 5-1,5-3 are rectangle outlet; 5-2 is tabula; 6-1,6-2 are cuniform channel; 4-4,5-4,6-3 are housing.
In Fig. 7～9: 7-1,7-2,7-3,7-4 are rectangle entrance; 7-5 is mediastinum; 8-1,8-2,8-3,8-4 are rectangle outlet; 8-5 is tabula; 9-1,9-2,9-3,9-4 are cuniform channel; 7-6,8-6,9-5 are housing.
In Figure 10～12: 10-1,10-2,10-3,10-4,10-5,10-6,10-7,10-8 are rectangle entrance; 10-9 is mediastinum; 11-1,11-2,11-3,11-4,11-5,11-6,11-7,11-8 are rectangle outlet; 11-9 is tabula; 12-1,12-2,12-3,12-4,12-5,12-6,12-7,12-8 are cuniform channel; 10-10,11-10,12-9 are housing.
specific implementation method:
By the following examples the present invention is further described specifically.In following embodiment, the consumption of each component is quality consumption.Be necessary to point out at this, below embodiment just to of the present invention, further illustrate, can not be interpreted as limiting the scope of the invention, person skilled in art can carry out some nonessential improvement and adjustment to the present invention according to the invention described above content.
The raw material of a kind of polycaprolactone (matrix)/polyethylene glycol oxide (decentralized photo) medicament slow release composite comprises following component and weight portion content:
Illustrate: the weight of cefalexin (for medicine) is 1% of Biodegradable high molecular matrix and decentralized photo gross weight.
The first step, first gets the raw materials ready by said components;
Second step, is placed in 60 ℃ of vacuum drying ovens dry 6 hours by medicine;
The 3rd step, the dry cefalexin that second step is obtained is placed in high mixer premixing 5 minutes together with polycaprolactone, polyethylene glycol oxide, its rotating speed is 100 revs/min, obtains medicine and polymer pre-composition, by premix composite particles in vacuum drying oven 50 ℃ dry 3 hours.
The 4th step, the medicine that the 3rd step is obtained and polymer pre-composition are put into shown in Fig. 1 in the single screw extrusion machine 1 of the biaxial tension mixing granulation integrated apparatus consisting of single screw extrusion machine 1, adapter 2, single or combined bidirectional stretching blender 3 and chiller 4.At this, the structure of biaxial tension mixing granulation integrated apparatus once is first described.In Fig. 1, chiller adopts three roller coolers, and extruder discharging mouth is connected with adapter charging aperture, adapter discharging opening is connected with single or combined bidirectional stretching blender charging aperture, single or combined bidirectional stretching blender discharging opening and chiller are connected; Wherein, extruder discharging mouth end, adapter feed inlet end and discharge port end, single or combined bidirectional stretching blender feed inlet end and discharge port end are plane, use screw to connect; The screw diameter of extruder 1 is 65mm, and draw ratio is 28:1; Adapter discharging opening, single or combined bidirectional stretching blender charging aperture and discharging opening are rectangular configuration, and its width is parallel to macromolecule melt flow direction, and thickness is perpendicular to macromolecule melt flow direction, and its width and thickness are respectively 100mm and 5mm; Adapter 2 adopts Fig. 2 structures, its adapter runner discharging opening 2-1 be rectangle (seeing Fig. 3).Biaxial tension blender 3 in Fig. 1 can adopt single biaxial tension blender to form, and also can adopt the biaxial tension blender of 2～20 linear companies of being connected of head and the tail to form.The combined bidirectional stretching blender of the present embodiment is eight grades of combined bidirectional stretching blenders, concrete 1 minute 2 type (that is: the number n=2 of cuniform channel) the biaxial tension blenders that adopt 8 head and the tail linearities to be connected form, in each biaxial tension blender, be provided with the cuniform channel 6-1 that two varying levels stretch, 6-2, article two, cuniform channel is all along the attenuation that broadens gradually of melt flows direction, towards different level heights, extend simultaneously, the 2 biaxial tension blenders (seeing Fig. 6) that form 1 minute, the front end charging aperture 4-1 of two cuniform channels, 4-2 is that (seeing Fig. 4) arranged in left and right at blender charging aperture place, the end discharging opening 5-1 of two cuniform channels, 5-3 is (seeing Fig. 5) arranged vertically up and down at blender discharging opening place, the front end of each cuniform channel and end are rectangular configuration, the twice that end width is front end length, and end thickness is nose thickness 1/2nd.
After polycaprolactone/polyethylene glycol oxide/cefalexin pre-composition is put into the single screw extrusion machine 1 shown in figure l and is passed through the charge door of extruder, transportation section, melt zone, homogenizing zone, mobile polymer melt is squeezed into adapter 2 and is split into two strands at the charging aperture place of combined bidirectional stretching blender 3, enter respectively two different cuniform channels, then occur superimposed at cuniform channel end; Stretching ratio can occur macromolecule melt when flowing through cuniform channel is the biaxial tension deformation of 2 times, it disperses and state of orientation is optimized, and every process biaxial tension blender once disperses just to optimize once with state of orientation, so just can further improve dispersity in polymeric matrix of decentralized photo and medicine and build the planform of composite by the method for melt blending, realize medicine-releasing performance and mechanical property Synchronous lifting; Polymer melt is cooling through three roller coolers 5 again, then at convection oven inner drying, and (sheet type) of the present invention medicament slow release composite that can obtain being dried.Wherein, the temperature of the charge door of single screw extrusion machine 1, transportation section, melt zone, homogenizing zone, adapter, biaxial tension blender is respectively 60 ℃, 100 ℃, 100 ℃, 100 ℃, 100 ℃, 100 ℃.
In above-mentioned the 4th step, if soaking in phosphate buffer (PBS), polycaprolactone/polyethylene glycol oxide while not adopting biaxial tension blender/cefalexin composite within 24 hours, discharges the medicine that surpasses 50%, demonstrate the significantly prominent phenomenon of releasing, and because the present embodiment has adopted eight grades of combined bidirectional stretching blenders that are comprised of 81 minute 2 types (n=2) biaxial tension blenders, its polycaprolactone/polyethylene glycol oxide obtaining/cefalexin composite discharges 10% medicine for 24 hours, within 7 days, discharge 91%, demonstrate more mild controllable release behavior.Eight grades of its hot strengths of combined bidirectional stretching blender that simultaneously adopt 8 biaxial tension blenders to form are also brought up to 5.6 MPa by 2.3 original MPa, the melt that polycaprolactone/polyethylene glycol oxide/cefalexin composite be described in combined bidirectional stretching blender, be subject to after strong shearing force field effect drug release behavior and hot strength equal be improved significantly; Realized the lifting of drug slow release function improvement and mechanical property simultaneously, polycaprolactone/polyethylene glycol oxide/cefalexin composite functionalization and high performance are unified.
It is worth mentioning that, in the biaxial tension mixed-forming integrated apparatus adopting at embodiment 1: the first, in the housing of each biaxial tension blender, the cuniform channel that n varying level stretches can be set, n can be between 2～10 value, i.e. 10≤n≤2; Such as when the n=4, the 4 biaxial tension melt mixers (referring to Fig. 7～9) that form 1 minute; When n=8, the 8 biaxial tension melt mixers (referring to Figure 10～12) that form 1 minute; Wherein, the entrance of melt flow channel is rectangle, is horizontal; Each runner, along the attenuation that broadens gradually of melt flows direction, extends towards different level heights simultaneously, and its exit is rectangle and is arranged vertically; The exit width of each runner equals or approaching n times of equaling throat width, and exit thickness equals or the approaching 1/n that equals inlet thickness.The second, melt mixer can select a biaxial tension melt mixer to form.The 3rd, melt mixer also can select two or more (such as: 2～20) biaxial tension melt mixer along melt flows direction is linear, connect, to form multistage-combination (that is: when n is identical) or multistage hybrid combining when inconsistent (that is: n have) biaxial tension melt mixer, mediastinum between adjacent channels entrance is thin type structure, tabula between outlet is thin type structure, now only requires that whole entrance size and the whole outlet size between adjacent blender matches.As required, the combined bidirectional stretching melt mixer of the present embodiment can select the of the same type of varying number and or dissimilar biaxial tension blender linearity be connected to form multistage-combination or multistage hybrid combining biaxial tension melt mixer, thereby design and determine the morphosis of the polymer-based blend of structure or composite, the material that processability is controlled, the Intelligentized regulating and controlling of implementation structure, form and performance.The 4th, single screw extrusion machine 1 also can adopt double screw extruder structure; Three roller coolers 4 also can adopt air-cooled engine.
The raw material of a kind of polylactic acid (matrix)/polyethylene glycol oxide (decentralized photo) medicament slow release composite comprises following component and weight portion content:
Illustrate: the weight of diclofenac sodium (for medicine) is 5% of Biodegradable high molecular matrix and decentralized photo gross weight.
The first step, first gets the raw materials ready by said components;
Second step, is placed in 60 ℃ of vacuum drying ovens dry 6 hours by medicine;
The 3rd step, the dry diclofenac sodium that second step is obtained, polylactic acid are placed in high mixer premixing 5 minutes together with polyethylene glycol oxide, and its rotating speed is 100 revs/min, obtains medicine and polymer pre-composition.Again the medicine obtaining and polymer pre-composition dropped into double screw extruder melt blending, extrude, after pelletize polylactic acid/polyethylene glycol oxide/diclofenac sodium premix composite particles, by premix granule in vacuum drying oven 50 ℃ dry 3 hours, wherein the temperature of double screw extruder charge door, transportation section, melt zone, homogenizing zone, mouthful mould is respectively 100 ℃, 180 ℃, 180 ℃, 180 ℃, 180 ℃.
The 4th step, puts into dried polylactic acid/polyethylene glycol oxide/diclofenac sodium premix composite particles in the single screw extrusion machine 1 of the biaxial tension mixed-forming integrated apparatus consisting of single screw extrusion machine 1, adapter 2, combined bidirectional stretching blender 3 and chiller (specifically adopting three roller coolers) 4 shown in Fig. 1; Wherein, the structure of adapter and biaxial tension blender is as shown in Fig. 2-12, that is: the biaxial tension mixing granulation integrated apparatus that the present embodiment 2 adopts is identical with embodiment 1; The polymer melt obtaining through extruder fusion plastification is flowed through after adapter, combined bidirectional stretching blender, (sheet type) polylactic acid/polyethylene glycol oxide/diclofenac sodium composite that obtains being dried after convection oven inner drying again after chiller is cooling, i.e. medicament slow release composite.Wherein, the charge door of single screw extrusion machine 1, transportation section, melt zone, homogenizing zone, adapter, biaxial tension mixer temperature are respectively 100 ℃, 170 ℃, 180 ℃, 180 ℃, 180 ℃, 180 ℃.
In above-mentioned the 4th step, if soaking in phosphate buffer (PBS), polylactic acid/polyethylene glycol oxide while not adopting biaxial tension blender/diclofenac sodium composite within 48 hours, discharges the medicine that surpasses 60%, demonstrate the significantly prominent phenomenon of releasing, and because the present embodiment has adopted by 41 minute 2 types (n=2) (Fig. 4-6) and 2 six grades of hybrid combining biaxial tension blenders that 1 minute 4 types (n=4) (Fig. 7-9) biaxial tension blender forms, its polylactic acid/polyethylene glycol oxide obtaining/diclofenac sodium composite discharges 13% medicine for 48 hours, the drug release curve of 11 days is afterwards linear substantially, within 13 days, discharge altogether 87% medicine, demonstrate more mild controllable release behavior.Adopt 41 minute 2 types (n=2) and 2 six grades of hybrid combining biaxial tension blenders that 1 minute 4 types (n=4) biaxial tension blender forms simultaneously, its hot strength is also brought up to 13.2 MPa by 10.1 original MPa, the melt that polylactic acid/polyethylene glycol oxide/diclofenac sodium composite is described in combined bidirectional stretching blender, be subject to after strong shearing force field effect drug release behavior and hot strength all be improved significantly; Realized the lifting of drug slow release function improvement and mechanical property simultaneously, polylactic acid/polyethylene glycol oxide/diclofenac sodium composite functionalization and high performance are unified.
It is worth mentioning that, in the biaxial tension mixed-forming integrated apparatus adopting at embodiment 2: the first, in the housing of each biaxial tension blender, the cuniform channel that n varying level stretches can be set, n can be between 2～10 value, i.e. 10≤n≤2; Such as when the n=4, the 4 biaxial tension melt mixers (referring to Fig. 7～9) that form 1 minute; When n=8, the 8 biaxial tension melt mixers (referring to Figure 10～12) that form 1 minute; Wherein, the entrance of melt flow channel is rectangle, is horizontal; Each runner, along the attenuation that broadens gradually of melt flows direction, extends towards different level heights simultaneously, and its exit is rectangle and is arranged vertically; The exit width of each runner equals or approaching n times of equaling throat width, and exit thickness equals or the approaching 1/n that equals inlet thickness.The second, melt mixer can select a biaxial tension melt mixer to form.The 3rd, melt mixer also can select two or more (such as: 2～20) biaxial tension melt mixer along melt flows direction is linear, connect, to form multistage-combination (that is: when n is identical) or multistage hybrid combining when inconsistent (that is: n have) biaxial tension melt mixer, mediastinum between adjacent channels entrance is thin type structure, tabula between outlet is thin type structure, now only requires that whole entrance size and the whole outlet size between adjacent blender matches.As required, the combined bidirectional stretching melt mixer of the present embodiment can select the of the same type of varying number and or dissimilar biaxial tension blender linearity be connected to form multistage-combination or multistage hybrid combining biaxial tension melt mixer, thereby design and determine the morphosis of the polymer-based blend of structure or composite, the material that processability is controlled, the Intelligentized regulating and controlling of implementation structure, form and performance.The 4th, single screw extrusion machine 1 also can adopt double screw extruder structure; Three roller coolers 4 also can adopt air-cooled engine.
The raw material of a kind of polycaprolactone-polylactic acid (matrix)/polyethylene glycol oxide (decentralized photo) medicament slow release composite comprises following component and weight portion content:
Illustrate: the weight of ibuprofen cefalexin (for medicine) is 20% of Biodegradable high molecular matrix 1-2 and decentralized photo gross weight.
The first step, first gets the raw materials ready by said components;
Second step, is placed in 60 ℃ of vacuum drying ovens dry 6 hours by medicine;
The 3rd step, the dry ibuprofen that second step is obtained, polycaprolactone, polylactic acid drop into together double screw extruder melt blending, extrude, after pelletize medicine and polymer premix granule, by premix composite particles in vacuum drying oven 50 ℃ dry 3 hours, wherein the temperature of double screw extruder charge door, transportation section, melt zone, homogenizing zone, mouthful mould is respectively 80 ℃, 170 ℃, 180 ℃, 180 ℃, 180 ℃.
The 4th step, puts into dried polycaprolactone-polylactic acid/polyethylene glycol oxide/ibuprofen premix composite particles in the single screw extrusion machine 1 of the biaxial tension mixed-forming integrated apparatus consisting of single screw extrusion machine 1, adapter 2, combined bidirectional stretching blender 3 and chiller 4 shown in Fig. 1; Wherein, the structure of adapter and biaxial tension blender is as shown in Fig. 2-12, that is: the biaxial tension mixed-forming integrated apparatus that the present embodiment 3 adopts is identical with embodiment 1; The polymer melt obtaining through extruder fusion plastification is flowed through after adapter, combined bidirectional stretching blender, cooling through three roller coolers again, then at convection oven inner drying, (sheet type) polycaprolactone-polylactic acid/polyethylene glycol oxide/ibuprofen composite that obtains being dried, i.e. medicament slow release composite.Wherein, the temperature of the charge door of single screw extrusion machine 1, transportation section, melt zone, homogenizing zone, adapter, biaxial tension blender is respectively 80 ℃, 170 ℃, 180 ℃, 180 ℃, 180 ℃, 180 ℃.
In above-mentioned the 4th step, if soaking in phosphate buffer (PBS), polycaprolactone-polylactic acid/polyethylene glycol oxide while not adopting biaxial tension blender/ibuprofen composite within 48 hours, discharges the medicine that surpasses 40%, 7 days afterwards burst size less thaies 6%, demonstrating the release initial stage has significantly prominent releasing, in not enough phenomenon of later stage burst size.And because the present embodiment has adopted by 21 minute 4 types (Fig. 7-9) and 1 three grades of hybrid combining biaxial tension blender that 1 minute 8 types (Figure 10-12) biaxial tension blender forms, its polycaprolactone-polylactic acid/polyethylene glycol oxide obtaining/ibuprofen composite discharges 20% medicine for 48 hours, the release amount of medicine of 7 days is about 51% afterwards, what show that method that the present embodiment adopts can significantly reduce the release initial stage prominently releases behavior, and the later stage release that increases medicine, improve utilization ratio of drug.Three grades of its hot strengths of hybrid combining biaxial tension blender that simultaneously adopt 3 biaxial tension blenders to form are also brought up to 3.4 MPa by 1.9 original MPa, the melt that polycaprolactone-polylactic acid/polyethylene glycol oxide/ibuprofen composite be described in combined bidirectional stretching blender, be subject to after strong shearing force field effect drug release behavior and hot strength equal be improved significantly; Realized the lifting of drug slow release function improvement and mechanical property simultaneously, polycaprolactone-polylactic acid/polyethylene glycol oxide/ibuprofen composite functionalization and high performance are unified.
It is worth mentioning that, in the biaxial tension mixed-forming integrated apparatus adopting at embodiment 3: the first, in the housing of each biaxial tension blender, the cuniform channel that n varying level stretches can be set, n can be between 2～10 value, i.e. 10≤n≤2; Such as when the n=4, the 4 biaxial tension melt mixers (referring to Fig. 7～9) that form 1 minute; When n=8, the 8 biaxial tension melt mixers (referring to Figure 10～12) that form 1 minute; Wherein, the entrance of melt flow channel is rectangle, is horizontal; Each runner, along the attenuation that broadens gradually of melt flows direction, extends towards different level heights simultaneously, and its exit is rectangle and is arranged vertically; The exit width of each runner equals or approaching n times of equaling throat width, and exit thickness equals or the approaching 1/n that equals inlet thickness.The second, melt mixer can select a biaxial tension melt mixer to form.The 3rd, melt mixer also can select two or more (such as: 2～20) biaxial tension melt mixer along melt flows direction is linear, connect, to form multistage-combination (that is: when n is identical) or multistage hybrid combining when inconsistent (that is: n have) biaxial tension melt mixer, mediastinum between adjacent channels entrance is thin type structure, tabula between outlet is thin type structure, now only requires that whole entrance size and the whole outlet size between adjacent blender matches.As required, the combined bidirectional stretching melt mixer of the present embodiment can select the of the same type of varying number and or dissimilar biaxial tension blender linearity be connected to form multistage-combination or multistage hybrid combining biaxial tension melt mixer, thereby design and determine the morphosis of the polymer-based blend of structure or composite, the material that processability is controlled, the Intelligentized regulating and controlling of implementation structure, form and performance.The 4th, single screw extrusion machine 1 also can adopt double screw extruder structure; Three roller coolers 4 also can adopt air-cooled engine.
The raw material of a kind of poly-succinic fourth diester (matrix)/polyethylene glycol-ethylene oxide (decentralized photo) medicament slow release composite comprises following component and weight portion content:
Illustrate: the weight of diclofenac sodium (for medicine) is 35% of Biodegradable high molecular matrix and decentralized photo 1-2 gross weight.
The first step, first gets the raw materials ready by said components;
Second step, is placed in 60 ℃ of vacuum drying ovens dry 6 hours by medicine;
The 3rd step, the dry diclofenac sodium that second step is obtained is placed in high mixer premixing 5 minutes together with Polyethylene Glycol, polyethylene glycol oxide, and its rotating speed is 100 revs/min, obtains medicine and Polyethylene Glycol, polyethylene glycol oxide pre-composition; Again the medicine obtaining and Polyethylene Glycol, polyethylene glycol oxide pre-composition dropped into double screw extruder melt blending, extrude, after pelletize polyethylene glycol-ethylene oxide/diclofenac sodium premix granule, by premix granule in vacuum drying oven 50 ℃ dry 3 hours, wherein the temperature of double screw extruder charge door, transportation section, melt zone, homogenizing zone, mouthful mould is respectively 50 ℃, 80 ℃, 80 ℃, 80 ℃, 80 ℃; Finally, by the polyethylene glycol-ethylene oxide/diclofenac sodium premix granule obtaining drop into double screw extruder melt blending together with poly-succinic fourth diester, extrude, after pelletize medicine and polymer premix composite particles, by premix composite particles in vacuum drying oven 50 ℃ dry 3 hours, wherein the temperature of double screw extruder charge door, transportation section, melt zone, homogenizing zone, mouthful mould is respectively 80 ℃, 130 ℃, 150 ℃, 150 ℃, 150 ℃.
The 4th step, puts into dried poly-succinic fourth diester/polyethylene glycol-ethylene oxide/diclofenac sodium premix composite particles in the single screw extrusion machine 1 of the biaxial tension mixed-forming integrated apparatus consisting of single screw extrusion machine 1, adapter 2, combined bidirectional stretching blender 3 and chiller (i.e. three roller coolers) 4 shown in Fig. 1; Wherein, the structure of adapter and biaxial tension blender is as shown in Fig. 2-12, that is: the biaxial tension mixed-forming integrated apparatus that the present embodiment 4 adopts is identical with embodiment 1; The polymer melt obtaining through extruder fusion plastification is flowed through after adapter, combined bidirectional stretching blender, three roller coolers are cooling, and at convection oven inner drying, (sheet type) poly-succinic fourth diester/polyethylene glycol-ethylene oxide/diclofenac sodium composite that obtains being dried, i.e. medicament slow release composite.Wherein, the temperature of the charge door of single screw extrusion machine 1, transportation section, melt zone, homogenizing zone, adapter, biaxial tension blender is respectively 80 ℃, 150 ℃, 150 ℃, 150 ℃, 150 ℃, 150 ℃.
In above-mentioned the 4th step, if poly-succinic fourth diester/polyethylene glycol-ethylene oxide/diclofenac sodium composite does not soak and within 24 hours, discharges the medicine that surpasses 45% in phosphate buffer (PBS) while adopting biaxial tension blender, demonstrate the significantly prominent phenomenon of releasing, and because the present embodiment has adopted eight grades of combined bidirectional stretching blenders that are comprised of 81 minute 2 type biaxial tension blenders (Fig. 4-6), poly-succinic fourth diester/polyethylene glycol-ethylene oxide/diclofenac sodium composite that it obtains discharges 18% medicine for 24 hours, within 10 days, discharge altogether 89% medicine, demonstrate more mild controllable release behavior.Eight grades of its hot strengths of combined bidirectional stretching blender that simultaneously adopt 81 minute 2 type biaxial tension blenders to form are also brought up to 6.9 MPa by 5.4 original MPa, the melt that poly-succinic fourth diester/polyethylene glycol-ethylene oxide/diclofenac sodium composite be described in combined bidirectional stretching blender, be subject to after strong shearing force field effect drug release behavior and hot strength equal be improved significantly; Realized the lifting of drug slow release function improvement and mechanical property simultaneously, poly-succinic fourth diester/polyethylene glycol-ethylene oxide/diclofenac sodium composite functionalization and high performance are unified.
It is worth mentioning that, in the biaxial tension mixed-forming integrated apparatus adopting at embodiment 4: the first, in the housing of each biaxial tension blender, the cuniform channel that n varying level stretches can be set, n can be between 2～10 value, i.e. 10≤n≤2; Such as when the n=4, the 4 biaxial tension melt mixers (referring to Fig. 7～9) that form 1 minute; When n=8, the 8 biaxial tension melt mixers (referring to Figure 10～12) that form 1 minute; Wherein, the entrance of melt flow channel is rectangle, is horizontal; Each runner, along the attenuation that broadens gradually of melt flows direction, extends towards different level heights simultaneously, and its exit is rectangle and is arranged vertically; The exit width of each runner equals or approaching n times of equaling throat width, and exit thickness equals or the approaching 1/n that equals inlet thickness.The second, melt mixer can select a biaxial tension melt mixer to form.The 3rd, melt mixer also can select two or more (such as: 2～20) biaxial tension melt mixer along melt flows direction is linear, connect, to form multistage-combination (that is: when n is identical) or multistage hybrid combining when inconsistent (that is: n have) biaxial tension melt mixer, mediastinum between adjacent channels entrance is thin type structure, tabula between outlet is thin type structure, now only requires that whole entrance size and the whole outlet size between adjacent blender matches.As required, the combined bidirectional stretching melt mixer of the present embodiment can select the of the same type of varying number and or dissimilar biaxial tension blender linearity be connected to form multistage-combination or multistage hybrid combining biaxial tension melt mixer, thereby design and determine the morphosis of the polymer-based blend of structure or composite, the material that processability is controlled, the Intelligentized regulating and controlling of implementation structure, form and performance.The 4th, single screw extrusion machine 1 also can adopt double screw extruder structure; Three roller coolers 4 also can adopt air-cooled engine.
The raw material of a kind of ethyl cellulose (matrix)/polyethylene glycol oxide (decentralized photo) medicament slow release composite comprises following component and weight portion content:
Illustrate: the weight of diclofenac sodium and cefalexin (for medicine) is 12% of Biodegradable high molecular matrix and decentralized photo gross weight.
The first step, first gets the raw materials ready by said components;
Second step, is placed in 60 ℃ of vacuum drying ovens dry 6 hours by medicine;
The 3rd step, the dry diclofenac sodium that second step is obtained, cefalexin are placed in high mixer premixing 5 minutes together with ethyl cellulose, and its rotating speed is 100 revs/min, the medicine obtaining and ethyl cellulose pre-composition; Again the medicine obtaining and ethyl cellulose pre-composition dropped into double screw extruder melt blending, extrude, after pelletize ethyl cellulose/diclofenac sodium-cefalexin premix granule, by premix granule in vacuum drying oven 50 ℃ dry 3 hours, wherein the temperature of double screw extruder charge door, transportation section, melt zone, homogenizing zone, mouthful mould is respectively 120 ℃, 170 ℃, 180 ℃, 180 ℃, 180 ℃; Then, by the ethyl cellulose/diclofenac sodium obtaining-cefalexin premix granule drop into double screw extruder melt blending together with polylactic acid, extrude, after pelletize medicine and polymer premix composite particles, by premix composite particles in vacuum drying oven 50 ℃ dry 3 hours, wherein the temperature of double screw extruder charge door, transportation section, melt zone, homogenizing zone, mouthful mould is respectively 100 ℃, 170 ℃, 180 ℃, 180 ℃, 180 ℃.
The 4th step, puts into dried medicine and polymer premix composite particles in the single screw extrusion machine 1 of the biaxial tension mixed-forming integrated apparatus consisting of single screw extrusion machine 1, adapter 2, combined bidirectional stretching blender 3 and chiller (i.e. three roller coolers) 4 shown in Fig. 1; Wherein, the structure of adapter, biaxial tension blender and pelletize mouth mould is as shown in Fig. 2-12, that is: the biaxial tension mixed-forming integrated apparatus that the present embodiment 5 adopts is identical with embodiment 1; The polymer melt obtaining through extruder fusion plastification is flowed through after adapter, combined bidirectional stretching blender, cooling through chiller again, then (sheet type) ethyl cellulose/polyethylene glycol oxide/diclofenac sodium-cefalexin composite that obtains being dried at convection oven inner drying, i.e. medicament slow release composite.Wherein, the temperature of the charge door of single screw extrusion machine 1, transportation section, melt zone, homogenizing zone, adapter, biaxial tension blender is respectively 100 ℃, 170 ℃, 180 ℃, 180 ℃, 180 ℃, 180 ℃.
In above-mentioned the 4th step, if soaking 48 hours cefalexin burst sizes in phosphate buffer (PBS), ethyl cellulose/polyethylene glycol oxide/diclofenac sodium while not adopting biaxial tension blender-cefalexin composite surpasses 60%, diclofenac sodium burst size is about 35%, all demonstrate the significantly prominent phenomenon of releasing, and because the present embodiment has adopted by 41 minute 2 types (Fig. 4-6) and 2 six grades of hybrid combining biaxial tension blenders that 1 minute 4 types (Fig. 7-9) biaxial tension blender forms, its ethyl cellulose/polyethylene glycol oxide/diclofenac sodium obtaining-cefalexin composite discharges 7% cefalexin for 48 hours, within 21 days, burst size approximately 91%, 48 hours burst sizes approximately 5% of diclofenac sodium, the drug release curve of 27 days is afterwards linear substantially, within 29 days, discharge altogether 87% medicine, demonstrate two kinds of composite controllable release that medicine is good.Adopt 41 minute 2 types (n=2) and 2 six grades of hybrid combining biaxial tension blenders that 1 minute 4 types (n=4) biaxial tension blender forms simultaneously, its hot strength is also brought up to 30.7 MPa by 23.5 original MPa, the melt that ethyl cellulose/polyethylene glycol oxide/diclofenac sodium-cefalexin composite is described in combined bidirectional stretching blender, be subject to after strong shearing force field effect drug release behavior and hot strength all be improved significantly; Realized the lifting of drug slow release function improvement and mechanical property simultaneously, ethyl cellulose/polyethylene glycol oxide/diclofenac sodium-cefalexin composite functionalization and high performance are unified.
It is worth mentioning that, in the biaxial tension mixed-forming integrated apparatus adopting at embodiment 5: the first, in the housing of each biaxial tension blender, the cuniform channel that n varying level stretches can be set, n can be between 2～10 value, i.e. 10≤n≤2; Such as when the n=4, the 4 biaxial tension melt mixers (referring to Fig. 7～9) that form 1 minute; When n=8, the 8 biaxial tension melt mixers (referring to Figure 10～12) that form 1 minute; Wherein, the entrance of melt flow channel is rectangle, is horizontal; Each runner, along the attenuation that broadens gradually of melt flows direction, extends towards different level heights simultaneously, and its exit is rectangle and is arranged vertically; The exit width of each runner equals or approaching n times of equaling throat width, and exit thickness equals or the approaching 1/n that equals inlet thickness.The second, melt mixer can select a biaxial tension melt mixer to form.The 3rd, melt mixer also can select two or more (such as: 2～20) biaxial tension melt mixer along melt flows direction is linear, connect, to form multistage-combination (that is: when n is identical) or multistage hybrid combining when inconsistent (that is: n have) biaxial tension melt mixer, mediastinum between adjacent channels entrance is thin type structure, tabula between outlet is thin type structure, now only requires that whole entrance size and the whole outlet size between adjacent blender matches.As required, the combined bidirectional stretching melt mixer of the present embodiment can select the of the same type of varying number and or dissimilar biaxial tension blender linearity be connected to form multistage-combination or multistage hybrid combining biaxial tension melt mixer, thereby design and determine the morphosis of the polymer-based blend of structure or composite, the material that processability is controlled, the Intelligentized regulating and controlling of implementation structure, form and performance.The 4th, single screw extrusion machine 1 also can adopt double screw extruder structure; Three roller coolers 4 also can adopt air-cooled engine.
Claims (10)
1. a method of preparing medicament slow release composite, take Biodegradable high molecular as matrix and decentralized photo, it is characterized in that the method comprises the steps:
The first step, is 50～99%:50～1% by Biodegradable high molecular matrix, Biodegradable high molecular decentralized photo by weight percentage, and medicine is pressed 0.01～40% batching of Biodegradable high molecular matrix and decentralized photo gross weight;
Second step, carries out dried by said medicine;
The 3rd step, adopts high mixed and/or melting mixing technique to obtain corresponding pre-composition in the medicine after dried and Biodegradable high molecular matrix and decentralized photo;
The 4th step, the pre-composition that the 3rd step is obtained is put in the extruder (1) of the biaxial tension mixed-forming integrated apparatus consisting of extruder (1), adapter (2), single or combined bidirectional stretching melt mixer (3) and chiller (4), wherein in the body shell of biaxial tension melt mixer, is provided with the wedge shape melt flow channel that 2～10 varying levels extend; Polymer melt flow through adapter and the wedge shape melt flow channel of extending at the varying level of biaxial tension melt mixer (3) in shunting, biaxial tension deformation and superimposed rear outflow, cooling through apparatus for supercooling (4) again, can obtain medicament slow release composite.
2. the method for preparing medicament slow release composite according to claim 1, is characterized in that the mixed technique of the height adopting in above-mentioned the 3rd step refers to medicine and mixing that Biodegradable high molecular matrix and decentralized photo carry out in high mixer.
3. the method for preparing medicament slow release composite according to claim 1, is characterized in that the melting mixing technique adopting in above-mentioned the 3rd step refers to the melting mixing that medicine and Biodegradable high molecular matrix and decentralized photo carry out in extruder.
4. the method for preparing medicament slow release composite according to claim 1, it is characterized in that the mixed melting mixing technique of the height that adopts in above-mentioned the 3rd step refer to by medicine and Biodegradable high molecular matrix together with decentralized photo after high-speed mixer and mixing, then in extruder melting mixing.
5. the method for preparing medicament slow release composite according to claim 1, it is characterized in that the mixed melting mixing technique of the height adopting in above-mentioned the 3rd step refers to medicine first after high mixer mixes with Biodegradable high molecular matrix or decentralized photo, melting mixing in extruder, the then melting mixing in extruder with Biodegradable high molecular decentralized photo or matrix again.
6. the method for preparing medicament slow release composite according to claim 1, is characterized in that the Biodegradable high molecular matrix described in the first step is one or more in polycaprolactone, polylactic acid, poly-succinic fourth diester, ethyl cellulose, hydroxypropyl cellulose, cellulose acetate.
7. the method for preparing medicament slow release composite according to claim 1, is characterized in that the Biodegradable high molecular decentralized photo described in the first step is one or more in polyethylene glycol oxide, Polyethylene Glycol, starch, polyacrylic acid, polyvinyl alcohol.
8. the method for preparing medicament slow release composite according to claim 1, is characterized in that the medicine described in the first step is one or more in ibuprofen, cefalexin, vancomycin, theophylline, hydrochlorothiazide, diclofenac sodium, amoscanate.
9. according to the method for preparing medicament slow release composite described in claim 1,3,4 or 5, it is characterized in that charge door, transportation section, melt zone, the homogenizing zone of the extruder that melting mixing technique in above-mentioned the 3rd step is used, the temperature of mouthful mould is respectively 30～180 ℃, 50～220 ℃, 50～220 ℃, 50～220 ℃, 50～220 ℃.
10. the method for preparing medicament slow release composite according to claim 1, is characterized in that charge door, transportation section, melt zone, homogenizing zone, the adapter (2) of the extruder (1) that the 4th step is used, the temperature of biaxial tension melt mixer (3) is respectively 30～180 ℃, 50～220 ℃, 50～220 ℃, 50～220 ℃, 50～220 ℃, 50～220 ℃.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107049995A (en) * | 2017-06-01 | 2017-08-18 | 四川大学 | A kind of method for preparing Thermo-sensitive insoluble drug release composite |
| CN109925290A (en) * | 2017-12-18 | 2019-06-25 | 广州白云山明兴制药有限公司 | Theo-Dur and its preparation process |
| CN110252219A (en) * | 2019-07-12 | 2019-09-20 | 宁波工程学院 | A kind of polylactic acid cladding liposoluble vitamin composite material and preparation method |
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| CN103391769A (en) * | 2011-02-17 | 2013-11-13 | 霍夫曼-拉罗奇有限公司 | A process for controlled crystallization of an active pharmaceutical ingredient from supercooled liquid state by hot melt extrusion |
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| CN103391769A (en) * | 2011-02-17 | 2013-11-13 | 霍夫曼-拉罗奇有限公司 | A process for controlled crystallization of an active pharmaceutical ingredient from supercooled liquid state by hot melt extrusion |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107049995A (en) * | 2017-06-01 | 2017-08-18 | 四川大学 | A kind of method for preparing Thermo-sensitive insoluble drug release composite |
| CN109925290A (en) * | 2017-12-18 | 2019-06-25 | 广州白云山明兴制药有限公司 | Theo-Dur and its preparation process |
| CN109925290B (en) * | 2017-12-18 | 2021-03-16 | 广州白云山明兴制药有限公司 | Theophylline sustained release tablet and preparation process thereof |
| CN110252219A (en) * | 2019-07-12 | 2019-09-20 | 宁波工程学院 | A kind of polylactic acid cladding liposoluble vitamin composite material and preparation method |
| CN110252219B (en) * | 2019-07-12 | 2021-08-17 | 宁波工程学院 | Polylactic acid coated fat-soluble vitamin composite material and preparation method thereof |
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