CN1732899A - Implantation type local drug delivery device and three-dimensional printing preparation method thereof - Google Patents
Implantation type local drug delivery device and three-dimensional printing preparation method thereof Download PDFInfo
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- CN1732899A CN1732899A CN 200510018930 CN200510018930A CN1732899A CN 1732899 A CN1732899 A CN 1732899A CN 200510018930 CN200510018930 CN 200510018930 CN 200510018930 A CN200510018930 A CN 200510018930A CN 1732899 A CN1732899 A CN 1732899A
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Abstract
The invention discloses an implantation type local drug delivery device and three-dimensional printing preparation process, wherein the medicine administration device is a double layered disc arrangement, the upper layer is a storage layer whose central portion is a drug-containing portion, while the peripheral area is a carrier portion, the lower layer is a matrix layer. the storage layer's drug containing portion comprises medicinal composition and carrier material, the storage layer's carrier portion is composed of carrier material, the matrix layer comprises medicinal composition and carrier material composition.
Description
Technical field
The invention belongs to medicine control release technic field, be specifically related to a kind of implanted control doser that utilizes advanced 3 D-printing (3DP) Rapid Prototyping technique preparation to be used for the treatment of effect.It is the pharmaceutical preparation of purpose that this doser preferentially is used for the topical therapeutic, and preferentially takes the form implanted.
Background technology
Implantable drug delivery system (implantable drug delivery device-IDDD) is a kind of with sterile solid sustained release preparation, and underwent operative is implanted or imported intravital control medicine-releasing system through syringe needle.Sterile solid sustained release preparation, is used for tract, tissue or subcutaneous implantation through certain prepared by medicine or medicine and excipient.
Some problems that implanted pharmaceutical preparation brings in the time of can avoiding injecting, the place infects easily as pin hole, brings inconvenience to patient, and the meeting engender tension causes endocrine regulation etc. during animal-use drug.It has advantages such as long-acting, that control slow release, biocompatibility is good.Some diseases such as osteomyelitis often cause the infection site hemoperfusion bad because of surrounding tissue infects, and oral or intravenous injection antibacterial arrives the limited amount of infection site, often causes therapeutic outcome not good.By the drug delivery implant device medicament is directly implanted diseased region, local drug concentration height, and medicine seldom enters systemic circulation, thus when improving therapeutic effect, avoid the side effect of oral or drug administration by injection.
Lafarge at first proposed subcutaneous implantation pill and obtained the imagination of lasting release for a long time in 1867, nineteen thirty-seven Deansley and Parkes carry out research in the animal body for the first time, pill (sheet) is implanted subcutaneous tissue, and medicine discharges with certain speed in a long time, keeps effective blood drug concentration.Zheng Qi newly wait with degradable artificial bone grafting material tricalcium phosphate carrying third generation quinolones broad ectrum antibiotic ciprofloxacin make tricalcium phosphate/ciprofloxacin slow release pill (TCDC) and detect its external bacteriostasis and implantation rabbit femoral greater trochanter after drug release behavior, TCDC is to golden Portugal bacterium as a result, escherichia coli, orthopaedics such as bacillus pyocyaneus infect common pathogen powerful and persistent bacteriostasis.Britain Zenica company adopts lactide-glycolide copolymer with LHRH analog, the congruent melting of Gao She Rayleigh, through extrude-shearing method makes small cylinder, content of dispersion is 3.6 milligrams, directly pack in a kind of special syringe, can directly this pastille cone be injected into the heeling-in of patient's subcutaneous abdomen through cylinder piston during use.But medicine is slow release 28 days in vivo, is used for the treatment of carcinoma of prostate and some gynaecopathia.Having report that carmustine and poly-anhydride are made diameter is that 14 millimeters, thickness are carmustine-poly-anhydride heeling-in controlled release tablet (Gliedel contains carmustine 3.85%) of 1 millimeter, and treatment recurrent cerebral glioma has curative effect preferably.After the patient excises brain tumor, implant 6～8 controlled release tablet at operative site, can continue 3 weeks of release at intracranial, drug level is 4～2000 times of intravenously administrable around the implant site.
Traditional implantable drug delivery system depends on the purpose that passive flooding mechanism reaches sustained release.Along with the big quantity research of Different Preparation, developed into and utilized various external factor to realize that the long period accurately discharges the therapeutic dose medicine in vivo, or, regularly discharged the therapeutic dose medicine in recent years according to the treatment needs.Existing numerous implanted drug delivery systems come out, and as steroidal anti-inflammatory medicine implant system, analgesic implant system, orthopaedics illness medicine implant system etc., are used for the treatment as illness such as infection of bone, bone tumor and bone are damaged.
At present, the forming technology of implanted pharmaceutical preparation mainly contains: high-temperature calcination preparation method and by given shape mould preparation method.The preparation method of the disclosed implanted pottery of patent CN107845A anti-tuberculosis anti-cancer anti-inflammation slow release body, be to be pharmaceutical carrier, add an amount of flux oxide, under the certain high temperature calcining with potteries such as hydroxyapatite, make porous cavity, its intracavity medicine slowly discharges by the micropore of pottery.Patent CN2416900Y and CN1208611A etc. are disclosed with disease topical delayed release devices such as mould and extrusion equipment preparation treatment gynecological, cancers, by given shape mould preparation method is carrier with polymer normally, comprise and carrier, medicine divided and after other compositions mix by proportioning, add direct forming in the mould; Or after the heating, cooling forming again; Or behind the adding solvent, remove shaping again; Or be shaped by extrusion equipment.Medicine comes out by polymer diffusion or along with the decomposition of polymer slowly releases.
Prepared process limitations, existing implanted pharmaceutical preparation mainly is sphere or solid stick simple in structure, is difficult to satisfy the more reasonably needs of therapeutic regimen.Yet reasonably therapeutic regimen must be can improve curative effect, reduce toxicity, delay the pharmaceutical preparation of effects such as drug resistance, and these pharmaceutical preparatioies often need complicated spatial structure, internal microstructure, are that traditional handicraft cannot or hardly reach.
Rapid Prototyping technique (Rapid Prototyping, hereinafter to be referred as RP) be a kind of novel forming technique based on discrete stack shaping thought, be state-of-the-art technology such as integrated computer, numerical control, laser and new material and the product of the future research and development technology that grows up.Fast shaping technology success is both at home and abroad at present developed kind more than 10, and the 3 D-printing that Massachusetts Institute Technology (MIT) develops the earliest (Three Dimensional Printing-3DP) Rapid Prototyping technique is the most vital technology in the present quick shaping industry.Three-dimensional data model in this technical basis computer carries out the outline data that hierarchy slicing obtains each layer cross section, computer is the printhead on the information control three-dimensional printer in view of the above, spray one deck liquid adhesive selectively on one deck powder of completing in advance, make the part powder bonded, formation has the lamellar entity profile of a small thickness, after one deck powder forming is finished, the bonding of following one deck powder, so circulation, adopt adhesive means to make it successively be piled into one again, just can produce designed new product exemplar, model or mould finally obtain exemplar.Because the 3DP technology adopts the thought of " layering manufacturing ", does not produce heat in the forming process, the medicine loose structure that generation is had complex-shaped surface mould has special advantages.Have the advantages that medicine is accurately controlled, preparation technology automatization is high, and equipment is simple, material is cheap, cost is low, volume is little, pollution-free in the work process, forming speed is fast.
Wu etc. [J.control.Release, 1996,40 (1): 77-88] at first introduce 3DP technology preliminary exploratory study have been carried out in the preparation of doser.Katstra etc. [J.control.Release, 2000 (66): 1-9] adopt 3DP technology, make powder with lactose, make binding agent with PVP and Tween20 aqueous solution,, have prepared and have been used for oral medicine control Atrigel as model drug with fluorescein sodium.
Present implantable drug delivery system is implemented in the purpose that slowly discharges medicine in a period of time by once implanting.But, keep the generation that certain drug level will cause problems such as drug effect reduction, drug resistance in this administering mode for a long time.Therefore, how according to pathological characteristic, in conjunction with the effect characteristics of chemotherapeutics, avoiding producing drug resistance, improve medication effect, is the new problem that the implantable drug delivery system is faced.
Summary of the invention
The object of the present invention is to provide a kind of implanted local drug delivery device, this doser can be realized intermittence, high concentration medicine pulse release, and this heavy dose of gap medication can be avoided chemical sproof generation when realizing long-acting administration; The invention provides the 3 D printing preparation method thereof of this implantable drug delivery system.
The invention provides a kind of implanted local drug delivery device, it is characterized in that: this doser is double-deck disc-shaped structure, and its upper strata is a storage layer, and the middle part of storage layer is the pastille district, and its periphery is the carrier district, and lower floor is a casing play; Storage layer pastille district is ingredient and carrier material, and storage layer carrier district is a carrier material, and casing play is ingredient and carrier material.
Above-mentioned carrier material is one or more the mixture in the following material: poly-epsilon-caprolactone, polylactic acid, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly (lactide-co-glycolide), polyacrylamide, poly--beta-hydroxy butyl ester and hydroxyapatite.
Be added with porogen in the above-mentioned carrier material.Described porogen is sodium chloride, potassium chloride, Polyethylene Glycol, low molecular polyethylene alcohol, gelatin or hydroxypropyl emthylcellulose.
Said medicine is anti-infectives in the orthopaedics illness, antitumor drug or tuberculosis class medicine, as: levofloxacin, ciprofloxacin, cefoperazone, cephalo husband monooctyl ester, gentamycin, vancomycin, doxorubicin, lomustine, methotrexate, cisplatin, fluorouracil, Rimactazid, ethambutol, streptomycin, pyrazinamide, amikacin.
The 3 D printing preparation method thereof of above-mentioned implanted local drug delivery device, its step comprises:
(1) utilizes the computer acquisition to need the three-dimensional data model of the doser of preparation, and carry out two-dimentional hierarchy slicing, obtain the outline data of each layer cross section of doser;
(2) preparation casing play:
(2.1) earlier at work platforms upper berth one deck support powder, printhead on the three-dimensional printer is under computer control, outline data according to this layer cross section moves on X-Y plane, and spraying ingredient and print the mixture of liquid, with the support powder formation two-dimensional sheet entity that bonds;
(2.2) the work platforms distance of a layer thickness that descends repeats above-mentioned steps (2.1), until finishing casing play;
(3) preparation storage layer:
(3.1) the work platforms distance of a layer thickness that descends, and at storage layer upper berth one deck support powder, for the cross-sectional layers that comprises the pastille district, handle (3.2) set by step, other cross-sectional layers (3.3) is set by step handled;
(3.2) printhead on the three-dimensional printer is under computer control, moves on X-Y plane according to the outline data of this layer cross section, and liquid is printed in spraying in the carrier district, the support powder in bonding carrier district; Afterwards, adopt the mixture of another one printhead spraying ingredient and printing liquid, the support powder in bonding pastille district;
(3.3) printhead on the three-dimensional printer is under computer control, moves on X-Y plane according to the outline data of this layer cross section, and liquid is printed in spraying, with the support powder formation two-dimensional sheet entity that bonds;
(3.4) repeating step (3.1) is finished until storage layer to (3.3);
(4) drying is removed unnecessary support powder and is got final product.
Above-mentioned printing liquid is made up of binding agent and modifier, and wherein binding agent is chloroform or acetone; The composition of modifier and content are: in binding agent 100ml, and polyvinylpyrrolidone 0.5～5g, sodium lauryl sulphate 0.5～2g, glycerol 0.5～2ml, distilled water 5～15ml, ethanol 10～20ml.
The present invention is in conjunction with the advantage of 3 D-printing technology, and the 3 D-printing fast shaping technology by optimizing prepares a kind of doser that is used to implant, and this doser has complicated space, internal microstructure and controlled thin-walled portion.To do demonstration support to its technique effect in specific embodiment part.
The present invention adopts 3 D-printing (3DP) fast shaping technology, with polymer polylactic acid PLA, PLGA, PCL and hydroxyapatite etc. is carrier material, add porogen compositions such as sodium chloride, Polyethylene Glycol, the three-dimensional printer terminal is according to the printhead on the preparation structural information control three-dimensional printer of design in advance then, the liquid adhesive that sprays chloroform, acetone etc. selectively is on the polymer powder of completing in advance, so repeat, up to obtaining 3D solid product-doser.
Description of drawings
Fig. 1 is the project organization sketch map of implantable drug delivery system;
Fig. 2 is the implantable drug delivery system outside drawing
Fig. 3 is the micro-Electronic Speculum view of implantable drug delivery system microcosmic;
Fig. 4 contains the release in vitro curve chart that the levofloxacin medicine divides implantable drug delivery system;
The specific embodiment
The present invention is further detailed explanation below in conjunction with accompanying drawing and example.
As shown in Figure 1, this doser is double-deck disc-shaped structure, and specifically, this device upper strata is a storage layer, and the middle part of storage layer is pastille district 1, and its periphery is carrier district 2, and lower floor is a casing play 3; Storage layer pastille district 1 is become to be grouped into carrier material by ingredient, and storage layer carrier district 2 is become to be grouped into by carrier material, and casing play 3 is become to be grouped into carrier material by ingredient.The releasing mechanism of the ingredient of this doser is such, and at first the ingredient in the casing play 3 forms a high concentration pulse release; Ingredient in the storage layer discharges so lag behind owing to be positioned at the carrier material inside that does not contain the medicine composition at this moment.Along with dividing release speed, reduces the casing play medicine, ingredient in the storage layer pastille district 1 constantly sees through 2 diffusions of carrier district and begins to discharge, add that the 2 materials degraded of storage layer carrier district itself forms more microcellular structure, ingredient in the final storage layer pastille district 1 discharges and the ingredient of casing play discharges common secondary high concentration pulse release that forms, and keep a period of time, finish until release.Doser among the present invention reaches according to above principle.
Carrier material used in the present invention adopts compatible good, the medicine of human-body biological is easy to the material that sees through, have no side effect, is divided into non-biodegradation type and Biodegradable two classes.Last class mainly be represented as polymethyl methacrylate (polymethylmethacrylate, PMMA), apatite wollastonite glass ceramics (apatite wollastonite glass ceramic), hydroxyapatite (hydroxyapatite, HA) etc.Back one class uses more then for collagen, poly-epsilon-caprolactone (PCL), polylactic acid (PLA), gather Acetic acid, hydroxy-, bimol. cyclic ester (PGA), poly (lactide-co-glycolide) (PLGA), polyacrylamide and gather-beta-hydroxy butyl ester (PHB) etc.This esters biodegradated polymer materal of birdsing of the same feather flock together of PLA, PLGA and PCL is the biomaterial that is used for doser through drugs approved by FDA, these degraded macromolecular materials are after use, owing to its constantly hydrolysis, be broken into the monomer micromolecule, the medicine that contains is discharged fully, final carrier material is degraded into carbon dioxide and water, do not need to carry out second operation and take out, thereby alleviate patient's misery.In the non-biodegradable material, hydroxyapatite is the Main Ingredients and Appearance of inorganic salt in the body bone tissue, have good biological activity, biocompatibility and bone conduction effect, its chemical property is stable, can guide the growth of bone, and form firm synostosis with osseous tissue, and can be used as the carrier of orthopaedics implant, also be simultaneously to generally acknowledge that well behaved bone repairs substitution material.
In order to regulate the rate of release of doser Chinese medicine molecule, in carrier material, can be added with porogen, this porogen is water miscible micromolecule or macromolecular compound, as: sodium chloride, potassium chloride, Polyethylene Glycol, low molecular polyethylene alcohol, gelatin, hydroxypropyl emthylcellulose.
The size of doser of the present invention and wherein carrier material, porogen are identical with existing doser with the proportioning of ingredient, the present invention does not have specific (special) requirements.Use during for the ease of implant surgery and reach better releasing effect, doser size of the present invention is generally: diameter is about 7～10mm, height is about 5～8mm.
Doser among the present invention needing to be suitable for the disease treatment of implantable drug delivery, particularly the drug delivery implant of anti-infectives, antitumor drug, tuberculosis class medicine in the orthopaedics illness.Wherein, anti-infectives can be a levofloxacin, ciprofloxacin, cefoperazone, cephalo husband monooctyl ester, gentamycin, vancomycin; Antitumor drug can be a doxorubicin, lomustine, methotrexate, cisplatin, fluorouracil; Tuberculosis class medicine can be a rifampicin, isoniazid, ethambutol, streptomycin, pyrazinamide, amikacin.
The invention provides the 3 D printing preparation method thereof of implantable drug delivery system, the steps include:
(1) according to the implantable drug delivery system structure that designs, utilize area of computer aided (CAD) to obtain the three-dimensional data model of doser, and carry out two-dimentional hierarchy slicing, obtain the outline data of each layer cross section of doser, and then these data are imported the computer control terminal of three-dimensional printers; With three-dimensional printer computer control terminal initialization, make working table movement arrive assigned address, for the ground floor bonding is prepared.
(2) carrier and ingredient mix powder are transported on the work platforms, carry out roll extrusion shop one deck powder by the shop rod, terminal moves on double track on the X-Y plane according to the printhead on the numerical control code control three-dimensional printer of ground floor shape correspondence then, liquid is printed in spraying selectively, the part powder bonded is got up to form the two-dimensional sheet entity with a small thickness, the ground floor shape is just decided, and is bonded on the work platforms.After ground floor bonding was finished, work platforms was driven by Z axle upper piston and leans on the descend distance of a layer thickness of bar, said mixture is carried out new one deck shop powder, and guarantee that with spreading excellent roll extrusion agglutinating powder is a bed thickness.Then read second layer cross section information again by same printing liquid, carry out second layer bonding with quadrat method, the second layer just is bonded on the ground floor.Next it is exactly the 3rd layer, the 4th layer ... so repeatedly, until the whole thickness of finishing the doser casing play.
(3) after last one deck of doser casing play is finished, make the descend distance of a layer thickness of work platforms equally, change and want agglutinating powder composition, pure carrier material powder is transported to work platforms, making powder thickness with the shop rod is a bed thickness.According to storage layer ground floor shape information, printing liquid, the method in (2) bonds set by step.The ground floor of storage layer structure just is bonded on the casing play.The repetition said process is finished storage layer and is not contained the medicine Composition Region, and then bonding contains the medicine Composition Region.
(4) pure support powder is carried on the agglutinating last one deck of step (3), making powder thickness with the shop rod is a bed thickness.Use the printing liquid identical with step (3), the peripheral storage layer of this layer that bond is the pastille subregion not, and then with another one printhead spraying ingredient and printing liquid mixture, the pastille district, center of this floor that bonds finishes this one deck bonding.Repeat the process of this step then and finish storage layer pastille Composition Region.
(5) contain on the medicine Composition Region at storage layer and continue the bonding that storage layer does not contain the medicine Composition Region, this process and step (3) are identical, and boning until whole doser finishes.
(6) doser after dry at normal temperatures 24 hours raises work platforms, and removing does not have agglutinating support powder, finally obtains the designed labyrinth implantable drug delivery system that has.Took out this device vacuum drying 48 hours.
The bonds well agent that the used printing liquid of three-dimensional printing-forming method is carrier material in the doser among the present invention, the carrier material of different performance uses different printing liquid.Chloroform and acetone are the good solvents of carrier materials such as PLA, PCL, and they be easy to the volatilization, be the suitable binding agent of this class carrier material.At ink jet-print head performance requirement in the three-dimensional printer, usually use mixed solvent, and adding modifier makes printing liquid be easy to spraying.3 D-printing method printing liquid is the mixed solvent of acetone or chloroform, ethanol, water, polyvinylpyrrolidone, sodium lauryl sulphate and glycerol etc. among the present invention.Wherein, chloroform, acetone are binding agents, and ethanol, water, polyvinylpyrrolidone, sodium lauryl sulphate and glycerol are in order to print the modifier that liquid is easy to spray adding.The content (in binding agent 100ml) of printing each composition in the liquid is: polyvinylpyrrolidone 0.5～5g, sodium lauryl sulphate 0.5～2g, glycerol 0.5～2ml, distilled water 5～15ml, ethanol 10～20ml.
Below the present invention is described, but the present invention not only is confined to these with some specific embodiments
Embodiment.
Embodiment 1:
Earlier respectively polylactic acid (molecular weight is 100k/GPC), hydroxyapatite, sodium chloride are pulverized powdered and sieves with grinding alms bowl, the polylactic acid powder diameter is controlled in Φ 150 μ m～175 mu m ranges, and hydroxyapatite and sodium chloride powder particle diameter are controlled at Φ 100 μ m～150 mu m ranges.Throw the 20g polylactic acid in stirred vessel, with after stirring in 2g hydroxyapatite and the 3g sodium chloride adding stirred vessel, take out 15g stand-by (being referred to as mixed-powder A) again.In container, add 10g levofloxacin powder and mix homogeneously (being referred to as mixed powder B) then.After other gets 100ml acetone, 10ml ethanol, 10ml distilled water and 0.5ml glycerol and mixes, add the 1g polyvinylpyrrolidone more respectively and the 1.5g sodium lauryl sulphate fully dissolves in container, measure 80ml and inject first printhead.Add the 10g levofloxacin in former container again, second printhead is injected in dissolving back fully.
Clean up the three-dimensional printer work platforms, send instruction by computer CAD and begin preparation.According to designed structure, spread one deck 200 μ m polylactic acid, hydroxyapatite, sodium chloride and levofloxacin mixed powder B earlier, the spraying of first printhead is printed liquid 3 times, and work platforms then repaves powder, spraying after descending, so repeat to bond 10 layers, be the casing play of implantable drug delivery system.Then storage layer structure division bonding changes the mixed-powder A that spreads polylactic acid, hydroxyapatite and sodium chloride, and every layer thickness also is 200 μ m, and printhead is constant, and the spraying of first printhead is printed liquid 3 times, repeats to bond 5 layers.Since 16 layers, earlier with after the spraying of first printhead, then second printhead sprays behind the powder of shop, this layer first printhead spraying 3 times, second printhead spraying 6 times.So repeat to bond 10 layers, after promptly 25 layers of bonding are finished 26 layers only return to the spraying of first printhead, and the shop powder remains the mixed-powder A of polylactic acid, hydroxyapatite, sodium chloride, each layer spraying 3 times.Repeat to bond 5 layers, finish normal temperature drying, gumming, vacuum drying, sterilization until the 30th layer of bonding.
Embodiment 2:
Earlier respectively poly-epsilon-caprolactone (molecular weight is 60k/GPC), sodium chloride are pulverized powdered and sieves with grinding alms bowl, the poly-epsilon-caprolactone powder diameter is controlled in Φ 150 μ m～175 mu m ranges, and sodium chloride powder particle diameter is controlled at Φ 100 μ m～150 mu m ranges.Throw the 20g poly-epsilon-caprolactone in stirred vessel, with after stirring in the 3g sodium chloride adding stirred vessel, take out 12g stand-by (being referred to as mixed-powder C) again.In container, add 12g fluorouracil powder and mix homogeneously (being referred to as mixed-powder D) then.After other gets 100ml chloroform, 15ml ethanol, 10ml distilled water, 1ml glycerol and mixes, add the 2g polyvinylpyrrolidone more respectively and the 1g sodium lauryl sulphate fully dissolves in container, measure 80ml and inject first printhead.Add the 12g fluorouracil in former container again, second printhead is injected in the dissolving back.
Clean up the three-dimensional printer work platforms, send instruction by computer CAD and begin preparation.According to designed structure, spread one deck 200 μ m poly-epsilon-caprolactones, sodium chloride and fluorouracil mixed powder B earlier, the spraying of first printhead is printed liquid 3 times, and work platforms then repaves powder, spraying after descending, so repeat to bond 10 layers, be the casing play of implantable drug delivery system.Then storage layer structure division bonding changes the mixed-powder C that spreads poly-epsilon-caprolactone, sodium chloride, and every layer thickness also is 200 μ m, and printhead is constant, and the spraying of first printhead is printed liquid 3 times, repeats to bond 5 layers.Since 16 layers, earlier with after the spraying of first printhead, then second printhead sprays behind the powder of shop, this layer first printhead spraying 3 times, second printhead spraying 6 times.So repeat to bond 10 layers, after promptly 25 layers of bonding are finished 26 layers only return to the spraying of first printhead, and the shop powder remains the mixed-powder C of poly-epsilon-caprolactone, sodium chloride, each layer spraying 3 times.Repeat to bond 5 layers, finish normal temperature drying, gumming, vacuum drying, sterilization until the 30th layer of bonding.
Embodiment 3:
Earlier respectively polylactic acid (molecular weight is 100k/GPC), poly-epsilon-caprolactone (molecular weight is 60k/GPC), hydroxyapatite, sodium chloride are pulverized powdered and sieves with grinding alms bowl, the polylactic acid powder diameter is controlled in Φ 150 μ m～175 mu m ranges, and the particle diameter of hydroxyapatite and sodium chloride powder is controlled at Φ 100 μ m～150 mu m ranges.Throw the 20g polylactic acid in stirred vessel, with after stirring in 2g hydroxyapatite and the 3g sodium chloride adding stirred vessel, in container, add 20g rifampicin and mix homogeneously (being referred to as mixed-powder F) again.Get 15g poly-epsilon-caprolactone and 3g Polyethylene Glycol (molecular weight 4000/GPC) mix homogeneously (being referred to as mixed-powder E), in addition get 100ml acetone, 10ml ethanol, 10ml distilled water, 0.5ml glycerol and in container, mix after, add the 1g polyvinylpyrrolidone more respectively and the 1.5g sodium lauryl sulphate fully dissolves, measure 80ml and inject first printhead.Add the 10g rifampicin in former container again, second printhead is injected in the dissolving back.
Clean up the three-dimensional printer work platforms, send instruction by computer CAD and begin preparation.According to designed structure, spread one deck 200 μ m polylactic acid, hydroxyapatite, sodium chloride and rifampicin mixed-powder F earlier, the spraying of first printhead is printed liquid 3 times, and work platforms then repaves powder, spraying after descending, so repeat to bond 10 layers, be the casing play of implantable drug delivery system.Then storage layer structure division bonding changes the mixed-powder E that spreads poly-epsilon-caprolactone and Polyethylene Glycol, and every layer thickness also is 200 μ m, and printhead is constant, and the spraying of first printhead is printed liquid 3 times, repeats to bond 5 layers.Since 16 layers, earlier with after the spraying of first printhead, then second printhead sprays behind the powder of shop, this layer first printhead spraying 3 times, second printhead spraying 6 times.So repeat to bond 10 layers, after promptly 25 layers of bonding are finished 26 layers only return to the spraying of first printhead, and the shop powder remains the mixed-powder E of poly-epsilon-caprolactone and Polyethylene Glycol, each layer spraying 3 times.Repeat to bond 5 layers, finish normal temperature drying, gumming, vacuum drying, sterilization until the 30th layer of bonding.
Embodiment 4～9: its preparation process is identical with embodiment 1,2,3, different the seeing the following form of employed material and ingredient etc.
| Carrier material | The pore material | Binding agent | Ingredient | |
| Embodiment 4 |
PGA PLGA, HA PLA, HA gather-beta-hydroxy butyl ester PCL polyacrylamide | Polyvinyl alcohol potassium chloride sodium chloride | Acetone chloroform chloroform acetone chloroform chloroform | Levofloxacin isoniazid ciprofloxacin doxorubicin cefoperazone vancomycin |
Embodiment 10:
Earlier respectively polylactic acid (molecular weight is 100k/GPC), poly (lactide-co-glycolide) PLGA (molecular weight is 70k/GPC), hydroxyapatite, sodium chloride are pulverized powdered and sieves with grinding alms bowl, polylactic acid, PLGA powder diameter are controlled in Φ 150 μ m～175 mu m ranges, and the particle diameter of hydroxyapatite and sodium chloride powder is controlled at Φ 100 μ m～150 mu m ranges.Throwing 10g polylactic acid and 10gPLGA mixes to stirred vessel, take out 15g stand-by (being referred to as mixed-powder G), with after stirring in 2g hydroxyapatite and the 3g sodium chloride adding stirred vessel, in container, add 20g ethambutol and mix homogeneously (being referred to as mixed-powder H) again.After other gets 100ml acetone, 10ml ethanol, 10ml distilled water, 0.5ml glycerol and mixes, add the 1g polyvinylpyrrolidone more respectively and the 1.5g sodium lauryl sulphate fully dissolves in container, measure 80ml and inject first printhead.Add the 10g ethambutol in former container again, second printhead is injected in the dissolving back.
Clean up the three-dimensional printer work platforms, send instruction by computer CAD and begin preparation.According to designed structure, spread one deck 200 μ m mixed-powder H earlier, the spraying of first printhead is printed liquid 3 times, and work platforms then repaves powder, spraying after descending, and so repeats to bond 10 layers, is the casing play of implantable drug delivery system.Then storage layer structure division bonding changes shop mixed-powder G, and every layer thickness also is 200 μ m, and printhead is constant, and the spraying of first printhead is printed liquid 3 times, repeats to bond 5 layers.Since 16 layers, earlier with after the spraying of first printhead, then second printhead sprays behind the powder of shop, this layer first printhead spraying 3 times, second printhead spraying 6 times.So repeat to bond 10 layers, after promptly 25 layers of bonding are finished 26 layers only return to the spraying of first printhead, and the shop powder remains mixed-powder G, each layer spraying 3 times.Repeat to bond 5 layers, finish normal temperature drying, gumming, vacuum drying, sterilization until the 30th layer of bonding.
Embodiment 11:
Described in embodiment 10, change the ratio of carrier material polylactic acid and poly (lactide-co-glycolide) PLGA, promptly throw 5g polylactic acid and 15gPLGA and mix; Ingredient changes gentamycin into; Binding agent changes chloroform into, and other processes are identical with embodiment 10.
Embodiment 12:
Described in embodiment 10, changing the carrier material mixture is polylactic acid and PCL mixture, promptly throws 10g polylactic acid and 10gPCL and mixes; Ingredient changes lomustine into; Do not add porogen sodium chloride composition, other processes are identical with embodiment 10.
Embodiment 13:
Described in embodiment 10, changing the carrier material mixture is poly (lactide-co-glycolide) PLGA and PCL mixture, promptly throws 10g poly (lactide-co-glycolide) PLGA and 10gPCL and mixes; Ingredient changes cisplatin into, and binding agent changes chloroform into; Other processes are identical with embodiment 10.
Embodiment 14:
Described in embodiment 10, changing the carrier material mixture is PLA and poly--beta-hydroxy butyl ester mixture, promptly throwing 10g PLA and 10g gathers-and the mixing of beta-hydroxy butyl ester; Ingredient changes methotrexate into; Other processes are identical with embodiment 10.
Embodiment 15:
Described in embodiment 10, changing the carrier material mixture is PGA, PLA and hydroxyapatite mixture, promptly throws 10g PGA, 10g to gather-beta-hydroxy butyl ester and the mixing of 2g hydroxyapatite; Ingredient changes methotrexate into; Binding agent changes chloroform into, does not add the porogen composition, and other processes are identical with embodiment 10.
Do further demonstration explanation from several aspects to technique effect of the present invention below.
(1), the structure of implantable drug delivery system and traditional performance analysis
Macroscopical surface structure sign aspect of doser of the present invention as shown in Figure 2, is the disc structure of high 6mm, diameter 8mm, shows that obtaining shape meets designing requirement.
Microstructure characterization method of the present invention is used the said three-dimensional body stereomicroscope, and its step is earlier preparation after the intensive drying ,-25 ℃ of coolings, to be cut the cross section that obtains needs then along the center in vacuum desiccator.As shown in Figure 3.Medication device has tangible bank structure sheaf and framing structure layer up-down structure as can be seen.
As the tablet of implanting usefulness, its hardness factor directly influences the release and the use of preparation, with durometer implantation preparation is measured.Friability is the technological level of reflection tablet manufacturing, one of important indicator of control tablet quality.According to " hardness and the friability quality standard inspection of 2000 editions appendix of Chinese pharmacopoeia to make tablet with a collection of medication device, result's demonstration meets the requirements.
(2), the external release test of implantable drug delivery system
Get the doser of the present invention's preparation,, obtain the release in vitro data of pharmaceutical preparation with reference to version pharmacopeia drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2000) in 2000.Release medium is 0.9% normal saline, and temperature is 37.0 ± 0.5 ℃.Measured once, and changed the release medium of equivalent then in per 24 hours.See that Fig. 4 is the release in vitro curve chart that contains the levofloxacin ingredient.The result shows that ingredient presents the high concentration pulse release twice.
Claims (8)
1, a kind of implanted local drug delivery device is characterized in that: this doser is double-deck disc-shaped structure, and its upper strata is a storage layer, and the middle part of storage layer is pastille district (1), and its periphery is carrier district (2), and lower floor is casing play (3); Storage layer pastille district (1) is ingredient and carrier material, and storage layer carrier district (2) is a carrier material, and casing play (3) is ingredient and carrier material.
2, doser according to claim 1 is characterized in that: described carrier material is one or more the mixture in the following material: poly-epsilon-caprolactone, polylactic acid, poly-Acetic acid, hydroxy-, bimol. cyclic ester, poly (lactide-co-glycolide), polyacrylamide, poly--beta-hydroxy butyl ester and hydroxyapatite.
3, doser according to claim 1 is characterized in that: be added with porogen in the carrier material.
4, doser according to claim 3 is characterized in that: described porogen is sodium chloride, potassium chloride, Polyethylene Glycol, low molecular polyethylene alcohol, gelatin or propyl methocel.
5, according to claim 1,2 or 3 described dosers, it is characterized in that: described medicine is anti-infectives in the orthopaedics illness, antitumor drug or tuberculosis class medicine.
6, according to claim 1,2 or 3 described dosers, it is characterized in that: described medicine is a kind of in the following medicine: levofloxacin, ciprofloxacin, cefoperazone, cephalo husband monooctyl ester, gentamycin, vancomycin, doxorubicin, lomustine, methotrexate, cisplatin, fluorouracil, Rimactazid, ethambutol, streptomycin, pyrazinamide, amikacin.
7, the 3 D printing preparation method thereof of arbitrary described doser in the claim 1 to 6, its step comprises:
(1) utilizes the computer acquisition to need the three-dimensional data model of the doser of preparation, and carry out two-dimentional hierarchy slicing, obtain the outline data of each layer cross section of doser;
(2) preparation casing play:
(2.1) earlier at work platforms upper berth one deck support powder, printhead on the three-dimensional printer is under computer control, outline data according to this layer cross section moves on X-Y plane, and spraying ingredient and print the mixture of liquid is with the support powder formation two-dimensional sheet entity that bonds;
(2.2) the work platforms distance of a layer thickness that descends repeats above-mentioned steps (2.1), until finishing casing play;
(3) preparation storage layer:
(3.1) the work platforms distance of a layer thickness that descends, and at storage layer upper berth one deck support powder, for the cross-sectional layers that comprises the pastille district, handle (3.2) set by step, other cross-sectional layers (3.3) is set by step handled;
(3.2) printhead on the three-dimensional printer is under computer control, moves on X-Y plane according to the outline data of this layer cross section, and liquid is printed in spraying in the carrier district, the support powder in bonding carrier district; Afterwards, adopt the mixture of another one printhead spraying ingredient and printing liquid, the support powder in bonding pastille district;
(3.3) printhead on the three-dimensional printer is under computer control, moves on X-Y plane according to the outline data of this layer cross section, and liquid is printed in spraying, with the support powder formation two-dimensional sheet entity that bonds;
(3.4) repeating step (3.1) is finished until storage layer to (3.3);
(4) drying is removed unnecessary support powder and is got final product.
8, method according to claim 7 is characterized in that: described printing liquid is made up of binding agent and modifier, and wherein binding agent is chloroform or acetone; The composition of modifier and content are: in binding agent 100ml, and polyvinylpyrrolidone 0.5～5g, sodium lauryl sulphate 0.5～2g, glycerol 0.5～2ml, distilled water 5～15ml, ethanol 10～20ml.
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