CN102145272B - Method and device for continuously preparing particles and collection unit thereof - Google Patents
Method and device for continuously preparing particles and collection unit thereof Download PDFInfo
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- CN102145272B CN102145272B CN 201010532721 CN201010532721A CN102145272B CN 102145272 B CN102145272 B CN 102145272B CN 201010532721 CN201010532721 CN 201010532721 CN 201010532721 A CN201010532721 A CN 201010532721A CN 102145272 B CN102145272 B CN 102145272B
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Abstract
The invention discloses a method and a device for continuously preparing particles and a collection unit thereof. The collection unit is used for collecting a plurality of particles in a solution and comprises a receiving tank and a first baffle plate, wherein the receiving tank has a water outlet, and the first baffle plate is disposed in the receiving tank in a detachable manner. The first baffle plate traverses the receiving tank, and the two ends of the first baffle plate respectively contact the side walls of the receiving tank, thereby the first baffle plate divides the receiving tank into a first compartment and a second compartment. The water outlet is disposed at the second compartment. When the solution with particles is injected from the first compartment to the receiving tank, the particles will subside near the first baffle plate, and the solution will flow into the second compartment by passing or traversing the first baffle plate and will be discharged from the water outlet.
Description
Technical field
The present invention relates to a kind of method, device and collector unit thereof for preparing particulate, and particularly relate to a kind of method, device and collector unit thereof that can the continuous production particulate.
Background technology
Make the popular carrier that microcapsules or particulate have become various active components gradually with various natural or synthetic polymer and resin, such as medicine, diagnostic reagent or analogous components.Biological decomposable microcapsules and particulate are exactly the long-acting prescription (depot formulation) that is commonly called as, for a long time (above the time that is generally expected that) release of active ingredients.
The preparation particulate usually involves at least a decentralized photo and is formed in the continuous phase, and decentralized photo generally includes active component and polymer, forms particulate after solidifying in continuous phase; Microcapsules also are to utilize similar multiplephase to make, and in traditional manufacturing technique, after water/organic phase/water (W/O/W) emulsion forms, can be solidified in the forming the capsule overcoat of decentralized photo by a polymer of separating out mutually wherein.
In 1980, but Japan's five field pharmacy are application biology decomposing macromolecular lactic-co-glycolic acid-2-hydroxybutyric acid copolymer (poly (lactic/glycolic acid) at first, PLGA) coat luteinizing principle Leuprolide acetate, in production technique, use the slow-release type microcapsule of the dual emulsion process manufacture craft coating medicine of water/organic phase/water (W/O/W), solidifying in the microcapsules manufacture craft at it is that medicine and an emulsified solution of PLGA (W/O) are injected polyvinyl alcohol (polyvinyl alcohol, PVA) aqueous solution carries out the emulsification second time, and solidifies capsule with the water seasoning.
Because surface of microcapsule still can left drug and PVA, usually can add the clear water stirring and washing, and collect with centrifugation.Yet the hardness of PLGA polymeric capsule is not high, produces the problems such as deformation and gathering through being very easy to cause capsule after centrifugal.
Moreover, centrifugal collection microcapsules must personnel operation.Operating process comprise microcapsules are solidified after together with the solution packing to a plurality of centrifuge tubes, also must be careful after centrifugal remove supernatant, with a small amount of solution the microcapsules Eddy diffusion is got up again, after the collection again drying make powder.Tradition microcapsules manufacture craft is a kind of batch of manufacture craft in fact, need the operator to operate centrifuge and just can finish the collection step, not only virtually improve manufacturing cost, and be subject to the manufacture craft that its collection method can't construction goes out a continous way, also indirectly limit its production scale.In addition, the microcapsules that make have the problem of deformation or gathering, also can produce negative impact to drug release pattern.
Summary of the invention
The object of the present invention is to provide a kind of method, device and collector unit thereof of continuous production particulate, utilize the principle of natural subsidence to collect particulate, both can avoid particulate deformation and gathering, can collect continuously particulate again, so that the preparation particulate forms a continuous manufacturing process.
According to a first aspect of the invention; it proposes a kind of collector unit; in order to collect several particulates in the solution; collector unit comprises storage tank and the first baffle plate; storage tank has apopore; the first baffle plate is to be arranged at removably in the storage tank; the first baffle plate crosses storage tank; and the two ends of the first baffle plate contact respectively the sidewall of storage tank; the first baffle plate is divided into the first compartment and the second compartment with storage tank thus; wherein apopore is positioned at the second compartment; wherein contain fine-grained solution by after the first compartment injection storage tank; particulate can be deposited near the first baffle plate, and solution then can be crossed or pass the first baffle plate and enter the second compartment, and discharges from apopore.
According to a second aspect of the invention, the device that it proposes a kind of continuous production particulate comprises raw material supply unit, emulsification unit, solidified cell and above-mentioned collector unit.The raw material supply unit is supplied the aqueous solution and organic solution independently and continuously; the aqueous solution comprises interfacial agent; organic solution comprises active component and degradable macromolecular material; emulsification unit acceptance and mixed aqueous solution and organic solution are to form emulsion; emulsion comprises several particulates that are comprised of biodegradable macromolecular material and active component; solidified cell is accepted emulsion and it is sneaked into consolidation liquid; solidify thus particulate; collector unit comprises storage tank and the first baffle plate; storage tank has apopore; the first baffle plate is to be arranged at removably in the storage tank; the two ends that the first baffle plate crosses storage tank and the first baffle plate contact respectively the sidewall of storage tank; the first baffle plate is divided into the first compartment and the second compartment with storage tank thus; wherein apopore is positioned at the second compartment; wherein contain fine-grained solution by after the first compartment injection storage tank; particulate can be deposited near the first baffle plate; solution then can be crossed or pass the first baffle plate and enter the second compartment, and discharges from apopore.
According to a third aspect of the invention we, the method that it proposes a kind of continuous production particulate comprises that (a) provides the aqueous solution, comprises interfacial agent; (b) provide organic solution, comprise active material and degradable macromolecular material; (c) mixed aqueous solution and organic solution form emulsion, and emulsion comprises several particulates that are comprised of degradable macromolecular material and active component; (d) emulsion is passed into consolidation liquid to solidify particulate; And (e) use above-mentioned collector unit separating particles; collector unit comprises storage tank and the first baffle plate; storage tank has apopore; the first baffle plate is arranged in the storage tank removably; the two ends that the first baffle plate crosses storage tank and the first baffle plate contact respectively the sidewall of storage tank; the first baffle plate is divided into the first compartment and the second compartment with storage tank thus; wherein apopore is positioned at the second compartment; wherein contain fine-grained solution by after the first compartment injection storage tank; particulate can be deposited near the first baffle plate; solution then can be crossed or pass the first baffle plate and enter the second compartment, and discharges from apopore.。
For foregoing of the present invention can be become apparent, embodiment cited below particularly, and cooperate appended accompanying drawing, be described in detail below:
Description of drawings
Fig. 1 is the block diagram of device of a kind of continuous production particulate of one embodiment of the invention;
Fig. 2 is the stereogram of device of a kind of continuous production particulate of one embodiment of the invention;
Fig. 3 A is the schematic perspective view of a kind of collector unit of one embodiment of the invention;
Fig. 3 B is the partial enlarged drawing of a kind of collector unit of one embodiment of the invention;
Fig. 4 is the schematic perspective view of the first collector unit of the embodiment of the invention;
Fig. 5 is the schematic perspective view of the second collector unit of the embodiment of the invention;
Fig. 6 is the schematic perspective view of the third collector unit of the embodiment of the invention;
Fig. 7 is the schematic perspective view of the 4th kind of collector unit of the embodiment of the invention;
Fig. 8 is the schematic perspective view of the 5th kind of collector unit of the embodiment of the invention;
Fig. 9 is the flow chart of method of a kind of continuous production particulate of one embodiment of the invention;
Figure 10 A lists the result of Olanzapine micron ball medicine release efficiency;
Figure 10 B draws Olanzapine micron ball medicine release efficiency result's curve map;
Figure 11 A lists the result of Granisetron micron ball medicine release efficiency;
Figure 11 B draws Granisetron micron ball medicine release efficiency result's curve map.
The main element symbol description
100: the device of continuous production particulate
110: the raw material supply unit
112,114: accumulator tank
116: loader
120: emulsification unit
122: the emulsification cavity
130: solidified cell
140,240,340,440,540,640: collector unit
150,250,350,450,550,650: storage tank
150a, 250a, 350a, 450a, 550a, 650a: the first compartment
150b, 250b, 350b, 450b, 550b, 650b: the second compartment
250c, 650c: the 3rd compartment
152,252,352,452,552,652: apopore
154: edge strip
160,260,360,460,560,660: the first baffle plates
361,461,561: breach
262,362,462,562,662: second baffle
564,664: the three baffle plates
670: the four baffle plates
672: the five baffle plates
674: the six baffle plates
The specific embodiment
The present invention mainly proposes a kind of method and device of continuous production particulate, its collector unit is to utilize the principle of natural subsidence to collect particulate, both can avoid particulate deformation and gathering, can collect continuously particulate again, so that the preparation particulate forms a continuous manufacturing process.Below cooperation diagram describes several groups of embodiments in detail, and right the art has knows the knowledgeable usually when understanding, the literal that this specification is carried and diagram can't cause limit to wish protection domain of the present invention only for a kind of embodiment under the spirit of the present invention.
[device of preparation particulate]
Please refer to Fig. 1, it illustrates the block diagram according to the device of a kind of continuous production particulate of one embodiment of the invention.One embodiment of the invention propose a kind of device 100 of continuous production particulate, comprise raw material supply unit 110, emulsification unit 120, solidified cell 130 and collector unit 140, and details are as follows one by one.
Raw material supply unit 110 comprises independently two accumulator tanks 112 and 114, stores respectively different types of raw material, for example is the aqueous solution and organic solution, and the aqueous solution comprises interfacial agent, and organic solution comprises active component and degradable macromolecular material; Raw material in the accumulator tank can be exported continuously, for example is to make it be higher than feed-line with storages truss is high, and solution then injects in the feed-line serially, perhaps, pump is set extracts the interior solution of accumulator tank.Raw material supply unit 110 more comprises conveyer 116, in order to transporting velocities indivedual or two accumulator tanks of Collaborative Control, conveyer 116 for example is the instrument of peristaltic pump, centrifugal pump, reciprocating pump, drop speed regulator, control valve or other controllable flow speed, adjusts thus the mixed proportion of plurality of raw materials.The required raw material of particulate is made in order to supply independently and continuously in raw material supply unit 110, is preferably can regulate its supply rate and blend together ratio to adjust it.
Emulsification unit 120 acceptance and mixed aqueous solution and organic solution are with the formation emulsion, but emulsification unit 120 for example is homogenizer, agitator or other blend tools, and emulsion comprises several particulates that are comprised of biodegradable macromolecular material and active component.
Solidified cell 130 is accepted emulsion and it is sneaked into consolidation liquid; Solidified cell 130 can comprise container and the stirring tool that a large amount of consolidation liquids are housed, fine-grained emulsion injection consolidation liquid will be contained and the particulate solidified forming can be helped, can also break up particulate and avoid assembling by continuing to mix, solidified cell 130 can also comprise vavuum pump in addition, the container that mixed solution is housed moved in the airtight cavity vacuumize, improve the evaporation rate of organic solution.
Because the device of preparation particulate is different according to its production scale, the equipment that each unit is suitable for is also different not to the utmost, this specification proposes a kind of device of continuous production particulate with laboratory scale, as shown in Figure 2, Fig. 2 illustrates the stereogram according to the device of a kind of continuous production particulate of one embodiment of the invention, so is familiar with the art and has and know that usually the knowledgeable is when can doing suitable change and retouching with different demands such as manufacturing scale, control methods.
Please refer to Fig. 2, accumulator tank 112 is the containers with control valve, and filling includes the aqueous solution of interfacial agent, and accumulator tank 114 is wide-mouth bottles, and filling includes the organic solution of active component and degradable macromolecular material.The position that accumulator tank 112 arranges is higher than feed-line, and has control valve, so the aqueous solution can flow into feed-line automatically, and by the control valve coutroi velocity; Accumulator tank 114 connects peristaltic pump 116, can adjust the flow velocity of organic solution.
The aqueous solution and organic solution are inputted emulsification unit 120 simultaneously to form particulate, emulsification unit 120 is the emulsification cavity (IKA with homogenizer, UTL25digital with S25KV-25GIL knife), its input port is a Y-piece, one is as the inlet of the aqueous solution, one is as the inlet of organic solution, another one is connected to emulsification cavity 122, the aqueous solution and organic solution are pre-mixed in Y-piece inputs emulsification cavity 122 formation emulsions again, and the delivery outlet of emulsification unit 120 then is connected to solidified cell 130.
Solidified cell 130 is that two capacity are 4 liters beaker, and both interconnect, and each beaker has stirring system, avoids assembling in order to disperse particles.In addition, also can increase a vavuum pump (not illustrating), connect solidified cell 130, in order to accelerate the rate of volatilization of organic solution.Solidified cell 130 front ends are connected to emulsification unit 120, and the rear end is connected to collector unit 140.
Fig. 3 A illustrates the schematic perspective view according to a kind of collector unit of one embodiment of the invention, and Fig. 3 B illustrates the partial enlarged drawing according to a kind of collector unit of one embodiment of the invention.Please refer to Fig. 3 A, collector unit 140 comprises storage tank 150 and the first baffle plate 160, the first baffle plate 160 is arranged in the storage tank 150 removably, the first baffle plate 160 crosses storage tank 150, and the two ends of the first baffle plate 160 contact respectively the sidewall of storage tank 150, the first baffle plate 160 is divided into the first compartment 150a and the second compartment 150b with storage tank 150 thus, and storage tank 150 has apopore 152, and apopore 152 is positioned at the second compartment 150b.
Fig. 3 B illustrates the partial enlarged drawing according to a kind of collector unit of one embodiment of the invention.Please refer to Fig. 3 B, be respectively equipped with two edge strips 154 on two sidewalls of 160 liang of end in contact storage tanks 150 of the first baffle plate, edge strip 154 is fixed on the sidewall of storage tank 150, distance on the same sidewall between the two edges 154 approximates greatly the width of the first baffle plate 160, although there is not fixing annexation between the first baffle plate 160 and the storage tank 150, the first baffle plate 160 can be inserted in the storage tank 150 along edge strip 154, and be restricted between the edge strip 154 easily shift position, the first baffle plate 160 also can move up and takes out from storage tank 150 along edge strip 154, thus, the first baffle plate 160 just is arranged in the storage tank 150 removably.The art has knows the knowledgeable usually when understanding that the first baffle plate also has other set-up modes to reach dismountable purpose, and the present invention is not limited thereto.
The lower edge of the first baffle plate 160 is close to storage tank 150 bottom surfaces, and the height of the first baffle plate 160 is preferably the height less than storage tank 150.When containing after fine-grained solution injects storage tank 150 by the first compartment 150a; particulate can be blocked or natural subsidence (being between entry place and the first baffle plate 160) before the first baffle plate 160; solution then can be crossed the first baffle plate 160 and enter the second compartment 150b, and discharges from apopore 152.Because solution can be flowed out by apopore 152, just have living space in the storage tank 150 and allow solution continue to inject, thus, contain after the curing in the injection collector unit 140 that fine-grained mixed solution can continue, particulate also can be stayed constantly in the storage tank 150 and be collected.Collection process utilizes suspension to be subjected to gravitating and the principle of natural subsidence, and at the bottom of baffle plate be set in the solution path stop that particulate helps particulate to fall to storage tank quickly, do not need the operator to operate in the process, without any need for the instrument of precision or the consumptive material of costliness yet.
In addition, also can be when collecting step or afterwards, cleaning fluid (such as deionized water) is injected in the storage tank 140, cleaning fluid can be flowed out by apopore 152 equally, take away active component or the organic solution of microparticle surfaces, also can not produce the problem of particulate deformation or gathering, therefore but the quality of improving product.
Treat particulates in the solidified cell 130 all fall to storage tank 150 bottoms and fluid removal is clean after, the first baffle plate 160 can be removed, with particle suspension and collect, make powder with freeze-drying with a small amount of deionized water at last.
The collector unit 140 that the present embodiment proposes is the most basic blank; in the solution path, baffle plate is set; baffle plate could be flowed out by apopore so that all must flow through behind the solution injection storage tank; reach thus the effect that stops particulate or force its sedimentation; collector unit can also have other embodiment; such as changing baffle position, quantity, combination, spacing etc. to reach identical or better effect, below enumerate collector unit and the drawing illustrate of several different aspects.
The first collector unit
Fig. 4 illustrates the schematic perspective view according to the first collector unit of embodiments of the invention.Collector unit 240 comprises storage tank 250, the first baffle plate 260 and second baffle 262, the first baffle plate 260 all is arranged in the storage tank 250 with second baffle 262 removably, the first baffle plate 260 crosses storage tank 250 with second baffle 262, and the first baffle plate 260 and the two ends of second baffle 262 contact respectively the sidewall of storage tank 250, and the first baffle plate 260 is divided into the first compartment 250a, the second compartment 250b and the 3rd compartment 250c with second baffle 262 with storage tank 250 thus.Storage tank 250 has apopore 252, and apopore 252 is positioned at the 3rd compartment 250c.
When containing after fine-grained solution injects storage tank 250 by the first compartment 250a; majority of particles can be blocked or natural subsidence before the first baffle plate 260; solution then can be crossed the first baffle plate 260 and enter the second compartment 250b; the small part particulate can be blocked or natural subsidence before second baffle 262; solution then can be crossed second baffle 262 and enter the 3rd compartment 250c, and discharges from apopore 252.Because collector unit 240 has more baffle plate, the ratio that the particulate that is injected by solidified cell is blocked is higher, collection more complete.
The second collector unit
Fig. 5 illustrates the schematic perspective view according to the second collector unit of the embodiment of the invention.Collector unit 340 comprises storage tank 350 and the first baffle plate 360, the first baffle plate 360 is arranged in the storage tank 350 removably, the two ends that the first baffle plate 360 crosses storage tank 350 and the first baffle plate 360 contact respectively the sidewall of storage tank 350, and the first baffle plate 360 is divided into the first compartment 350a and the second compartment 350b with storage tank 350 thus.Storage tank 350 has apopore 352, and apopore 352 is positioned at the second compartment 350b.
The first baffle plate 360 lower edges have breach 361, when the first baffle plate 360 is assembled in storage tank 350 when interior, the segment distance S of being separated by between the bottom surface of the first baffle plate 360 lower edges and storage tank 350.When containing after fine-grained solution injects storage tank 350 by the first compartment 350a; majority of particles can be blocked or natural subsidence near the first baffle plate 360; particularly when by breach 361; particulate is in low shallow waters and can settles down comparatively rapidly, and solution then can pass the first baffle plate 360 and be discharged by apopore 352.Collector unit 340 utilizes breach to create a miniature shallow water territory between the first baffle plate 360 and storage tank 350, and is arranged at mixed solution and must through part, can accelerates the particulate sinking speed.
The third collector unit
Fig. 6 illustrates the schematic perspective view according to the third collector unit of the embodiment of the invention.Collector unit 440 comprises storage tank 450, the first baffle plate 460 and second baffle 462, the first baffle plate 460 all is arranged in the storage tank 450 removably with second baffle 462, and the first baffle plate 460 and second baffle 462 cross the sidewall that storage tank 450 and its two ends contact respectively storage tank 450.
The first baffle plate 460 lower edges have breach 461, when the first baffle plate 460 is assembled in storage tank 450 when interior, the segment distance S of being separated by between the bottom surface of the first baffle plate 460 lower edges and storage tank 450; The lower edge of second baffle 462 is close to storage tank 450 bottom surfaces, and the height of second baffle 462 is less than the height of storage tank 450.
The first baffle plate 460 and second baffle 462 both next-door neighbours, the first baffle plate 460 be near entry place one sides, and second baffle 462 is near apopore 452 1 sides, mixed solution the first baffle plate 460 second baffle 462 of flowing through again of can flowing through first; The first baffle plate 460 is divided into the first compartment 450a and the second compartment 450b with second baffle 462 with storage tank 450, and storage tank 450 has apopore 452, and apopore 452 is positioned at the second compartment 450b.
When containing after fine-grained solution injects storage tank 450 by the first compartment 450a; majority of particles can be blocked or natural subsidence near the first baffle plate 460; the part particulate is forced to during by breach 461 slow down; the second baffle 462 that the particulate that slows down very easily is close to stops or settles down, and solution is then discharged by apopore 452 at last.The multiple baffle plate of collector unit 440 combinations, the spatial design such as its position, breach, spacing, height are for helping the particulate sedimentation to have the effect of addition.
The 4th kind of collector unit
Fig. 7 illustrates the schematic perspective view according to the 4th kind of collector unit of the embodiment of the invention.Collector unit 540 comprises storage tank 550, the first baffle plate 560, second baffle 562 and the 3rd baffle plate 564, the first baffle plate 560, second baffle 562 and the 3rd baffle plate 564 all are arranged in the storage tank 550 removably, cross the sidewall that storage tank 550 and its two ends contact respectively storage tank 550.
The first baffle plate 560 lower edges have individual breach 561, the segment distance S1 of being separated by between the bottom surface of the first baffle plate 560 lower edges and storage tank 550 after the assembling, the lower edge of second baffle 562 is close to storage tank 550 bottom surfaces, its height is less than the height of storage tank 550, the 3rd baffle plate 564 lower edges have breach 565, the segment distance S2 of being separated by between the bottom surface of the 3rd baffle plate 564 lower edges and storage tank 550 after the assembling, S1 and S2 are respectively between 1-5 centimetre.
The first baffle plate 560, second baffle 562 and the 3rd baffle plate 564 threes are close to setting, and storage tank 550 is divided into the first compartment 550a and the second compartment 550b.Storage tank 550 has apopore 552, and apopore 552 is positioned at the second compartment 550b.
The relative position of baffle plate contains fine-grained solution and injects after the storage tank 550 first baffle plate 560 of can sequentially flowing through, second baffle 562 and the 3rd baffle plate 564 as shown in Figure 7.When containing after fine-grained solution injects storage tank 550 by the first compartment 550a; majority of particles can be blocked or natural subsidence near the first baffle plate 560; the part particulate is forced to during by breach 561 slow down; the second baffle 562 that the particulate that slows down very easily is close to stops or settles down; arrive the 3rd baffle plate 564 even if there is a small amount of particulate to cross second baffle 562; the shallow water territory that also must cause by breach 565 and sedimentation or be forced to slow down, solution is discharged by apopore 552 at last.The multiple baffle plate of collector unit 540 combinations designs between the microvoids such as its position, distance, breach, height, for helping the particulate sedimentation to have the effect of addition.
The 5th kind of collector unit
Fig. 8 illustrates the schematic perspective view according to the 5th kind of collector unit of the embodiment of the invention.Collector unit 640 comprises storage tank 650, the first baffle plate 660, second baffle 662, the 3rd baffle plate 664, the 4th baffle plate 670, the 5th baffle plate 672 and the 6th baffle plate 674, storage tank 650 has entry place separately (such as pipeline place, Fig. 8 left side) and apopore 652, the first to six baffle plate 660-674 sequentially arranges along entry place toward apopore 652 directions, all baffle plates all are arranged in the storage tank 650 removably, cross the sidewall that storage tank 650 and its two ends contact respectively storage tank 650.
The first baffle plate 660, second baffle 662 and the 3rd baffle plate 664 threes are close to setting, the 4th baffle plate 670, the 5th baffle plate 672 and the 6th baffle plate 674 threes are close to setting, and two groups of baffle plates are divided into the first compartment 650a, the second compartment 650b and the 3rd compartment 650c with storage tank 650.Storage tank 650 has apopore 652, and apopore 652 is positioned at the 3rd compartment 650c.
The first baffle plate 660 lower edges have individual breach, the segment distance S of being separated by between the bottom surface of the first baffle plate 660 lower edges and storage tank 650 after the assembling, the lower edge of second baffle 662 is close to storage tank 650 bottom surfaces and its height less than the height of storage tank 650, the 3rd baffle plate 664 lower edges have breach, the segment distance S of being separated by between the bottom surface of the 3rd baffle plate 664 lower edges and storage tank 650 after the assembling.Similarly, the 4th baffle plate 670 lower edges have breach, the segment distance S of being separated by between the bottom surface of the first baffle plate 670 lower edges and storage tank 650 after the assembling, the lower edge of second baffle 672 is close to storage tank 650 bottom surfaces and its height less than the height of storage tank 650, the 3rd baffle plate 674 lower edges have breach, the segment distance S of being separated by between the bottom surface of the 3rd baffle plate 674 lower edges and storage tank 650 after the assembling.
The relative position of baffle plate contains fine-grained solution and injects after the storage tank 650 first baffle plate 660 of can sequentially flowing through, second baffle 662, the 3rd baffle plate 664, the 4th baffle plate 670, the 5th baffle plate 672 and the 6th baffle plate 674 as shown in Figure 8.When containing after fine-grained solution injects storage tank 650 by the first compartment 650a; majority of particles can be blocked or natural subsidence near the first baffle plate 660; the second baffle 662 that very easily is close to of being forced to slow down during the breach of part particulate by the first baffle plate 660 stops or settles down; even if particulate is crossed second baffle 662 and is arrived the 3rd baffle plate 664; can be forced to by the breach of the 3rd baffle plate 664 sedimentation or deceleration again; then; the solution that contains a small amount of particulate the 4th identical baffle plate 670 of configuration of must flowing through; the 5th baffle plate 672 and the 6th baffle plate 674; the remaining particulate that will remain little stops or settles down, and solution is discharged by apopore 652 at last.Collector unit 640 has two groups of baffle plates, all make up a plurality of baffle plates in every group of baffle plate, design details between the microvoids such as its position, distance, breach, height, for helping the particulate sedimentation to have the effect of addition, many group baffle plates can improve the ratio that particulate is blocked in addition, so that particulate can more complete being collected.
Specifically, the storage tank 650 of the present embodiment is a rectangle cell body, the cell body length L is between the 300-500 millimeter, the cell body width W is between the 200-400 millimeter, the cell body height H is between the 30-50 millimeter, and apopore 652 diameters on the cell body sidewall are between the 5-15 millimeter, and entry place can be that the pipeline of directly inserting also can be the hole on the sidewall, its diameter is equally between the 5-15 millimeter, and the distance of apopore 652 (or blasthole) lower edge and storage tank 650 bottom surfaces is between the 10-20 millimeter; The cell body height H is greater than the first baffle plate 660 height h1, the first baffle plate 660 height h1 are again greater than second baffle 662 height h2, the first baffle plate 660 height are between the 20-40 millimeter, second baffle 662 height h2 are between the 10-20 millimeter, distance A between the first baffle plate 660 and the second baffle 662 approximately is 5 millimeters, between the first baffle plate 660 and the 3rd baffle plate 664 approximately is 10 millimeters apart from B, the breach of the 3rd baffle plate 664 lower edges and the interval S of storage tank 650 bottom surfaces are between the 1-5 millimeter, and the distance X of the breach of the 3rd baffle plate 664 and storage tank 650 sidewalls approximately is the 1-10 millimeter.More than illustrate the size of collector unit each several part, right the art has knows that usually the knowledgeable is when understanding, size, the shape of storage tank and baffle plate, distance, combination are set all can be according to different demands suitable change and retouching, and the present invention is not limited thereto.
[method of continuous production particulate]
Utilize said apparatus, the present invention also proposes a kind of method of continuous production particulate, comprises the following steps.Fig. 9 illustrates the method according to a kind of continuous production particulate of one embodiment of the invention.At first, step S02, the aqueous solution is provided, the aqueous solution comprises interfacial agent, and organic solution is provided, and organic solution comprises active material and degradable macromolecular material, decomposable macromolecular material for example is high molecular lactic/glycolic acid-2-hydroxybutyric acid copolymer (poly (lactic/glycolic acid), PLGA), active material for example is Olanzapine or Granisetron, and the mixed proportion of the aqueous solution and organic solution for example is 200: 1.
Then, shown in step S04, mixed aqueous solution and organic solution form emulsion, and emulsion comprises several particulates that are comprised of degradable macromolecular material and active component.Then, shown in step S06, emulsion is passed into consolidation liquid to solidify particulate, consolidation liquid for example is polyvinyl alcohol (PVA) solution.At last, such as step S08, use the described collector unit 140 of above-described embodiment, 240,340,440,540,640 separating particles, perhaps, also cleaning fluid can be passed in the storage tank, residual active component or the organic solution of contact particulate clean surface, cleaning fluid can be discharged by apopore at last equally.
Because not containing the solution of particulate can be flowed out by apopore, just have living space in the storage tank and include fine-grained mixed solution continuation injection, thus, contain after the curing in the injection collector unit that fine-grained mixed solution can continue, particulate also can be blocked constantly or be deposited in the storage tank and be collected.In addition, collection process is to utilize suspension to be subjected to gravitating and the principle of natural subsidence, in the solution path, baffle plate is set and stops particulate, allow particulate fall at the bottom of the storage tank, do not need the operator to operate in the process, can be integrated into a continuous manufacturing process from producing to the process of collecting, have the potentiality that expand the scale of production.
In addition; the particulate that makes according to said apparatus and method does not have deformation and rendezvous problem; and can long-acting release of active ingredients; below lift several groups of the results shows; right technical field of the present invention has knows that usually the knowledgeable is working as and can understand; the apparatus and method of the continuous production particulate that the present invention proposes are not limited to following medicine and copolymer kind, also can be applicable to particulate or microcapsules that other materials forms.
[preparation of Olanzapine micron ball]
[material] high molecular lactic/glycolic acid-2-hydroxybutyric acid copolymer (poly (lactic/glycolic acid), PLGA) (the mole ratio is 85/15) itself has (chloroform.25 ℃ of stickiness 0.84dl/g, c=0.1g/dl), available from PURAC.Every g of watermiscible vitamin E (tocopheryl polyethylene glycol succinate with 278mg tocopherol, TPGS), Olanzapine is all available from USP NFgrade, polyvinyl alcohol (Polyvinyl alcohol, interfacial agent during PVA) as organic phase/water emulsification, average mole amount is 30,000 to 70,000, available from Sigma-Aldrich.Organic solution is prepared as follows: PLGA, Olanzapine and TPGS are dissolved in 10ml carrene (dichloromethane), organic phase during as organic phase/water emulsification, every milliliter of carrene contains 160mg PLGA, 64 mg Olanzapine and 40mg TPGS, water is that the 0.1%PVA temperature maintains 6-8 ℃, and the mixed proportion of organic phase/water is 0.5%.
The device of [method and particulate outward appearance] continuous production particulate as shown in Figure 2, collector unit device as shown in Figure 8.The organic solution of 80ml and 16, the aqueous solution of 000ml exports emulsification unit to the speed of per minute 1.25ml/min and 250ml/min respectively, emulsification unit is an emulsification cavity (IKA with homogenizer, UTL25digital with S25KV-25GIL knife), its input port is Y-piece, one is as the inlet of the aqueous solution, one is as the inlet of organic solution, another one is connected to the emulsification cavity, two-phase is pre-mixed in Y-piece to be inputted in the emulsification cavity again, and it is 8000rpm that homogenizer is set rotating speed.In following step, solution after the emulsification injects solidified cell, solidified cell is that two capacity are 4 liters beaker, both interconnect, particulate in each beaker stirs with the stirrer of rotating speed 500rpm, and after solidifying, particulate collects with collector unit 640, with 0.1%F-68 aqueous cleaning twice, with washed with de-ionized water once.At last, product is made powder with freeze-drying.
The particle diameter of particulate is about 26.6 microns, and light microscope and scanning electron microscope analysis result show that the structure of particulate is average and be three-dimensional ball-type.In addition, the coating efficiency (encapsulating efficiency) of high-effect LC instrument (270nm) measurement Olanzapine is 87%.
[test of medicine release efficiency] above-mentioned experiment prepares particulate, get the 20mgOlanzapine-TPGS-PLGA particulate and place in the 50ml centrifuge tube, be dissolved in 12ml PBS solution (0.01M comprises 0.01%Tween 80 and 0.01%sodium azide), 37 ℃ of water-baths are shaken with 60rpm.Regularly sampling in eight weeks, and with high-effect LC instrument analysis drug release rate.
The result of testing in vitro Olanzapine drug release rate is shown in Figure 10 A and Figure 10 B, the particulate that the apparatus and method of this discovery embodiment make is when just beginning to offer medicine, just present stable rate of release, therefore, has less primary effect (initial effect), and whole medicine release efficiency presents constant speed and discharges (approaching linear), namely discharges in vivo medicine (meeting zero level release dynamics rule) with given pace, near the zero level drug release pattern.Constant speed discharges can reduce the blood concentration fluctuation situation, increases the compliance that the patient takes medicine.
[preparation of Granisetron micron ball]
[material] PLGA (the mole ratio is 50/50), TPGS, Granisetron, PVA.Organic solution is prepared as follows: PLGA, Granisetron and TPGS are dissolved in 10ml carrene (dichloromethane), organic phase during as organic phase/water emulsification, every milliliter of carrene contains 160mg PLGA, 16mg Granisetron and 10mg TPGS, water is that the 0.1%PVA temperature maintains 6-8 ℃, and the mixed proportion of organic phase/water is 0.5%.
[method and particulate outward appearance] process for making is identical with precedent, and the particle diameter of particulate is about 20.5 microns, and coating efficiency (encapsulating efficiency) is about 81%.
[test of medicine release efficiency] above-mentioned experiment prepares particulate, get the 20mgGranisetron-TPGS-PLGA particulate and place in the 50ml centrifuge tube, be dissolved in 12ml PBS solution (0.01M comprises 0.01%Tween 80 and 0.01%sodium azide), 37 ℃ of water-baths are shaken with 60rpm.Regularly sampling in five days, and with high-effect LC instrument analysis drug release rate.
The result of testing in vitro Granisetron drug release rate is shown in Figure 11 A and Figure 11 B.
Device, method and the collector unit thereof of the disclosed continuous production particulate of the above embodiment of the present invention; the mixed solution that injects collector unit can be placed in shallow water (being in the storage tank) or pass through more low shallow waters (between baffle plate breach and the storage tank); so that the particulate that suspends can settle down fast; after mixed solution is injected into collector unit; particulate can be stopped by baffle plate or during by breach rapid subsidence get off; solution can be flowed out by apopore regularly, allows mixed solution be continued to inject storage tank.Therefore, the method for preparing particulate that the present embodiment proposes comprises that the steps such as emulsification, curing and collection can be integrated into continuous manufacture craft, without any need for personnel operation, that is to say, in case the device of the present embodiment need not any manual operation and namely can make continuously and collect particulate after setting and finishing and start.
On the other hand, the method that tradition is collected particulate is to collect in mode centrifugal or that filter being suspended in the particulate that solidifies in the groove, traditional manufacturing technique belongs to a batch manufacture craft, after curing schedule, just need the operator to operate collection procedure or the equipment of operating machine is just collected particulate, compare with traditional manufacturing technique, the method and apparatus of the continuous production particulate that the present embodiment discloses has following advantage:
1. collect the particulate process from supplying raw materials to and belong to continuous manufacturing process, the potentiality that enlarge the manufacturing scale are arranged.
2. be suitable for sterile working.The plant bulk that the present embodiment proposes is moderate simple in structure, and operation in the sterilized space can both be sterilized or move in all unit, and the whole section manufacture craft that therefore prepares particulate can operate under aseptic environment, guarantees the quality of product.
3. the method for preparing particulate of the present embodiment exposure is integrated into continuous manufacturing process, in case apparatus settings is finished and started, need not any manual operation and namely can make continuously and collect particulate.
4. the particulate that makes according to the apparatus and method of the present embodiment has less primary effect and more near the zero level drug release pattern.
In sum, though disclosed the present invention in conjunction with above embodiment, it is not to limit the present invention.Be familiar with in the technical field of the invention this operator, without departing from the spirit and scope of the present invention, can be used for a variety of modifications and variations.Therefore, protection scope of the present invention should with enclose claim was defined is as the criterion.
Claims (21)
1. collector unit, in order to collect a plurality of particulates in the solution, this collector unit comprises:
Storage tank has apopore; And
The first baffle plate, be arranged at removably in this storage tank, the two ends that this first baffle plate crosses this storage tank and this first baffle plate contact respectively the sidewall of this storage tank, this first baffle plate is divided into one first compartment and one second compartment with this storage tank thus, and wherein this apopore is positioned at this second compartment;
This solution that wherein contains those particulates is injected after this storage tank by this first compartment, and those particulates can be deposited near this first baffle plate, and this solution then can be crossed or pass this first baffle plate and enter this second compartment, and discharges from this apopore.
2. collector unit as claimed in claim 1, wherein the height of this storage tank is less than the internal diameter of this storage tank.
3. collector unit as claimed in claim 1, wherein the height of this storage tank is between the 30-50 millimeter.
4. collector unit as claimed in claim 1, wherein the height of this first baffle plate is less than the height of this storage tank.
5. collector unit as claimed in claim 1, wherein this first baffle plate lower edge has at least one breach, when this first baffle group is loaded in this storage tank, the spacing of being separated by between the bottom surface of this first baffle plate lower edge and this storage tank.
6. collector unit as claimed in claim 5, wherein this spacing is between 1-5 centimetre.
7. collector unit as claimed in claim 5 wherein also comprises:
Second baffle, be arranged at removably in the storage tank, this second baffle crosses the sidewall that this storage tank and its two ends contact respectively this storage tank, and the lower edge of this second baffle all contacts this storage tank bottom surface, and the height of this second baffle is less than the height of this storage tank; And
Wherein, this solution this first baffle plate this second baffle of flowing through again of flowing through first.
8. collector unit as claimed in claim 7, wherein the height of this second baffle is less than the height of this first baffle plate.
9. collector unit as claimed in claim 7 wherein also comprises:
The 3rd baffle plate is arranged in the storage tank removably, and the 3rd baffle plate crosses the sidewall that this storage tank and its two ends contact respectively this storage tank, the spacing of being separated by between the bottom surface of the 3rd baffle plate lower edge and this storage tank;
Wherein, this solution flow through first this first baffle plate, this second baffle, the 3rd baffle plate of flowing through again.
10. the device of a continuous production particulate comprises:
The raw material supply unit is supplied an aqueous solution and an organic solution independently and continuously, and this aqueous solution comprises an interfacial agent, and this organic solution comprises an active component and a degradable macromolecular material;
Emulsification unit is accepted and is mixed this aqueous solution and this organic solution to form an emulsion, and this emulsion comprises a plurality of particulates that are comprised of this degradable macromolecular material and this active component;
Solidified cell is accepted this emulsion and it is sneaked into a consolidation liquid, solidifies thus those particulates; And
Collector unit comprises:
Storage tank has apopore; And
The first baffle plate, be arranged at removably in this storage tank, the two ends that this first baffle plate crosses this storage tank and this first baffle plate contact respectively the sidewall of this storage tank, this first baffle plate is divided into one first compartment and one second compartment with this storage tank thus, and wherein this apopore is positioned at this second compartment;
This solution that wherein contains those particulates is injected after this storage tank by this first compartment, and those particulates can be deposited near this first baffle plate, and this solution then can be crossed or pass this first baffle plate and enter this second compartment, and discharges from this apopore.
11. device as claimed in claim 10, wherein this emulsification unit is a homogenizer.
12. device as claimed in claim 10, wherein this raw material supply unit also comprises a conveyer, in order to control the transporting velocity of this organic solution.
13. device as claimed in claim 12, wherein this conveyer is a peristaltic pump, a centrifugal pump or a reciprocating pump.
14. device as claimed in claim 10, wherein this solidified cell also comprises a vavuum pump.
15. the method for a continuous production particulate comprises:
One aqueous solution is provided, comprises an interfacial agent;
One organic solution is provided, comprises an active material and a degradable macromolecular material;
Mix this aqueous solution and this organic solution forms an emulsion, this emulsion comprises a plurality of particulates that are comprised of this degradable macromolecular material and this active material;
This emulsion is passed into a consolidation liquid to solidify those particulates; And
Use a collector unit to isolate those particulates, this collector unit comprises a storage tank and one first baffle plate, and this storage tank has an apopore, and this first baffle plate is arranged in this storage tank and between entry place and this apopore removably; The solution that wherein contains those particulates is injected after this storage tank by this entry place, and those particulates can be deposited near this first baffle plate, and solution then can be crossed or pass this first baffle plate and discharge from this apopore.
16. method as claimed in claim 15, wherein this degradable macromolecular material is high molecular lactic/glycolic acid-2-hydroxybutyric acid copolymer.
17. method as claimed in claim 15, wherein this active material is Olanzapine.
18. method as claimed in claim 15, wherein this active material is Granisetron.
19. method as claimed in claim 15, wherein this consolidation liquid is poly-vinyl alcohol solution.
20. method as claimed in claim 15, wherein the mixed proportion of this aqueous solution and this organic solution is 200: 1.
21. method as claimed in claim 15 wherein also comprises:
One cleaning fluid is passed in this storage tank, contact those particulates and discharged by this apopore.
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| US25823009P | 2009-11-05 | 2009-11-05 | |
| US61/258,230 | 2009-11-05 |
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| CN1513602A (en) * | 2003-07-09 | 2004-07-21 | 南开大学 | Zirconium gule substrate agglomeration type anion exchange microsphere and its preparation method |
| CN1654116A (en) * | 2004-02-09 | 2005-08-17 | 中国乐凯胶片集团公司 | Preparation method of microcapsule |
| CN101319055A (en) * | 2007-11-27 | 2008-12-10 | 中山大学 | Epoxy resin micro-capsule and its preparation method |
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| US6291013B1 (en) * | 1999-05-03 | 2001-09-18 | Southern Biosystems, Inc. | Emulsion-based processes for making microparticles |
| TWI225416B (en) * | 2001-06-29 | 2004-12-21 | Takeda Chemical Industries Ltd | Sustained-release composition and process for producing the same |
| AU2003262719A1 (en) * | 2002-08-14 | 2004-03-03 | Encap Technologies, Inc. | Microencapsulated and nanoencapsulated particles, moisture barrier resins, and processes for manufacturing same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1513602A (en) * | 2003-07-09 | 2004-07-21 | 南开大学 | Zirconium gule substrate agglomeration type anion exchange microsphere and its preparation method |
| CN1654116A (en) * | 2004-02-09 | 2005-08-17 | 中国乐凯胶片集团公司 | Preparation method of microcapsule |
| CN101319055A (en) * | 2007-11-27 | 2008-12-10 | 中山大学 | Epoxy resin micro-capsule and its preparation method |
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