TWI477266B - Mehtod and device of continuously preparing microspheres, and collection unit thereof - Google Patents

Description

Method and device for continuously preparing particles and collecting unit thereof

The present invention relates to a method, apparatus and collection unit for preparing microparticles, and more particularly to a method, apparatus and collection unit for continuously preparing microparticles.

Microcapsules or microparticles made from various natural or synthetic polymers and resins have become popular carriers of various active ingredients such as pharmaceuticals, diagnostic agents or the like. Biodegradable microcapsules and microparticles are commonly known as depot formulations that release active ingredients over extended periods of time (more than expected).

The preparation of microparticles generally involves the formation of at least one dispersed phase in the continuous phase, which typically comprises the active ingredient and the polymer, which forms a microparticle after solidification in the continuous phase; the microcapsules are also prepared using similar multiple phases in a conventional process. After the aqueous phase/organic phase/aqueous phase (W/O/W) emulsion is formed, the polymer precipitated from one of the phases solidifies in the formation of a capsule coat of the dispersed phase.

In 1980, Japan's Wada Pharmaceutical first developed the use of biodegradable polymer lactic acid-glycolic acid (PLGA) to coat the luteinizing hormone Leuprolide acetate. In the process of product, the double-emulsification process of the aqueous phase/organic phase/water phase (W/O/W) is used to coat the sustained-release microcapsules of the drug, and in the process of curing the microcapsules, the drug and the PLGA primary emulsification solution are used. (W/O) was injected with a polyvinyl alcohol (PVA) aqueous solution for the second emulsification, and the capsule was cured by an aqueous phase drying method.

Since the drug and PVA remain on the surface of the microcapsule, it is usually stirred and washed with water and collected by centrifugation. However, the hardness of the PLGA polymer capsule is not high, and it is very easy to cause deformation and aggregation of the capsule after centrifugation.

Furthermore, the microcapsules collected by centrifugation must be handled by personnel. The operation process includes solidifying the microcapsules together with the solution into a plurality of centrifuge tubes, and the supernatant must be carefully removed after centrifugation, and the microcapsules are resuspended in a small amount of solution, collected, and then dried to form a powder. The traditional microcapsule process is actually a batch process, which requires the operator to operate the centrifuge to complete the collection step, which not only increases the manufacturing cost invisibly, but also limits the inability to construct a continuous process and indirectly restricts its production. scale. In addition, the resulting microcapsules may have problems of deformation or aggregation and may also have a negative effect on the drug release pattern.

The invention relates to a method and a device for continuously preparing microparticles and a collecting unit thereof, which collects microparticles by the principle of natural sedimentation, can avoid the deformation and aggregation of the microparticles, and can continuously collect the microparticles, so that the microparticles are prepared to form a continuous process.

According to a first aspect of the present invention, a collecting unit is provided for collecting a plurality of particles in a solution, the collecting unit includes a receiving groove and a first baffle, and the receiving groove has a water outlet hole, and the first baffle is The first baffle is disposed in the accommodating groove, and the first baffle is traversed in the accommodating groove, and the two ends of the first baffle respectively contact the side wall of the accommodating groove, whereby the first baffle divides the accommodating groove into The first compartment and the second compartment, wherein the water outlet hole is located in the second compartment, wherein after the solution containing the particles is injected into the accommodating groove by the first compartment, the particles will settle near the first baffle, and the solution will pass over Or through the first baffle into the second compartment and discharged from the water outlet.

According to a second aspect of the present invention, there is provided an apparatus for continuously preparing fine particles, comprising a raw material supply unit, an emulsifying unit, a curing unit, and the above-described collecting unit. The raw material supply unit independently and continuously supplies the aqueous solution and the organic solution, the aqueous solution includes an interface active agent, the organic solution includes an active ingredient and a degradable polymer material, and the emulsification unit receives and mixes the aqueous solution and the organic solution to form an emulsion, and the emulsion includes a plurality of particles composed of a biodegradable polymer material and an active ingredient, the curing unit receives the emulsion and mixes it into the solidifying liquid, thereby solidifying the particles, and the collecting unit comprises a receiving groove and a first baffle, and the receiving groove has a water outlet hole, the first baffle plate is detachably disposed in the accommodating groove, the first baffle traverses the accommodating groove, and the two ends of the first baffle respectively contact the side wall of the accommodating groove, thereby A baffle divides the accommodating groove into a first compartment and a second compartment, wherein the water outlet hole is located in the second compartment, and after the solution containing the particles is injected into the accommodating groove by the first compartment, the particles will settle in the first compartment Near the baffle, the solution will pass over or through the first baffle into the second compartment and out of the water outlet.

According to a third aspect of the invention there is provided a method of continuously preparing microparticles comprising (a) providing an aqueous solution comprising an interfacial active agent; (b) providing an organic solution comprising an active material and a degradable polymeric material; (c) The mixed aqueous solution and the organic solution form an emulsion comprising a plurality of particles composed of a degradable polymer material and an active ingredient; (d) passing the emulsion into the solidifying liquid to solidify the particles; and (e) collecting using the above The unit separates the particles, and the collecting unit includes a receiving groove and a first baffle, the receiving groove has a water outlet hole, and the first baffle is detachably disposed in the receiving groove, and the first baffle is traversed The groove and the two ends of the first baffle respectively contact the side wall of the accommodating groove, whereby the first baffle divides the accommodating groove into the first compartment and the second compartment, wherein the water outlet hole is located in the second compartment, wherein After the solution containing the particles is injected into the accommodating tank from the first compartment, the particles settle in the vicinity of the first baffle, and the solution passes over or through the first baffle into the second compartment and is discharged from the effluent. .

In order to make the above-mentioned contents of the present invention more comprehensible, the following specific embodiments, together with the drawings, are described in detail below:

The invention mainly provides a method and a device for continuously preparing microparticles, wherein the collecting unit collects the microparticles by using the principle of natural sedimentation, can avoid the deformation and aggregation of the microparticles, and can continuously collect the microparticles, so that the microparticles are prepared to form a continuous process. The following is a detailed description of several sets of embodiments with reference to the drawings. However, it is obvious to those skilled in the art that the text and illustrations in the present specification are only one embodiment of the present invention, and the present invention is not The scope of protection is limited.

[Device for preparing microparticles]

Please refer to FIG. 1 , which is a block diagram of an apparatus for continuously preparing microparticles according to an embodiment of the invention. One embodiment of the present invention provides an apparatus 100 for continuously preparing microparticles, including a raw material supply unit 110, an emulsifying unit 120, a curing unit 130, and a collecting unit 140, which are described in detail below.

The raw material supply unit 110 includes two independent storage tanks 112 and 114, respectively storing different kinds of raw materials, such as an aqueous solution and an organic solution, the aqueous solution includes an interface active agent, the organic solution includes an active ingredient and a degradable polymer material; The raw material can be continuously outputted, for example, the storage tank is raised higher than the transfer line, the solution can be continuously injected into the transfer line, or the solution is pumped from the storage tank. The material supply unit 110 further includes a conveyor 116 for individually or cooperatively controlling the conveying speeds of the two storage tanks, such as a creeping pump, a centrifugal pump, a reciprocating pump, a drip governor, and a control valve. Or other tools that control the flow rate to adjust the mixing ratio of the various materials. The raw material supply unit 110 is used to independently and continuously supply the raw materials required for the production of the particles, and it is preferable to adjust the supply speed thereof to adjust the mixing ratio thereof.

The emulsification unit 120 receives and mixes the aqueous solution and the organic solution to form an emulsion. The emulsification unit 120 is, for example, a homogenizer, a stirrer or other miscible tool, and the emulsion comprises a plurality of particles composed of a biodegradable polymer material and an active ingredient. .

The curing unit 130 receives the emulsion and mixes it into the curing liquid; the curing unit 130 may include a container containing a large amount of curing liquid and a stirring tool, and injecting the emulsion containing the particles into the curing liquid may help the particles to solidify and form, and continue to stir and mix. The particles may be broken to avoid aggregation. In addition, the curing unit 130 may further include a vacuum pump, and the container containing the mixed solution is moved to the closed cavity to evacuate, thereby increasing the volatilization speed of the organic solution.

The collecting unit 140 receives the mixed solution containing the fine particles, and collects the fine particles by means of natural sedimentation, the detailed structure of which will be described in the following paragraph.

Since the apparatus for preparing the microparticles differs according to the production scale, and the equipments for each unit are also different, this specification proposes a device for continuously preparing microparticles on a laboratory scale, as shown in Fig. 2, and Fig. 2 shows A perspective view of a device for continuously preparing microparticles according to an embodiment of the present invention, but those skilled in the art will be able to make appropriate changes and refinements according to different requirements such as manufacturing scale and control method.

Referring to FIG. 2, the storage tank 112 is a container having a control valve filled with an aqueous solution containing an surfactant, and the storage tank 114 is a jar filled with an organic solution containing an active ingredient and a degradable polymer material. . The storage tank 112 is disposed at a higher position than the transfer line and has a control valve, so the aqueous solution will automatically flow into the transfer line and the flow rate is controlled by the control valve; the storage tank 114 is connected to the peristaltic pump 116 to adjust the flow rate of the organic solution.

The aqueous solution and the organic solution are simultaneously input into the emulsification unit 120 to form fine particles. The emulsification unit 120 is an emulsification cavity (IKA, UTL25 digital with S25KV-25GIL knife) having a homogenizer, and the input port is a Y-shaped tube, and one is used as an aqueous solution. The injection port is used as an injection port of the organic solution, and the other is connected to the emulsion cavity 122. The aqueous solution and the organic solution are premixed in the Y-shaped tube and then input into the emulsion cavity 122 to form an emulsion, and the output of the emulsion unit 120 is output. Then connected to the curing unit 130.

The curing unit 130 is two beakers having a capacity of 4 liters, which are connected to each other, and each of the beakers has a stirring system for dispersing the particles to avoid aggregation. In addition, a vacuum pump (not shown) may be added to connect the curing unit 130 to accelerate the evaporation rate of the organic solution. The front end of the curing unit 130 is connected to the emulsification unit 120, and the rear end is connected to the collection unit 140.

3A is a perspective view showing a collecting unit according to an embodiment of the present invention, and FIG. 3B is a partially enlarged view showing a collecting unit according to an embodiment of the present invention. Referring to FIG. 3A, the collecting unit 140 includes a receiving groove 150 and a first baffle 160. The first baffle 160 is detachably disposed in the receiving groove 150, and the first baffle 160 is traversed. The slot 150 and the two ends of the first baffle 160 respectively contact the sidewall of the accommodating slot 150, whereby the first baffle 160 divides the accommodating slot 150 into the first compartment 150a and the second compartment 150b. The tank 150 has a water outlet 152, and the water outlet 152 is located in the second compartment 150b.

FIG. 3B is a partial enlarged view of a collecting unit according to an embodiment of the present invention. Referring to FIG. 3B, two side strips 154 are respectively disposed on the two side walls of the first baffle 160 contacting the receiving groove 150. The side strips 154 are fixed on the side walls of the receiving groove 150, and the two side strips on the same side wall. The distance between the 154 is approximately equal to the width of the first baffle 160. Although the first baffle 160 has no fixed connection relationship with the accommodating groove 150, the first baffle 160 can be placed along the rib 154 into the accommodating groove. The first baffle 160 can be removed from the accommodating slot 150 along the side strip 154, so that the first baffle 160 can be removed. The disassembly manner is disposed in the accommodating groove 150. It will be apparent to those skilled in the art that the first baffle and other arrangements are detachable, and the present invention is not limited thereto.

The lower edge of the first baffle 160 is in close contact with the bottom surface of the accommodating groove 150. The height of the first baffle 160 is preferably smaller than the height of the accommodating groove 150. After the solution containing the particles is injected into the accommodating groove 150 by the first compartment 150a, the particles are blocked or naturally settled before the first baffle 160 (ie, between the water inlet and the first baffle 160), and the solution is The first baffle 160 is passed over the second compartment 150b and discharged from the water outlet 152. Since the solution will flow out of the water outlet hole 152, there is a space in the accommodating groove 150 for the solution to continue to be injected. Thus, the mixed solution containing the particles after solidification can be continuously injected into the collecting unit 140, and the particles can be continuously retained. It is collected in the groove 150 and collected. The collection process utilizes the principle that the suspended solids are attracted by gravity and naturally settles, and the baffle block particles are arranged in the solution passage to help the particles settle more quickly in the bottom of the receiving tank. No operator operation is required in the process, and no precise precision is required. Instruments or expensive consumables.

In addition, a cleaning liquid (such as deionized water) may be injected into the accommodating tank 140 at the same time as or after the collecting step, and the cleaning liquid may also flow out through the water outlet hole 152 to take away the active component or the organic solution on the surface of the particle. It does not cause the problem of particle deformation or aggregation, so it can improve the quality of the product.

After the particles in the unit to be solidified 130 are settled at the bottom of the accommodating tank 150 and the liquid is removed, the first baffle 160 can be removed, and the particles are suspended and collected with a small amount of deionized water, and finally made by freeze-drying. powder.

The collecting unit 140 proposed in this embodiment is the most basic prototype, and a baffle is arranged in the solution passage, so that the solution must flow through the baffle to flow out of the water outlet after the solution is injected into the accommodating groove, thereby blocking the particles or forcing them to settle. The effect of the collection unit may also be other embodiments, such as changing the position, number, combination, spacing, etc. of the baffle to achieve the same or better effect. Several different collection units are illustrated below and illustrated.

First collection unit

4 is a perspective view of a first collection unit in accordance with an embodiment of the present invention. The collecting unit 240 includes a receiving groove 250, a first baffle 260 and a second baffle 262. The first baffle 260 and the second baffle 262 are disposed in the accommodating groove 250 in a detachable manner. The 260 and the second baffle 262 traverse the accommodating groove 250, and the two ends of the first baffle 260 and the second baffle 262 respectively contact the sidewall of the accommodating groove 250, whereby the first baffle 260 and the second baffle The baffle 262 divides the accommodating groove 250 into a first compartment 250a, a second compartment 250b, and a third compartment 250c. The accommodating groove 250 has a water outlet hole 252, and the water outlet hole 252 is located in the third compartment 250c.

After the solution containing the particles is injected into the accommodating tank 250 by the first compartment 250a, most of the particles are blocked or naturally settled before the first baffle 260, and the solution passes over the first baffle 260 into the second compartment. 250b, a small portion of the particles will be blocked or naturally settled before the second baffle 262, and the solution will pass over the second baffle 262 into the third compartment 250c and exit the water outlet 252. Since the collecting unit 240 has more baffles, the proportion of particles injected by the curing unit is blocked and the collection is more complete.

Second collection unit

FIG. 5 is a schematic perspective view of a second collecting unit according to an embodiment of the invention. The collecting unit 340 includes a receiving groove 350 and a first baffle 360. The first baffle 360 is detachably disposed in the receiving groove 350. The first baffle 360 is transverse to the receiving groove 350 and the first baffle The two ends of the 360 are respectively contacted with the side walls of the accommodating groove 350, whereby the first baffle 360 divides the accommodating groove 350 into the first compartment 350a and the second compartment 350b. The accommodating groove 350 has a water outlet 352, and the water outlet 352 is located in the second compartment 350b.

The lower edge of the first baffle 360 has a notch 361. When the first baffle 360 is assembled in the accommodating groove 350, the lower edge of the first baffle 360 is spaced apart from the bottom surface of the accommodating groove 350 by a distance S. After the solution containing the particles is injected into the accommodating groove 350 by the first compartment 350a, most of the particles are blocked or naturally settled near the first baffle 360, especially when passing through the notch 361, the particles are in a low shallow water area. The solution settles more quickly, and the solution is discharged through the water outlet 352 through the first baffle 360. The collecting unit 340 creates a micro shallow water area between the first baffle 360 and the accommodating groove 350 by using a gap, and is disposed at a place where the mixed solution must pass, and can accelerate the sedimentation speed of the particles.

Third collection unit

FIG. 6 is a perspective view showing a third collecting unit according to an embodiment of the present invention. The collecting unit 440 includes a receiving groove 450, a first baffle 460 and a second baffle 462. The first baffle 460 and the second baffle 462 are disposed in the accommodating groove 450 in a detachable manner. The 460 and the second baffle 462 are transverse to the accommodating groove 450 and have opposite ends of the receiving groove 450.

The lower edge of the first baffle 460 has a notch 461. When the first baffle 460 is assembled in the accommodating groove 450, the lower edge of the first baffle 460 and the bottom surface of the accommodating groove 450 are separated by a distance S; The lower edge of the plate 462 is in close contact with the bottom surface of the accommodating groove 450, and the height of the second baffle 462 is smaller than the height of the accommodating groove 450.

The first baffle 460 and the second baffle 462 are adjacent to each other, the first baffle 460 is close to the water inlet side, the second baffle 462 is adjacent to the water outlet 452 side, and the mixed solution flows first through the first baffle 460. The first baffle 460 and the second baffle 462 divide the accommodating groove 450 into a first compartment 450a and a second compartment 450b. The accommodating groove 450 has a water outlet 452 and a water outlet 452. Located in the second compartment 450b.

After the solution containing the particles is injected into the accommodating groove 450 by the first compartment 450a, most of the particles are blocked or naturally settled near the first baffle 460, and some of the particles are forced to decelerate as they pass through the notch 461, and the decelerated particles are extremely easy. The solution is blocked or settled by the immediately adjacent second baffle 462, and the solution is finally discharged from the water outlet hole 452. The collecting unit 440 combines a plurality of baffles, and the space design such as position, notch, pitch, height, etc. has an additive effect on helping the sedimentation of the particles.

Fourth collection unit

FIG. 7 is a perspective view of a fourth collecting unit according to an embodiment of the invention. The collecting unit 540 includes a receiving groove 550, a first baffle 560, a second baffle 562 and a third baffle 564, and the first baffle 560, the second baffle 562 and the third baffle 564 are detachably The accommodating groove 550 is disposed in the accommodating groove 550, and the two ends of the accommodating groove 550 are respectively contacted with the side walls of the accommodating groove 550.

The lower edge of the first baffle 560 has a notch 561. The lower edge of the first baffle 560 is separated from the bottom surface of the accommodating groove 550 by a distance S1, and the lower edge of the second baffle 562 is closely attached to the bottom surface of the accommodating groove 550. The height of the third baffle 564 has a notch 565. The lower edge of the third baffle 564 is separated from the bottom surface of the accommodating groove 550 by a distance S2, and S1 and S2 are respectively separated. 1-5 cm.

The first baffle 560, the second baffle 562 and the third baffle 564 are disposed in close proximity, and the accommodating groove 550 is divided into a first compartment 550a and a second compartment 550b. The accommodating groove 550 has a water outlet 552, and the water outlet 552 is located in the second compartment 550b.

As shown in FIG. 7, the relative position of the baffle, after the solution containing the particles is injected into the accommodating groove 550, sequentially flows through the first baffle 560, the second baffle 562, and the third baffle 564. After the solution containing the particles is injected into the accommodating groove 550 by the first compartment 550a, most of the particles are blocked or naturally settled near the first baffle 560, and some of the particles are forced to decelerate as they pass through the notch 561, and the decelerated particles are extremely easy. Blocked or settled by the immediately adjacent second baffle 562, even if a small amount of particles pass over the second baffle 562 to the third baffle 564, it must be settled or forced to decelerate through the shallow water caused by the notch 565, and the solution is finally discharged from the water. The hole 552 is discharged. The collecting unit 540 combines a plurality of baffles, and the micro-space design such as position, distance, notch, height, etc. has an additive effect on helping the sedimentation of the particles.

Fifth collection unit

FIG. 8 is a perspective view of a fifth collecting unit according to an embodiment of the invention. The collecting unit 640 includes a receiving groove 650, a first baffle 660, a second baffle 662, a third baffle 664, a fourth baffle 670, a fifth baffle 672 and a sixth baffle 674, and the accommodating groove 650 has Separate water inlets (such as the line on the left side of Figure 8) and water outlets 652, the first to sixth baffles 660-674 are arranged in sequence along the water inlet to the water outlet 652, and all the baffles are detachably arranged. In the accommodating groove 650, the accommodating groove 650 is traversed and the two ends thereof are respectively contacted with the side walls of the accommodating groove 650.

The first baffle 660, the second baffle 662 and the third baffle 664 are disposed in close proximity, and the fourth baffle 670, the fifth baffle 672 and the sixth baffle 674 are disposed in close proximity, and the two baffles are accommodated. The groove 650 is divided into a first compartment 650a, a second compartment 650b, and a third compartment 650c. The accommodating groove 650 has a water outlet hole 652, and the water outlet hole 652 is located in the third compartment 650c.

The lower edge of the first baffle 660 has a notch. After the assembly, the lower edge of the first baffle 660 is spaced apart from the bottom surface of the accommodating groove 650 by a distance S, and the lower edge of the second baffle 662 is closely attached to the bottom surface of the accommodating groove 650. The height of the third baffle 664 has a notch, and the lower edge of the third baffle 664 is separated from the bottom surface of the accommodating groove 650 by a distance S. Similarly, the lower edge of the fourth baffle 670 has a notch. After assembly, the lower edge of the first baffle 670 is separated from the bottom surface of the accommodating groove 650 by a distance S, and the lower edge of the second baffle 672 is closely attached to the accommodating groove 650. The bottom surface and the height thereof are smaller than the height of the accommodating groove 650. The lower edge of the third baffle 674 has a notch. After assembly, the lower edge of the third baffle 674 is separated from the bottom surface of the accommodating groove 650 by a distance S.

As shown in FIG. 8, the relative position of the baffle, after the solution containing the particles is injected into the accommodating groove 650, sequentially flows through the first baffle 660, the second baffle 662, the third baffle 664, and the fourth baffle. 670, a fifth baffle 672 and a sixth baffle 674. After the solution containing the particles is injected into the accommodating groove 650 by the first compartment 650a, most of the particles are blocked or naturally settled near the first baffle 660, and some of the particles are forced to decelerate when passing through the notch of the first baffle 660. It is easy to be blocked or settled by the adjacent second baffle 662. Even if the particles pass the second baffle 662 to the third baffle 664, it will be forced to settle or decelerate through the notch of the third baffle 664, and then contain a small amount. The solution of the particles must flow through the fourth baffle 670, the fifth baffle 672, and the sixth baffle 674, which are configured to block or settle the remaining particles, and the solution is finally discharged from the water outlet 652. The collecting unit 640 has two groups The baffle, each baffle is combined with a plurality of baffles, and the micro-space design details such as position, distance, notch, height, etc. have an additive effect on helping the sedimentation of the particles, and the plurality of baffles can improve the interception of the particles. The ratio allows the particles to be collected more completely.

In detail, the accommodating groove 650 of the embodiment is a rectangular groove body having a length L of 300-500 mm, a groove width W of 200-400 mm, and a groove height H of 30- 50 mm, the water outlet 652 on the side wall of the tank is between 5 and 15 mm in diameter. The water inlet can be directly placed in the pipeline or the hole in the side wall. The diameter is also between 5 and 15 mm. The distance between the lower edge of the hole 652 (or the water inlet hole) and the bottom surface of the accommodating groove 650 is 10-20 mm; the height H of the groove body is greater than the height h1 of the first baffle 660, and the height h1 of the first baffle 660 is greater than the second block. The height of the plate 662 is h2, the height of the first baffle 660 is between 20-40 mm, the height of the second baffle 662 is h20 between 10-20 mm, and the distance A between the first baffle 660 and the second baffle 662 The distance B between the first baffle 660 and the third baffle 664 is about 10 mm, and the distance S between the notch of the lower edge of the third baffle 664 and the bottom surface of the accommodating groove 650 is between 1 and 1. 5 mm, the distance X between the notch of the third baffle 664 and the side wall of the accommodating groove 650 is about 1-10 mm. The above examples illustrate the dimensions of the various parts of the collection unit. However, it is obvious to those skilled in the art that the size, shape, arrangement distance, and combination of the receiving groove and the baffle can be appropriately modified and retouched according to different needs. The invention is not limited to this. For example, in an alternative embodiment, the receiving groove may be a non-rectangular groove, and the height of the receiving groove is smaller than an inner diameter of the receiving groove.

[Method of continuously preparing microparticles]

With the above device, the present invention also proposes a method for continuously preparing particles. The law includes the following steps. Figure 9 is a diagram showing a method of continuously preparing microparticles according to an embodiment of the present invention. First, in step S02, an aqueous solution is provided, the aqueous solution includes an interface active agent, and an organic solution is provided. The organic solution includes an active material and a degradable polymer material, and the decomposable polymer material is, for example, a polymer lactic acid/glycolic acid-2-hydroxybutyl group. The acid (poly(lactic/glycolic acid), PLGA), the active material is, for example, Olanzapine or Granisetron, and the mixing ratio of the aqueous solution to the organic solution is, for example, 200:1.

Next, as shown in step S04, the aqueous solution and the organic solution are mixed to form an emulsion comprising a plurality of particles composed of a degradable polymer material and an active ingredient. Then, as shown in step S06, the emulsion is passed through a solidifying liquid to cure the fine particles, for example, a polyvinyl alcohol (PVA) solution. Finally, in step S08, the collecting unit 140, 240, 340, 440, 540, 640 described in the above embodiment is used to separate the particles, or the cleaning liquid may be introduced into the receiving groove to contact the residual surface of the cleaning surface. The active ingredient or the organic solution, the cleaning solution can also be discharged from the outlet hole.

Since the solution containing no particles flows out of the water outlet hole, the mixed solution containing the particles in the space is continuously injected, so that the mixed solution containing the particles after solidification can be continuously injected into the collecting unit, and the particles can also be injected into the collecting unit. It is continuously blocked or settled in the accommodating tank and collected. In addition, the collection process is based on the principle that the suspended matter is attracted by gravity and naturally settles. The baffle is arranged in the solution passage to block the particles, so that the particles settle in the bottom of the receiving tank, and no operator operation is required in the process, from production to collection. Can be integrated into a continuous process, with great potential to expand production scale.

In addition, the particles prepared according to the above apparatus and method are not deformed. With the aggregation problem, and the active ingredient can be released for a long time, the following sets of experimental results prove that, in the technical field of the present invention, it is obvious to those skilled in the art that the apparatus and method for continuously preparing microparticles proposed by the present invention are not It is limited to the following types of drugs and copolymers, and can also be applied to particles or microcapsules composed of other materials.

[Preparation of Olanzapine Microspheres]

[Material] lactic acid/glycolic acid (PLGA) (molar ratio of 85/15) itself has a viscosity of 0.84 dl / g (chloroform.25 ° C , c = 0.1 g / dl), purchased from PURAC. Tocopheryl polyethylene glycol succinate (TPGS) and Olanzapine with 278 mg tocopherol are purchased from USP NF grade, and polyvinyl alcohol (PVA) as an surfactant for organic phase/aqueous phase emulsification. The molar amount was 30,000 to 70,000 and was purchased from Sigma-Aldrich. The organic solution was prepared as follows: PLGA, Olanzapine and TPGS were dissolved in 10 ml of dichloromethane as the organic phase in the organic phase/aqueous phase, and 160 mg of PLGA, 64 mg of Olanzapine and 40 mg of TPGS per ml of dichloromethane were used. The temperature of the 0.1% PVA was maintained at 6-8 ° C, and the mixing ratio of the organic phase/aqueous phase was 0.5%.

[Method and Microparticle Appearance] A device for continuously preparing fine particles is shown in Fig. 2, and the collecting unit is as shown in Fig. 8. 80 ml of the organic solution and 16,000 ml of the aqueous solution were respectively output to the emulsification unit at a rate of 1.25 ml/min and 250 ml/min, and the emulsification unit was an emulsification chamber with a homogenizer (IKA, UTL25 digital with S25KV-25GIL knife). The input port is a Y-shaped tube, one is used as an injection port of the aqueous solution, one is used as an injection port of the organic solution, the other is connected to the emulsion cavity, and the two phases are pre-mixed in the Y-shaped tube and then input into the emulsion cavity. The homogenizer is set to rotate at 8000 rpm. In the next step, the emulsified solution is injected into the curing unit. The curing unit is two beakers with a capacity of 4 liters. The two are connected to each other. The particles in each beaker are stirred by a stirrer with a rotation speed of 500 rpm. The microparticles were collected by collection unit 640, washed twice with 0.1% F-68 aqueous solution, and once with deionized water. Finally, the product was made into a powder by freeze drying.

The particle size of the particles is about 26.6 microns. The results of optical microscopy and scanning electron microscopy show that the structure of the particles is average and stereoscopic, as shown in Annexes 1 and 2. Annex I is the magnification of 100X (a) and 1000X (b) for optical microscope observation, and the magnification of magnification is 3000X (a) and 4000X (b) for the scanning electron microscope. In addition, the high-performance liquid chromatograph (270 nm) measured the encapsulating efficiency of Olanzapine to be 87%.

[Drug release efficiency test] The above experiment prepared microparticles, and 20 mg of Olanzapine-TPGS-PLGA microparticles were placed in a 50 ml centrifuge tube, dissolved in 12 ml of PBS solution (0.01 M, containing 0.01% Tween 80 and 0.01% sodium azide), 37 ° C water bath. , oscillated at 60rpm. Samples were taken periodically for eight weeks and the drug release rate was analyzed by high performance liquid chromatography.

Results of in vitro test of Olanzapine drug release rate as shown in Figures 10A and 10B, the microparticles produced by the apparatus and method of the presently discovered examples At the beginning of the administration, a stable release rate is exhibited, and therefore, there is less initial effect, and the overall drug release efficiency is a constant release (close to linear), that is, releasing the drug in vivo at a certain rate. (in accordance with the zero-order release kinetics), close to the zero-order drug release mode. Fixed-speed release can reduce blood drug concentration fluctuations and increase patient compliance.

[Preparation of Granisetron Microspheres]

[Materials] PLGA (mole ratio 50/50), TPGS, Granisetron, PVA. The organic solution was prepared as follows: PLGA, Granisetron and TPGS were dissolved in 10 ml of dichloromethane as the organic phase in the organic phase/aqueous phase, 160 mg PLGA, 16 mg Granisetron and 10 mg TPGS per ml of dichloromethane, aqueous phase. The temperature of the 0.1% PVA was maintained at 6-8 ° C, and the mixing ratio of the organic phase/aqueous phase was 0.5%.

[Method and Particle Appearance] The process method was the same as in the previous example. The particle diameter of the particles was about 20.5 μm, and the encapsulating efficiency was about 81%.

[Drug release efficiency test] The above experiment prepared microparticles, and 20 mg of Granisetron-TPGS-PLGA microparticles were placed in a 50 ml centrifuge tube, dissolved in 12 ml of PBS solution (0.01 M, containing 0.01% Tween 80 and 0.01% sodium azide), 37 ° C water bath. , oscillated at 60rpm. Samples were taken periodically over five days and the drug release rate was analyzed by high performance liquid chromatography.

The results of in vitro testing of the Granisetron drug release rate are shown in Figures 11A and 11B.

The apparatus, method and collection unit for continuously preparing microparticles disclosed in the above embodiments of the present invention, the mixed solution injected into the collection unit is placed in shallow water (ie, in a receiving tank) or through a shallower water area (baffle) Between the notch and the accommodating groove, the suspended particles can be quickly settled. After the mixed solution is injected into the collecting unit, the particles are blocked by the baffle or quickly settled through the notch, and the solution is fixedly discharged from the effluent hole. Let the mixed solution continue to be injected into the accommodating tank. Therefore, the method for preparing the microparticles provided in the embodiment includes the steps of emulsifying, solidifying and collecting, etc., which can be integrated into a continuous process without any human operation, that is, once the device of the embodiment is set and started, no need is required. Human operations allow continuous production and collection of particles.

On the other hand, the traditional method of collecting particles is to collect the particles suspended in the curing tank by centrifugation or filtration. The traditional process belongs to the batch process, and after the curing step, the operator needs to operate the collecting program or operate the mechanical equipment. The method and apparatus for continuously preparing microparticles disclosed in the present embodiment have the following advantages as compared with the conventional process:

1. The process of supplying raw materials to collecting particles is a continuous process and has the potential to expand the scale of manufacturing.

2. Suitable for aseptic processing. The device proposed in this embodiment has a moderate size and a simple structure. All the units can be sterilized or moved into a sterile space. Therefore, the whole process of preparing the particles can be operated in a sterile environment to ensure the quality of the product.

3. The method of preparing microparticles disclosed in this embodiment is integrated into a continuous process, and once the device setting is completed and started, the microparticles can be continuously manufactured and collected without any manual operation.

4. The microparticles produced according to the apparatus and method of the present embodiment have less initial effects and are closer to the zero-order drug release mode.

In conclusion, the present invention has been disclosed in the above embodiments, but it is not intended to limit the present invention. A person skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the scope of the invention is defined by the scope of the appended claims.

100‧‧‧Continuous preparation of microparticles

110‧‧‧Material supply unit

112, 114‧‧‧ storage tank

116‧‧‧ Inputs

120‧‧‧Emulsifying unit

122‧‧‧Emulsified cavity

130‧‧‧Curing unit

140, 240, 340, 440, 540, 640‧ ‧ collection units

150, 250, 350, 450, 550, 650‧‧ ‧ accommodating slots

150a, 250a, 350a, 450a, 550a, 650a‧‧‧ first compartment

150b, 250b, 350b, 450b, 550b, 650b‧‧‧ second compartment

250c, 650c‧‧‧ third compartment

152, 252, 352, 452, 552, 652‧‧‧ water holes

154‧‧‧Side strips

160, 260, 360, 460, 560, 660‧‧‧ first baffle

361, 461, 561‧‧ ‧ gap

262, 362, 462, 562, 662‧‧‧ second baffle

564, 664‧‧‧ third baffle

670‧‧‧four baffle

672‧‧‧ fifth baffle

674‧‧‧6th baffle

1 is a block diagram of an apparatus for continuously preparing microparticles according to an embodiment of the present invention.

2 is a perspective view of a device for continuously preparing microparticles according to an embodiment of the present invention.

FIG. 3A is a schematic perspective view of a collecting unit according to an embodiment of the invention.

FIG. 3B is a partial enlarged view of a collecting unit according to an embodiment of the present invention.

4 is a perspective view of a first collection unit in accordance with an embodiment of the present invention.

FIG. 5 is a schematic perspective view of a second collecting unit according to an embodiment of the invention.

FIG. 6 is a perspective view showing a third collecting unit according to an embodiment of the present invention.

FIG. 7 is a perspective view of a fourth collecting unit according to an embodiment of the invention.

FIG. 8 is a perspective view of a fifth collecting unit according to an embodiment of the invention.

Figure 9 is a flow chart showing a method of continuously preparing microparticles according to an embodiment of the present invention.

Figure 10A shows the results of the drug release efficiency of the Olanzapine microspheres.

Figure 10B is a graph showing the results of drug release efficiency of the Olanzapine microspheres.

Figure 11A shows the results of the drug release efficiency of the Granisetron microspheres.

Figure 11B plots the results of the drug release efficiency of the Granisetron microspheres.

640‧‧‧Collection unit

650‧‧‧ accommodating slots

650a‧‧‧First compartment

650b‧‧‧second compartment

650c‧‧‧ third compartment

652‧‧‧ water hole

660‧‧‧First baffle

662‧‧‧second baffle

664‧‧‧The third baffle

670‧‧‧four baffle

672‧‧‧ fifth baffle

674‧‧‧6th baffle

Claims (20)

a collecting unit for collecting a plurality of particles in a solution, the collecting unit comprising: a receiving groove having a water outlet hole; and a first baffle plate detachably disposed in the receiving groove The lower edge of the first baffle has at least one notch. When the first baffle is assembled in the accommodating groove, a distance between the lower edge of the first baffle and the bottom surface of the accommodating groove is spaced apart. The first baffle traverses the accommodating groove and the two ends of the first baffle respectively contact the side wall of the accommodating groove, whereby the first baffle divides the accommodating groove into a first compartment And a second compartment, wherein the water outlet is located in the second compartment; after the solution containing the microparticles is injected into the accommodating trench by the first compartment, the microparticles may settle on the first baffle Nearby, the solution will pass over or through the first baffle into the second compartment and exit the water outlet. The collection unit of claim 1, wherein the height of the accommodating groove is smaller than the inner diameter of the accommodating groove. The collection unit of claim 1, wherein the height of the receiving groove is between 30 and 50 mm. The collection unit of claim 1, wherein the height of the first baffle is less than the height of the accommodating groove. The collection unit of claim 1, wherein the spacing is between 1-5 cm. The collection unit described in claim 1 of the patent application, which further comprises: a second baffle is detachably disposed in the accommodating groove, the second baffle is traversed by the accommodating groove and the two ends thereof respectively contact the side wall of the accommodating groove, the second baffle The lower edge is all in contact with the bottom surface of the accommodating groove, and the height of the second baffle is smaller than the height of the accommodating groove; and wherein the solution first flows through the first baffle and then flows through the second baffle. The collecting unit of claim 1, wherein the height of the second baffle is smaller than the height of the first baffle. The collection unit of claim 6, further comprising: a third baffle disposed in the accommodating groove in a detachable manner, the third baffle traversing the accommodating groove and The two ends of the third baffle are respectively spaced apart from the bottom surface of the accommodating groove by a distance between the two ends of the accommodating groove; wherein the solution flows through the first baffle and the second baffle And then flows through the third baffle. An apparatus for continuously preparing microparticles, comprising: a raw material supply unit, independently and continuously supplying an aqueous solution and an organic solution, the aqueous solution comprising an interfacial active agent, the organic solution comprising an active ingredient and a degradable polymer material An emulsification unit, receiving and mixing the aqueous solution and the organic solution to form an emulsion comprising a plurality of particles composed of the biodegradable polymer material and the active ingredient; a curing unit receiving the emulsification And mixing the liquid into a solidifying liquid, thereby solidifying the particles; and a collecting unit comprising: a receiving slot having a water outlet hole; and a first baffle plate detachably disposed in the receiving groove, wherein the lower edge of the first baffle has at least one notch when the first baffle When being assembled in the accommodating groove, the lower edge of the first baffle is spaced apart from the bottom surface of the accommodating groove, wherein the first baffle traverses the accommodating groove and the two first baffles The end portions respectively contact the side walls of the accommodating groove, whereby the first baffle divides the accommodating groove into a first compartment and a second compartment, wherein the water outlet hole is located in the second compartment; After the solution of the particles is injected into the accommodating groove by the first compartment, the particles may settle near the first baffle, and the solution may pass over or pass through the first baffle into the second The compartment is discharged from the outlet. The device of claim 9, wherein the emulsification unit is a homogenizer. The apparatus of claim 9, wherein the raw material supply unit further comprises a conveyor for controlling the conveying speed of the organic solution. The device of claim 11, wherein the conveyor is a peristaltic pump, a centrifugal pump or a reciprocating pump. The device of claim 9, wherein the curing unit further comprises a vacuum pump. A method for continuously preparing microparticles, comprising: providing an aqueous solution comprising an intervening active agent; providing an organic solution comprising an active material and a degradable polymeric material; Mixing the aqueous solution and the organic solution to form an emulsion comprising a plurality of particles composed of the degradable polymer material and the active ingredient; and passing the emulsion into a solidifying liquid to cure the particles; Separating the particles by using a collecting unit, the collecting unit includes a receiving groove and a baffle, the receiving groove has a water outlet hole, and the baffle plate is detachably disposed in the receiving groove and The lower edge of the baffle has at least one notch between the water inlet and the water outlet hole. When the baffle is assembled in the accommodating groove, the lower edge of the baffle is separated from the bottom surface of the accommodating groove. a spacing; after the solution containing the particles is injected into the accommodating tank by the water inlet, the particles will settle near the baffle, and the solution will be discharged from the water outlet hole through or through the baffle. The method of claim 14, wherein the decomposable polymer material is a polymer lactic acid/glycolic acid-2-hydroxybutyric acid copolymer. The method of claim 14, wherein the active material is Olanzapine. The method of claim 14, wherein the active material is Granisetron. The method of claim 14, wherein the curing liquid is a polyvinyl alcohol solution. The method of claim 14, wherein the mixing ratio of the aqueous solution to the organic solution is 200:1. The method of claim 14, wherein the method further comprises: A cleaning liquid is introduced into the accommodating tank, and the particles are contacted and discharged from the water outlet hole.