A system and method for preparing microspheres

Abstract

The application discloses a microsphere preparation system and a preparation method, and the preparation system is composed of a fluid driving device, a microsphere generating device and a microsphere collector, and can realize enlarged production of microspheres. The fluid driving device is composed of a syringe pump and a liquid shunt, and the liquid shunt can ensure that the flow and the flow rate of the liquid in the dispersed phase and the continuous phase microchannels are the same. The microsphere generating device is composed of multiple three-way or four-way microchannel units combined in parallel, each microchannel unit contains a dispersed phase inlet, a continuous phase inlet and an outlet, the fluid driving device is used for pushing the fluid to enter each microchannel uniformly, and the outlets of the microchannels are merged into the microsphere collector respectively. The application can effectively ensure that the flow and the flow rate of the fluid in the dispersed phase and the continuous phase microchannels are constant, so that the size of the prepared microspheres is controllable, the particle size is uniform, multiple channels are simultaneously produced, and the production efficiency is significantly improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a microsphere preparation system and method. BACKGROUND

[0002] Microspheres refer to a microparticle dispersion system in which drugs are dispersed or adsorbed in a polymer matrix. Commonly used methods for preparing polymer microspheres include emulsion dispersion, emulsion polymerization, dispersion polymerization, suspension polymerization, and spray drying. Existing microsphere preparation methods generally have the problems of complex process, long process time, low sphericity of the prepared microspheres, and uneven particle size of the microspheres. Therefore, there is an urgent need to develop new microsphere preparation equipment to improve the production efficiency of microspheres and prepare microspheres with controllable size and uniform particle size.

[0003] Microfluidic technology is a method for preparing microspheres, which can prepare microspheres with uniform particle size. However, this technology has the disadvantages of long preparation time, low production rate, and difficulty in large-scale industrial production. Parallel connection of multiple preparation channels can improve the production rate, but in the microscale, the fluid flow and flow rate of each channel cannot be the same, which leads to different shapes and sizes of the microspheres prepared in each channel, affecting the uniformity of the microspheres. SUMMARY

[0004] One of the purposes of the present application is to provide a microsphere preparation system to solve the problem of poor uniformity of microspheres prepared by existing equipment due to different shapes and sizes of the microspheres.

[0005] The second purpose of the present application is to provide a microsphere preparation method to realize standardized and batch production of microspheres.

[0006] One of the purposes of the present application is achieved by a microsphere preparation system, comprising:

[0007] A continuous phase injection pump for uniformly pushing the continuous phase liquid into the continuous phase liquid distributor;

[0008] The continuous phase liquid distributor is a closed container with a plurality of distribution holes of the same aperture distributed at the bottom, each distribution hole is connected to the continuous phase inlet of a microchannel unit of the microsphere generating device through a pipeline, and is used to uniformly distribute the pumped continuous phase liquid into a plurality of channels;

[0009] A dispersed phase injection pump for uniformly pushing the dispersed phase liquid into the dispersed phase liquid distributor;

[0010] The dispersed phase liquid distributor is a closed container with a plurality of holes of the same size at the bottom, each of the holes is connected to the dispersed phase inlet of a microchannel unit of the microsphere generating device through a pipeline; and the dispersed phase liquid pumped in is uniformly distributed into a plurality of channels.

[0011] The microsphere generating device comprises a plurality of microchannel units of the same structure, each of the microchannel units is provided with a dispersed phase inlet, a continuous phase inlet and an outlet, and each of the outlets of the microchannel units is connected to a discharge pipe; and

[0012] The microsphere collector is arranged at the lower end of the discharge pipe connected to the microsphere generating device, and is used to collect the microspheres prepared by the microchannel units.

[0013] The microsphere preparation system further comprises:

[0014] The solidification and drying device is used to solidify and dry the microspheres collected in the microsphere collector, so as to obtain dried microspheres.

[0015] The microchannel unit is T-shaped, Y-shaped or cross-shaped, and the cross-shaped microchannel unit comprises two continuous phase inlets, one dispersed phase inlet and one outlet.

[0016] The microsphere generating device is used to generate microspheres from the dispersed phase liquid and the continuous phase liquid in the microchannel units, and then the microspheres flow out through the outlet.

[0017] The continuous phase liquid is a liquid comprising a pharmaceutical carrier material.

[0018] The dispersed phase liquid is a liquid comprising a target drug.

[0019] The microchannel unit is made of quartz, glass, metal or high polymer material (such as Teflon, polyether ether ketone, polyvinyl chloride and PTFE, etc.). The cross section of the channel of the microchannel unit is circular, elliptical, square or regular polygonal.

[0020] In the microsphere preparation system, the continuous phase liquid is distributed into the continuous phase channels of the microchannel units at the same flow rate and flow speed through the continuous phase inlets of the microchannel units, and the dispersed phase liquid is distributed into the dispersed phase channels of the microchannel units at the same flow rate and flow speed through the dispersed phase inlets of the microchannel units. At the intersection of the dispersed phase liquid and the continuous phase liquid, the dispersed phase liquid is sheared into monodisperse microspheres by the continuous phase liquid. Compared with the traditional single-channel preparation device, the juxtaposed structure of the plurality of microchannel units significantly improves the production efficiency of the microspheres, and large-scale preparation and industrial production of the microspheres can be realized.

[0021] The microsphere preparation system of the present application is provided with a continuous phase liquid flow divider and a dispersed phase liquid flow divider, so that the flow of the continuous phase liquid and the dispersed phase liquid injected into each microchannel unit is stable and uniform, and the flow rate and flow velocity of the liquid flowing through each microchannel unit are kept consistent, so that the shapes of the prepared microspheres are close to each other, and the sizes are basically the same, and a high uniformity is maintained.

[0022] The second object of the present application is achieved by a microsphere preparation method, comprising the following steps:

[0023] a. providing the above preparation system;

[0024] b. the continuous phase injection pump uniformly pushes the continuous phase liquid into the continuous phase liquid flow divider, and the dispersed phase injection pump uniformly pushes the dispersed phase liquid into the dispersed phase liquid flow divider;

[0025] c. the continuous phase liquid flow divider uniformly disperses the pumped continuous phase liquid into a multi-channel fluid to be injected into the microsphere generating device, and the dispersed phase liquid flow divider uniformly disperses the pumped dispersed phase liquid into a multi-channel fluid to be injected into the microsphere generating device;

[0026] d. in each microchannel unit of the microsphere generating device, the injected continuous phase liquid exerts shear force and surface tension on the injected dispersed phase liquid, so that the dispersed phase liquid forms microspheres, and the microspheres discharged from the liquid outlets of the microchannel units converge into the microsphere collector;

[0027] e. the converged microspheres in the microsphere collector are sent to the solidification and drying device for solidification and drying treatment, and dry microspheres are obtained.

[0028] In the microsphere preparation method of the present application, the particle size of the microspheres can be adjusted by changing the flow rate of the dispersed phase liquid, changing the flow rate of the continuous phase liquid, changing the opening size of the dispersed phase inlet in the microchannel unit, or changing the opening size of the continuous phase inlet in the microchannel unit.

[0029] The present application can adjust the size of the microspheres by changing the flow rate of the dispersed phase liquid, changing the flow rate of the continuous phase liquid, changing the opening size of the dispersed phase inlet in the microchannel unit, or changing the opening size of the continuous phase inlet in the microchannel unit, etc., so that microspheres with controllable size and uniform particle size can be prepared, the production efficiency of the microspheres is improved, and the industrial production of the microspheres is realized.

[0030] The beneficial effects of the present application are as follows:

[0031] 1. The liquid splitter can inject the dispersed phase liquid and the continuous phase liquid into the microsphere generating device at the same speed, which can ensure that the flow and flow rate of the liquid in the dispersed phase microchannel and the continuous phase microchannel in each microchannel unit are the same, the generated microspheres have good uniformity, and the microspheres with good monodispersity can be obtained after drying and solidification.

[0032] 2. By increasing the flow rate of the dispersed phase liquid or reducing the flow rate of the continuous phase liquid, the diameter of the microspheres can be increased; on the contrary, by reducing the flow rate of the dispersed phase liquid or increasing the flow rate of the continuous phase liquid, the diameter of the microspheres can be reduced. Thus, the controllable production of microspheres of different sizes is realized.

[0033] 3. The prepared microspheres have various types: by changing the pipe diameter of the continuous phase pipeline or the pipe diameter of the dispersed phase pipeline, microspheres of different sizes can be prepared.

[0034] 4. The prepared microspheres have good monodispersity: since the droplets are generated by the action force of the two-phase solution, and the two-phase solution is stable in the channel, the prepared microspheres have good monodispersity.

[0035] 5. Good repeatability: the microsphere preparation system of the present application can ensure the repeatability of different batches of microspheres. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 is a structural schematic diagram of the microsphere preparation system of the present application.

[0037] Figure 2 is a structural schematic diagram of the microchannel unit of different forms.

[0038] Figure 3 is Figure 1 a structural schematic diagram of the split hole in

[0039] Figure 4 is a microscope photograph of the prepared dexamethasone microspheres.

[0040] Figure 5 is a microscope photograph of the prepared octreotide microspheres.

[0041] In the figure: 11, continuous phase injection pump; 12, dispersed phase injection pump; 13, continuous phase liquid splitter; 14, dispersed phase liquid splitter; 15, microchannel unit; 16, microsphere collector; 17, split hole; 10a, continuous phase inlet, 10a1, continuous phase inlet, 10a2, continuous phase inlet; 10b, dispersed phase inlet; 10c, outlet. DETAILED DESCRIPTION

[0042] As Figure 1As shown, the microsphere preparation system of the present invention includes a continuous phase injection pump 11, a dispersed phase injection pump 12, a continuous phase liquid distributor 13, a dispersed phase liquid distributor 14, a microsphere generating device, a microsphere collector 16, and a curing and drying device (not shown). The continuous phase injection pump 11 is used to uniformly push the continuous phase liquid into the continuous phase liquid distributor 13. The dispersed phase injection pump 12 is used to uniformly push the dispersed phase liquid into the dispersed phase liquid distributor 14. The continuous phase liquid distributor 13 is a closed container with multiple distribution holes of the same diameter distributed at its bottom. Each distribution hole is connected to the continuous phase inlet 10a of a microchannel unit 15 in the microsphere generating device through a pipe, for uniformly dispersing the pumped continuous phase liquid into a multi-channel fluid. The dispersed phase liquid distributor 14 is also a closed container with multiple distribution holes of the same diameter distributed at its bottom. Each distribution hole is connected to the dispersed phase inlet 10b of a microchannel unit 15 of the microsphere generating device via a pipe, and is used to uniformly disperse the pumped dispersed phase liquid into a multi-channel fluid. The microsphere generating device includes several microchannel units 15 with identical structures. The microsphere generating device is used to generate microspheres from the dispersed phase liquid and the continuous phase liquid in the microchannel unit 15, and then the microspheres flow out through the outlet.

[0043] like Figure 2 As shown, each microchannel unit has a dispersed phase inlet 10a, a continuous phase inlet 10b, and an outlet 10c. The microchannel unit can be T-shaped, Y-shaped, or cross-shaped, while a cross-shaped microchannel unit includes two continuous phase inlets (10a1, 10a2), one dispersed phase inlet 10b, and one outlet 10c. The channel cross-section of the microchannel unit 15 can be circular, elliptical, square, or a regular polygon. The microchannel unit 15 can be made of materials such as quartz, glass, metal, or polymers (e.g., Teflon, polyetheretherketone, polyvinyl chloride, and PTFE).

[0044] Figure 1 In this process, a discharge pipe is connected to the outlet of each microchannel unit 15, with the lower end of the discharge pipe leading to the microsphere collector 16. The microsphere collector 16 is used to collect the microspheres prepared by the microchannel unit. The curing and drying device is used to cure and dry the microspheres collected in the microsphere collector to obtain dried microspheres.

[0045] The microsphere preparation method of the present invention includes the following steps:

[0046] a. Set up the microsphere preparation system described above;

[0047] b. The continuous phase injection pump 11 pushes the continuous phase liquid at a constant speed into the continuous phase liquid distributor 13, and the dispersed phase injection pump 12 pushes the dispersed phase liquid at a constant speed into the dispersed phase liquid distributor 14.

[0048] c. The continuous phase liquid distributor 13 evenly disperses the pumped continuous phase liquid into a multi-channel fluid to be injected into the microsphere generating device, and the dispersed phase liquid distributor 14 evenly disperses the pumped dispersed phase liquid into a multi-channel fluid to be injected into the microsphere generating device;

[0049] d. In each microchannel unit 15 of the microsphere generating device, the injected continuous phase liquid exerts a shearing force and a surface tension on the injected dispersed phase liquid, so that the dispersed phase liquid forms microspheres, and the microspheres discharged from the liquid outlets of the microchannel units converge into the microsphere collector 16;

[0050] e. The converged microspheres in the microsphere collector 16 are sent to the solidification and drying device for solidification and drying treatment, and dry microspheres are obtained.

[0051] Example 1: Preparation of dexamethasone microspheres.

[0052] Solution preparation: 10 Kg of PVA was dissolved in 500 L of aqueous solution as the aqueous phase; 50 g of dexamethasone and 500 g of PLGA were added to 4.5 L of dichloromethane and 0.5 L of methanol solution, dissolved and ultrasonicated for 30 s as the oil phase; the PVA aqueous solution was used as the continuous phase liquid, and the dexamethasone and PLGA dichloromethane solution was used as the dispersed phase liquid. The flow rate of the continuous phase liquid was set to 250 ml / min, and the flow rate of the dispersed phase liquid was set to 1.2 mL / min. An O / W type microsphere emulsion was prepared by using the microsphere preparation system of the present application, the organic solvent was removed by stirring, and microspheres were formed after solidification. The microspheres were washed with distilled water for 5 times, and the microspheres were collected and freeze-dried for 12 h to obtain dexamethasone acetate sustained-release microspheres. Figure 4 As can be seen from Figure 4 , the dexamethasone microspheres have uniform particle size, and the average diameter of the microspheres is about 40 μm.

[0053] Example 2: Preparation of octreotide microspheres.

[0054] Solution preparation: 50 g of octreotide acetate was accurately weighed and dissolved in 500 ml of ultrapure water as the aqueous phase, and 500 g of PLGA and 105 g of Span83 were accurately weighed and dissolved in 5 L of dichloromethane as the oil phase. After mixing, the W / O emulsion was ultrasonically emulsified under ice bath conditions. The prepared W / O emulsion was used as the dispersed phase, and 10 Kg of PVA was dissolved in 500 L of aqueous solution as the continuous phase. The flow rate of the continuous phase was set to 150 ml / min, and the flow rate of the dispersed phase was set to 1.5 mL / min. The microspheres were prepared by using the microsphere preparation system of the present application, the organic solvent was removed by magnetic stirring (250 r / min), the microspheres were washed with distilled water for 5 times, and then the microspheres were collected and freeze-dried for 12 h to obtain octreotide acetate sustained-release microspheres. Figure 5 As can be seen from Figure 5As can be seen, the octreotide microspheres have uniform particle size, and the average diameter of the microspheres is about 100 μm.

Claims

1. A microsphere preparation system, characterized in that, include: A continuous phase injection pump is used to uniformly push a continuous phase liquid into a continuous phase liquid distributor; A continuous phase liquid distributor is a closed container with several distribution holes of the same diameter distributed at its bottom. Each distribution hole is connected to the continuous phase inlet of a microchannel unit of a microsphere generating device through a pipe. It is used to uniformly disperse the pumped continuous phase liquid into a fluid with several channels. A dispersed phase injection pump is used to uniformly push the dispersed phase liquid into a dispersed phase liquid distributor; A dispersed phase liquid distributor is a closed container with several distribution holes of the same diameter distributed at its bottom. Each distribution hole is connected to the dispersed phase inlet of a microchannel unit of a microsphere generating device through a pipe. It is used to uniformly disperse the pumped dispersed phase liquid into a fluid with several channels. The microsphere generating device includes several microchannel units with identical structures. Each microchannel unit is provided with a dispersed phase inlet, a continuous phase inlet, and an outlet. A discharge pipe is connected to the outlet of each microchannel unit. The microsphere generating device is used to generate microspheres from dispersed liquid and continuous liquid in a microchannel unit, and then the microspheres flow out through an outlet. A microsphere collector is installed at the lower end of the discharge pipe connected to the microsphere generating device, and is used to collect the microspheres prepared by the microchannel unit; as well as A curing and drying device is used to cure and dry the microspheres collected in the microsphere collector to obtain dried microspheres. The continuous phase liquid is a liquid that includes a pharmaceutical carrier material; The dispersed phase liquid is a liquid containing the target drug.

2. The preparation system according to claim 1, characterized in that, The microchannel unit is T-shaped, Y-shaped, or cross-shaped. The cross-shaped microchannel unit includes two continuous phase inlets, one dispersed phase inlet, and one outlet.

3. The preparation system according to claim 1, characterized in that, The microchannel unit is made of quartz, glass, metal or polymer materials.

4. The preparation system according to claim 1, characterized in that, The cross-section of the microchannel unit is circular, elliptical, square, or regular polygonal.

5. A method for preparing microspheres, characterized in that, Includes the following steps: a. The preparation system described in any one of claims 1-4 is provided; b. The continuous phase injection pump pushes the continuous phase liquid at a constant speed into the continuous phase liquid distributor, and the dispersed phase injection pump pushes the dispersed phase liquid at a constant speed into the dispersed phase liquid distributor. c. The continuous phase liquid distributor uniformly disperses the pumped continuous phase liquid into several channels of fluid for injection into the microsphere generating device; the dispersed phase liquid distributor uniformly disperses the pumped dispersed phase liquid into several channels of fluid for injection into the microsphere generating device. d. In each microchannel unit of the microsphere generation device, the injected continuous phase liquid applies shear force and surface tension to the injected dispersed phase liquid, causing the dispersed phase liquid to form microspheres. The microspheres discharged from the outlet of each microchannel unit are collected into the microsphere collector. e. The microspheres collected in the microsphere collector are sent to the curing and drying device for curing and drying treatment to obtain dried microspheres.

6. The preparation method according to claim 5, characterized in that, The particle size of microspheres can be adjusted by changing the flow rate of the dispersed liquid, the flow rate of the continuous liquid, the opening size of the dispersed phase inlet in the microchannel unit, or the opening size of the continuous phase inlet in the microchannel unit.

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