REACTION DEVICE, MICROSPHERE PREPARATION DEVICE AND EXTRACTION METHOD AND LIPOSOME DRUG LOADING METHOD

Abstract

Disclosed is a reaction device, comprising: a reactor body (100) and a supply device (200), wherein the reactor body (100) has a first end (106) and a second end (107) and is used for accommodating a reaction liquid, with a first injection port (101) being provided between the first end (106) and the second end (107), and a discharge port (109) being provided at the second end (107); and the supply device (200) is in communication with the first injection port (101) to inject a continuous phase, wherein the continuous phase directionally flows in the reactor body (100) to form or maintain a parameter gradient in the reactor body (100). By means of injecting the continuous phase into the first injection port (101) on the reactor body (100), the solution presents a certain parameter gradient on two sides of the first injection port (101) in the reactor body (100).

Claims

1. A reaction device, comprising: a reactor body, configured to enclose a first liquid, having a first end and a second end, a first injection port is provided between a first end and second end of the reactor body, and a discharge port is provided at the second end of the reactor body; and a supply device, communicated with the first injection port, for injecting a continuous phase; wherein the continuous phase is a liquid that surrounds dispersed substances flows directionally within the reactor body to create or maintain a parametric gradient within the reactor body.

2. The reaction device according to claim 1, wherein the reactor body is slanted, an angle formed between the reactor body and the gravity direction of the Earth is greater than 0° but less than 90° or placed vertically, and the first end is positioned above the second end; the continuous phase is in gravity the flow is directed towards the second end under the action.

3. The reaction device according to claim 1, wherein the reactor body is placed horizontally, and the first end is provided with the second injection port, to inject a treatment liquid with an initial flow rate; the continuous phase is directed to flow toward the second end, driven by the treatment liquid.

4. The reaction device according to claim 1, wherein the first injection port is arranged in the middle, anywhere between the first end and the second end of the reactor body.

5. The reaction device according to claim 1, wherein the reactor body comprises a first accommodating portion and a second accommodating portion; a first joint, connecting the first accommodating portion and the second accommodating portion, one end of the first accommodating portion away from the first joint is the first end, and the first injection port is disposed in or on the first connector joint; the second joint communicates with the second accommodating portion to form the second end, and a discharge port is provided on the second joint.

6. The reaction device according to claim 1, wherein reaction device is an embryo microsphere solidification reactor or a liposome drug-carrying reactor.

7. A microsphere preparation device, comprising: material injection mechanism, configured to output embryo microsphere; a reaction device according to claim 1, wherein the first end of the reaction device is further provided with a third injection port, which communicates with the material injection mechanism, through the material injection mechanism, embryonic microspheres are injected, so that the embryonic microspheres settle in the reaction device and solidify, and form by extraction to form microspheres; and a collector is communicated with the second end of the reaction device to collect microspheres.

8. A microsphere solidification method, for extracting the organic solvent in embryo microsphere, comprising providing a reaction device according to claim 1, the first liquid is a microsphere receiving solution, the microsphere receiving solution uses water as a matrix to extract the organic solvent; embryonic microspheres are moved from the first end to the second end along the reactor body containing the microsphere receiving solution, the organic solvent of the embryonic microspheres is extracted out, and the embryonic microspheres is hardened to form microspheres; during the extraction, water is injected through the first injection port, and the water flows to the second end in the reactor body to form a concentration gradient of water on both sides of the first injection port.

9. A microsphere curing method according to claim 8, wherein water is continuously or intermittently injected into the first injection port; and/or; water flow is driven by gravity or a directional flow of the microsphere receiving solution; and/or; the flow rate of water injects the first injection port is controllable.

10. A liposome drug-loading method, wherein: providing a reaction device of claim 1, installing a phospholipid membrane reaction device, injecting an acidic or alkaline liquid through the first injection port to maintain a pH gradient on both sides of the phospholipase.

Description

DESCRIPTION OF DRAWINGS

[0048] The preferred embodiments will be described below in a clear and easy-to-understand manner with reference to the accompanying drawings, and the above-mentioned characteristics, technical features, advantages and implementation methods of the reaction device, the microsphere preparation device and the extraction method, and the liposome drug-loading method will be further described and illustrated.

[0049] FIG. 1 is a schematic diagram of an embodiment of the present invention;

[0050] FIG. 2 is a schematic diagram of another embodiment of the present invention;

[0051] FIG. 3 is a schematic diagram of another embodiment of the present invention;

[0052] FIG. 4 is a schematic structural diagram of the microsphere preparation device of the present invention.

[0053] Description of elements reference number: reactor body 100, first injection port 101, first accommodating portion 102, second accommodating portion 103, first joint 104, second joint 105, first end 106, second end 107, third injection port 108, the discharge port 109, the supply device 200, the connecting pipe 201, the material injection mechanism 300, and the collector 400.

DETAIL DESCRIPTION OF EMBODIMENTS

[0054] In order to more clearly describe the embodiments of the present invention or difference with respect to the technical solutions in the prior art, the specific embodiments of the present invention will be described below with reference to the accompanying drawings. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, other drawings can also be derived from these drawings without significant undue experimentation and method of using the same.

[0055] In order to keep the drawings concise, the drawings only schematically illustrate the components related to the present invention, and they may or may not represent its actual structure as a product. In addition, in order to make the drawings concise and easy to understand, in some drawings, only one of the components having the same structure or function is schematically shown, or only one of them is marked. As used herein, “one” not only means “only one”, but also “more than one”.

[0056] According to an embodiment provided by the present invention, as shown in FIG. 1, a reaction device includes: a reactor body 100 and a supply device 200, the reactor body 100, having a first end 106 and a second end 107, is configured to accommodate the first liquid. A first injection port 101 is provided between the first end 106 and the second end 107, and a discharge port 109 is provided at the second end 107; the supply device 200 is communicated with the first injection port 101 for injecting the continuous phase. Specifically, the supply device 200 is connected with the first injection port 101 through the connecting pipe 201, wherein the continuous phase flows directionally in the reactor body 100 to form or maintain a concertation gradient of the extracted organic solvent in the continuous phase the reactor body 100.

[0057] In this embodiment, by providing the first injection port 101 between the first end 106 and the second end 107 of the reactor body 100, so that the supply device 200 can inject the continuous phase into the first injection port 101, and the injected continuous phase, present in the reactor body 100, occurs along a concentration gradient described in detail below. In this embodiment, the concentration gradient of the continuous phase in the reactor body does not depend on the placement position and orientation of the reaction device, nor is it limited to the specific location of the first injection port 101. The reaction device in this embodiment is suitable for microsphere extraction. At the same time, it is also applicable to lipid drug-loaded reactors. In this embodiment, the specific application scenario of the reaction device is including but not limited to the preparation of embryo microspheres and the preparation of drug-loading lipids. The method of using the current reaction device in this embodiment only requires injecting a continuous phase into the first injection port 101 on the reactor body 100. The continuous phase can be used to form or maintain the concentration gradient in the reactor body 100, which is explained in detail in the following specific embodiment. In this embodiment, the first liquid is a mixed solution formed after the continuous phase handing of substances awaiting treatment. Such as in the embodiments of microsphere extraction, the continuous phase is water, the substance of awaiting treatment is embryo microspheres, the mixed solution formed after the continuous phase extracts the organic solvent in the embryo microspheres is the first liquid. The organic solvent extracted out of the embryonic microspheres can be dichloromethane, ethyl acetate, methanol, ethanol or acetic acid. The flowing continuous phase is injected into the first inlet 101, the flow rate of the first liquid between the first injection port 101 and the first accommodating part 102 is slower than that between the first injection port 101 and the second accommodating part 103. Take the organic solvent extracted from embryo microspheres as dichloromethane as an example, as a result, the dichloromethane concentration of the extracted from the embryonic microspheres between the first injection port 101 and the first accommodating part 102 is higher than that of the dichloromethane extracted from the embryonic microspheres between the first injection port 101 and the second accommodating part 103. Therefore, the concentration gradient of the dichloromethane is generated on both sides of the first injection port 101. It should be noted that the concentration gradient formed, in one example, the concentration trend of the gradient is a continuously changing in a linear distribution; in another example, the trend of the concentration gradient is in a non-linear distribution, or a stepwise distribution. In addition, the corresponding parameters within the reaction device may distribute as decreasing from high to low, increasing from low to high, or from high to low then to high again, or from low to high then return to low.

[0058] Referring again to FIG. 1, in another embodiment of the present invention, the reactor body 100 is slanted or placed vertically, the reactor is slanted means that the angle formed between the reactor body and the gravity direction of the Earth is greater than 0° but less than 90°, the slanted first end 106 is located above the second end 107; the continuous phase flows towards the second end 107 in a fixed direction under the force of gravity, the first injection port 101 is arranged in the middle, anywhere between one end 106 of reactor body 100 and another end 107 of the reactor body 100, in this embodiment, by arranging the first injection port 101 in the middle of the reactor body, while the reactor body 100 is placed vertically, when forming the embryo microspheres or drug-loading lipids, the concentration gradient in the reactor body 100 changes in a trend because of the continuous phase injected continuously in the middle, which is convenient for the formation of embryo microspheres and the formation of liposome drug carriers. Even when additional injection ports are provided, the weight of the substance injected by the other injection ports is less than the weight of the continuous phase injected by the first injection port, and the concentration gradient of the solution in the reactor body predominately depends on the continuous phase. The vertical placement of 100, when the embryo microspheres or liposomes are injected, they can well settle under the force of gravity, and the continuous phase can flow towards the second end 107, and embryonic microspheres or liposomes then pass through a solution having concentration gradient. The solution can better form embryonic microspheres or liposome-encapsulated drug carriers. In this embodiment, it is not limited to the specific application scenarios of the reaction device, as long as some preparations that meet the requirement of the reaction device, all processes can use the device disclosed herein.

[0059] As shown in FIG. 2, in another embodiment of the present invention, the body 100 of the reactor is placed horizontally, and the first end 106 is provided with a second injection port for injecting a treatment liquid with an initial flow rate, in microsphere production, the treatment solution refers to the liquid that helps to form embryonic microsphere and/or the liquid that is used as a continuous phase to extract the embryonic microspheres formed; the first injection port 101 is arranged in the middle, anywhere between the first end and the second end of the reactor body. In this embodiment, the reactor body 100 is placed horizontally, and the first end 106 is injected with a treatment liquid with a certain initial flow rate, so that the continuous phase can flow toward the second end 107, which facilitates the formation of concentration gradients of extracted organic solvent in the continuous phase.

[0060] In this embodiment, the provision of the second injection port enables the flow of the liquid inside the reactor body 100 to obtain a movement source, which is more conducive to extraction of microspheres and conducive to the formation of liposome drug-carriers. In this embodiment, when the reaction device is used to extract the microspheres, the treatment liquid can be a continuous phase with a certain initial flow rate, or can be a microsphere receiving liquid with a certain initial flow rate to drive the continuous phase flow.

[0061] As shown in FIG. 3, in another embodiment of the present invention, the reactor body 100 comprises: a first accommodating portion 102 and a second accommodating portion 103, a first joint 104 and a second joint 105; the first joint 104 is connected to the first joint 104 connects to accommodating portion 102 and a second accommodating portion 103, one end of the first accommodating portion 102 away from the first joint 104 is the first end 106, the first injection port 101 is provided on the first joint 104; the second joint 105 and the second accommodating portion 103 is in communication, becoming the second end 107, further discharge opening 109 is provided on the second joint 105. Specifically, the first accommodating portion 102 and the second accommodating portion 103 are connected to the outer wall of the end of the joint 104, on the outer wall of the end of the joint 104, external thread is provided. Inside of the first joint 104, the inner wall is provided with an internal thread to make the connection between the two, the connection between the first accommodating portion 102 and the first joint 104 more convenient and easier. Similarly, the outer wall of one end of the second accommodating portion 103 connected to the second joint is provided with an external thread, and the inner wall of the second joint is provided with internal threads so that the two, the connection between the second accommodating portion 103 and the first joint 104 are more convenient and easier. In this embodiment, it is not limited to use threaded connection to connects the accommodating portion and joint. In this embodiment, as long as the first joint 104 can be detachably connected to the first accommodating portion 102, the second accommodating portion 103, and the second joint can be detachably connected to the second accommodating portion 103.

[0062] It should be noted that the reaction device in the above embodiment is an embryonic microsphere extraction reactor or a liposome drug-carrier reactor, and the opening of the first injection port 101 on the reactor main body 100 makes the reactor body 100 open on the one hand. The concentration gradient of the organic solvent extracted into the continuous phase is formed in the inside of the reactor body, which is beneficial to formation of embryonic microsphere and liposome drug-carrier. On the other hand, the continuous injection of the continuous phase helps to maintain continuous formation of the embryonic microsphere and liposome drug-carrier.

[0063] As shown in FIG. 4, a microsphere preparation device comprises: a material injection mechanism 300, the reaction device described in any of the above-mentioned embodiments, and a collector 400. The material injection mechanism 300 is used to output embryonic microspheres, and the first end 106 of the reaction device is provided with a third injection port 108, which is communicated with the material injection mechanism 300. After the embryo microspheres are formed, they fall off from the material injection mechanism 300, settle in the reaction device, and form microspheres through extraction and solidification of the solvent. The collector 400 communicates with the second end 107 of the reaction device or is located at the end of the reactor body 100 as a part of the second end 107 to collect the microspheres, wherein the embryo microspheres formed, by the material injection mechanism 300, are transported into the reactor body 100. The first injection port 101 continuously injects the continuous phase, through the flow of the continuous phase and the diffusion of the organic solvent, a concentration gradient of the organic solvent extracted out of the embryonic microspheres forms a concentration gradient in the continuous phase is formed on both sides of the first injection port 101 in the body 100 of the reactor, the concentration of the organic solvent in the continuous phase between the first end 106 and the first injection port 101 is greater than the concentration of the organic solvent in the continuous phase between the first injection port 101 and the second end 107, and the embryonic microspheres are emulsified in the place where the concentration of the organic solvent is high, in order to improve the reproducibility of sphere formation, avoid the precipitation of polymers or other sphere-forming materials caused by excessive solvent extraction, and the adhesion and blockage of the microsphere forming mechanism. The spheres are solidified at low organic solvent concentration, and the solidified embryo microspheres are accumulated by the collector 400; and then post-processing is carried out in the post-processing equipment. During the post-processing, the microspheres are first rinsed to remove any impurities in the microspheres or in the continuous phase. The undesired residue is then lyophilized on the microspheres. The material injection mechanism 300 has an embryonic microsphere forming structure inside.

[0064] A microsphere solidification method for extracting an organic solvent in embryonic microspheres, implemented based on any one of the above-mentioned reaction devices, the first liquid is a microsphere receiving solution, and the microsphere receiving solution uses water as a matrix to extract the organic solvent.

[0065] The embryonic microspheres are made to flow from the first end 106 to the second end 107 along the reactor body 100 containing the microsphere receiving liquid, the organic solvent inside of the embryonic microspheres is extracted, and the embryonic microspheres harden to form microspheres.

[0066] During extraction, water is injected through the first injection port 101, and the water flows in the reactor body 100 to the second end 107 to form a concentration gradient of organic solvents in water on both sides of the first injection port 101.

[0067] Specifically, water can be injected continuously or intermittently; the embryonic microspheres can move directionally by gravity or the flow of the microsphere-receiving fluid. In the specific implementation, the injection mode of the water flow can be controlled as required, and continuous injection or intermittent injection can be selected. The flow rate of the continuous phase injected by the first injection port 101 can be adjusted to control the continuous phase. Or the distribution of concentration gradients of organic solvents or other added components in the continuous phase, while regulating the rate of preparation of microspheres or other granular products. When the reaction device is placed horizontally, the flow of the continuous phase from the reactor body 100 to the second end 107 becomes the driving force for the movement of embryonic microspheres or microspheres, or other granular products. The specific selection can be selected according to end use requirement, and the above-mentioned treatment liquid can be the directional flow microsphere receiving liquid in this embodiment.

[0068] A liposome drug-carrying preparation method is implemented based on any of the above-mentioned reaction devices, and the phospholipid membrane is installed at the first injection port 101, and the continuous phase is injected to make the phospholipid membrane maintain a pH gradient on both sides, so that the phospholipid membrane can better encapsulated drugs to form a liposome drug carrier.

[0069] It should be noted that the above embodiments can be freely combined as desired. The above are only the preferred embodiments of the present invention. It should be pointed out that for those skilled in the art, without departing from the principles of the present invention, several improvements and modifications can be made, which shall be deemed to be the part of the invention disclosed herein.