Syringe for generating a particle-based formulation

Abstract

Provide a syringe and related method for generating a particle-based formulation. 【Solution means】The syringe includes a barrel having a microfluidic mixer, a seal, and a piston. The displacement of the piston in the distal direction is configured to draw a first fluid into the first chamber of the barrel from a first fluid source and draw a second fluid into the second chamber of the barrel from a second fluid source. The displacement of the piston in the proximal direction is configured to discharge the first fluid and the second fluid from the first chamber and the second chamber into the microfluidic mixer, respectively, to mix the first fluid and the second fluid into a particle-based formulation.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 391,409, filed Jul. 22, 2022, the disclosure of which is incorporated herein by reference.

[0002] This application generally relates to generating particle - based formulations, and more particularly to syringes for generating particle - based formulations.

Background Art

[0003] Generating particle - based formulations for biomedical applications and the like can be costly and may involve complex and time - consuming steps. For example, to maintain the stability of some nanoparticle - based or microparticle - based formulations, low - temperature storage is required, which can complicate the supply chain and increase the costs associated with those particle - based formulations. Furthermore, current technologies for generating particle - based formulations can involve the use of complex equipment and numerous disposable mixing components that can occupy laboratory space. These problems can potentially limit or prevent the on - site / clinical - use - time generation of particle - based formulations.

[0004] Accordingly, there is a need for systems and methods for reproducibly generating particle - based formulations with high precision in an integrated process involving fewer operating steps and at a lower cost. Furthermore, there is a need for systems and methods for generating particle - based formulations at the clinical site / use time and at or near room temperature.

Summary of the Invention

[0005] These needs are met to a large extent by a syringe for generating a particle-based formulation. The syringe includes a barrel that defines a bore extending between a proximal end and a distal end of the barrel, a first inlet at the proximal end configured to be in fluid communication with a first fluid source and the bore, a second inlet at the proximal end configured to be in fluid communication with a second fluid source and the bore, and a microfluidic mixer in fluid communication with the bore and extending between the proximal end and the distal end. The syringe also includes a seal that fluidly seals the proximal end of the barrel. The syringe also includes a piston within the bore. Displacement of the piston in the distal direction is configured to draw a first fluid from the first fluid source into a first chamber of the syringe through the first inlet and draw a second fluid from the second fluid source into a second chamber of the syringe. Displacement of the piston in the proximal direction is configured to generate a particle-based formulation by discharging the first fluid and the second fluid from the first chamber and the second chamber, respectively, into the microfluidic mixer and mixing the first fluid and the second fluid.

[0006] The implementation form may include one or more of the following features. The microfluidic mixer may include a first inlet fluidly connected to the first chamber, and this first inlet is configured to receive the first fluid from the first chamber. The microfluidic mixer may include a second inlet fluidly connected to the second chamber, and this second inlet is configured to receive the second fluid from the second chamber. The microfluidic mixer may include a microfluidic channel and an outlet fluidly connected to the first inlet and the second inlet of the microfluidic mixer via this microfluidic channel. The syringe may include a tip cap configured to seal the outlet of the barrel. The piston can divide the bore into a third chamber on the distal side of the piston, and the outlet of the microfluidic mixer is configured to be fluidly connected to the third chamber. The outlet may include a one-way valve that allows a particle-based formulation to exit from the outlet of the microfluidic mixer and prevents or limits the particle-based formulation from re-entering the outlet of the microfluidic mixer from the third chamber. The displacement of the piston in the proximal direction is configured to discharge the particle-based formulation from the outlet of the microfluidic mixer into the third chamber. The displacement of the piston in the distal direction is the first displacement of the piston in the distal direction. After this first displacement of the piston in the distal direction and after the displacement of the piston in the proximal direction, the second displacement of the piston in the distal direction is configured to discharge the particle-based formulation through the outlet of the barrel. The plunger rod, piston, and seal divide the bore on the proximal side of the piston into the first chamber, and this first chamber is fluidly connected to the first inlet and the microfluidic mixer. The plunger rod, piston, and seal divide the bore on the proximal side of the piston into the second chamber, and this second chamber is fluidly connected to the second inlet and the microfluidic mixer. The plunger rod may include a gasket that prevents fluid communication between the first chamber and the second chamber. The plunger rod extends through the interface of the seal, and this interface has a shape complementary to the shape of the plunger rod to prevent rotation of the plunger rod within the barrel.The plunger rod is removably attached to the piston. The first chamber has a first volume and the second chamber has a second volume, and the first volume and the second volume change in response to displacement of the piston within the bore. The first inlet and the second inlet define corresponding Luer locks. The syringe may include a first plug configured to seal the first inlet and a second plug configured to seal the second inlet. The first fluid may contain lyophilized mRNA and the second fluid may contain lyophilized lipid. The syringe may include a needle configured to be attached to the outlet of the barrel. The seal defines an end cap.

[0007] Another aspect includes a method of generating a particle-based formulation within a syringe. The method of generating includes connecting a first fluid source to the first inlet of the syringe and connecting a second fluid source to the second inlet of the syringe. Generating also includes displacing the piston of the syringe in a distal direction to draw the first fluid from the first fluid source into the first chamber of the barrel of the syringe through the first inlet and to draw the second fluid from the second fluid source into the second chamber of the barrel through the second inlet. The first chamber and the second chamber are each located proximal to the piston. Generating also includes displacing the piston in a proximal direction to mix the first fluid and the second fluid within the microfluidic mixer of the syringe by discharging the first fluid from the first chamber into the microfluidic mixer of the syringe and discharging the second fluid from the second chamber into the microfluidic mixer of the syringe to generate a particle-based formulation.

[0008] Implementations of this alternative aspect may include one or more of the following features. The displacement of the piston in the proximal direction discharges the particle-based formulation from the microfluidic mixer into a third chamber of the barrel located on the distal side of the piston. Displacing the piston again in the distal direction to discharge the particle-based formulation from the outlet of the barrel. Attaching a needle to the outlet of the barrel before displacing the piston again in the distal direction. The method may include removing the tip cap from the outlet of the barrel after displacing the piston in the proximal direction. The method may include removing the first fluid source from the first inlet and the second fluid source from the second inlet, and connecting a first plug to the first inlet and a second plug to the second inlet, before displacing the piston in the proximal direction. The first fluid may include lyophilized mRNA, and the second fluid may include lyophilized lipid.

[0009] Various additional features and advantages of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description of the exemplary embodiments in conjunction with the accompanying drawings.

Brief Description of the Drawings

[0010] The following detailed description will be better understood when read in conjunction with the accompanying drawings. For purposes of illustration, examples are shown in the drawings, however, the subject matter is not limited to the specific elements and means disclosed. The drawings are as follows.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

DETAILED DESCRIPTION OF THE INVENTION

[0011] FIG. 1 shows a syringe 100 for generating a particle-based formulation. FIGS. 2-5 show examples of the use of the syringe 100. The syringe 100 can include a barrel 102 that can define a microfluidic mixer 104, such as a microfluidic chip. The syringe 100 can further include a plunger rod 106, and a piston 108 is attached to the distal end of the plunger rod 106. Although the plunger rod 106 is described, since other ways may exist to move the piston 108 within the barrel 102, the syringe 100 can also be provided without the plunger rod 102. In an embodiment, the plunger rod 106 can be removably attached to the piston 108. As will be further discussed later with respect to FIGS. 2-5, the displacement of the plunger rod 106 and the piston 108 in the distal direction to a distal position can draw the first fluid and the second fluid into the syringe 100 simultaneously. The subsequent displacement of the plunger rod 106 and the piston 108 from the distal position to the proximal position in the proximal direction can discharge the first fluid and the second fluid into the microfluidic mixer 104 and mix the first fluid and the second fluid into a particle-based formulation. The term "liquid", as used herein, may refer to any freely flowing substance and may include solid substances suspended in a freely flowing solution. The term "particle-based formulation" can include formulations of two or more substances and can include nanoparticles and / or microparticles. The subsequent displacement of the plunger rod 106 and the piston 108 from the proximal position to the distal position in the distal direction can discharge the particle-based formulation from the syringe 100.

[0012] According to various aspects of the present invention, the syringe 100 can enable the generation of particle-based formulations at the time of use with a minimum number of steps and without the need for cumbersome and non-essential equipment. In embodiments, each of the first fluid and the second fluid can be a lyophilized component, and the syringe 100 can mix the reconstituted lyophilized components stored at room temperature (e.g., a temperature of 10°C to 30°C) to generate, among other possibilities, particle-based formulations such as drugs, vaccines, etc. For example, the first fluid and / or the second fluid can include, among other possibilities, any combination of polymers, lipids, combinations of lipids and polymers, small molecule drugs, proteins, nucleic acids, gene editing formulations such as ASO, CRISPR / cas9, mRNA, siRNA, saRNA. In embodiments, the first fluid can include lyophilized mRNA that can be reconstituted in a buffer. In embodiments, the second fluid can be a lyophilized lipid mixture that can be reconstituted in an organic solvent such as ethanol. The syringe 100 can be used with some polymer-based nanoparticles and microparticles, as well as with other materials containing mRNA drugs or small molecules. The syringe 100 can generate particle-based formulations with high precision and high reproducibility and can be used in biomedical applications for generating highly potent drugs, vaccines, etc. By eliminating non-essential equipment and by enabling the generation of particle-based formulations at the time of use and at room temperature, the syringe 100 can significantly reduce the costs associated with the generation of particle-based formulations and increase the availability of particle-based formulations.

[0013] Returning to FIG. 1 and as described above, the syringe 100 may include a barrel 102 that can define a microfluidic mixer 104. In the embodiments shown in FIGS. 1-5, the barrel 102 can be made translucent to allow for visual inspection of the interior of the barrel 102. Further, or alternatively, part or all of the barrel 102 can be made opaque. In an embodiment, the microfluidic mixer 104 can be formed integrally with the barrel 102. For example, the barrel 102 can include a planar region or surface region on the outer surface of the barrel 102, and within that planar region, the microfluidic mixer 104 can be etched. The barrel 102 may include a cover 110 that can cover and seal the microfluidic mixer 104 from the external environment surrounding the syringe 100. In an embodiment, the cover 110 can be removable. Alternatively, the cover 110 can be fixedly immovable relative to the barrel 102. The microfluidic mixer 104 may form a first inlet 112, a second inlet 114, an outlet 116, and a microfluidic channel 118 that fluidly connects the outlet 116 to each of the first inlet 112 and the second inlet 114. In an embodiment, the microfluidic mixer 104 may include one or more valves capable of regulating the flow of fluid through the microfluidic mixer 104. For example, the outlet 116 may include a one-way valve that can allow a particle-based formulation to exit from the outlet 116 and prevent the particle-based formulation from re-entering the outlet 116. In addition to, or alternatively to, the first inlet 112 and / or the second inlet 114 may include a one-way valve that can prevent fluid from exiting the microfluidic mixer 104 through the first inlet 112 and / or the second inlet 114. The one-way valves as described in the present disclosure can be passive ones such as duckbill valves or active ones such as stopcock valves.

[0014] In an embodiment, the syringe 100 may include two or more microfluidic mixers 104. Those microfluidic mixers 104 may have the same characteristics and can interact with other structures of the syringe 100 as discussed throughout the present disclosure. In an alternative embodiment, the syringe 100 may have only one microfluidic mixer 104.

[0015] The barrel 102 can define a bore 120 that extends between the proximal end and the distal end of the barrel 102. For example, as shown in FIG. 1, the barrel 102 can define a first inlet 122 and a second inlet 124 that can be respectively located at the proximal end of the barrel 102. For example, as shown in FIG. 5, the barrel 102 can define an outlet 126 that can be located at the distal end of the barrel 102. The first inlet 122, the second inlet 124, and the outlet 126 can be in fluid communication with the bore 120. In an embodiment, any one or all of the first inlet 122, the second inlet 124, and the outlet 126 can include a fitting, such as a luer lock, that can connect any one of the first inlet 122, the second inlet 124, and the outlet 126 to one or more other structures. For example, as shown in FIG. 2, the first inlet 122 can be fluidly connected to a first fluid source 202 via corresponding first connector 206 and second connector 208, and the second inlet 124 can be connected to a second fluid source 204. In an embodiment, the first fluid source 202 and the second fluid source 204 can define vials for containing the first fluid and the second fluid, respectively. In an embodiment, the syringe 100 can include three or more inlets and can be fluidly connected to three or more fluid sources to integrally mix three or more fluids into a particle-based formulation.

[0016] In an embodiment, the outlet 126 can be fluidly connected to a vial, a needle, or other assembly. For example, the outlet 126 can be connected to a vial that collects a particle-based formulation for end use. Further or alternatively, in the embodiment of FIG. 5, the outlet 126 can be fluidly connected to a hollow needle 127 into which a particle-based formulation can be injected for end use. In an embodiment, the particle-based formulation formed by the syringe 100 can be purified. For example, the particle-based formulation can be purified after exiting the outlet 126 and before the particle-based formulation is transferred to a patient or end user.

[0017] Some or all of the syringe 100 can sometimes be sealed from the external environment. For example, the syringe 100 can include a seal such as an end cap 128 at the proximal end of the barrel 102. The plunger rod 106 can extend through the end cap 128 and, together with the end cap 128, can seal the proximal end of the barrel 102. In an embodiment, the plunger rod 106 can include a gasket 130 and / or the end cap 128 can include a gasket 132, and those gaskets seal the proximal end of the barrel 102. The gasket 130 can be provided on the shaft of the plunger rod 106. The syringe 100 can include a first plug 134 and a second plug 136 that can each seal the first inlet 122 and the second inlet 124 from the external environment. The syringe 100 can include a seal component 138, such as a luer lock or a tip cap for a needle guard / shield, that can seal the outlet 126 of the barrel 102. Any or all of the end cap 128, the plunger rod 106, the piston 108, the first plug 134, the second plug 136, and the seal component 138 can be removably connected to the syringe 100 via any number of joints or connections, including, for example, snap joints, threads, luer locks, etc.

[0018] The bore 120 of the barrel 102 can be divided into any number of chambers. In response to the displacement of the plunger rod 106 and the piston 108, fluid can be isolated within those chambers and selectively communicated between those chambers. In the embodiments shown in FIGS. 1-5, the bore 120 proximal to the piston 108 can be divided into a first chamber 140 and a second chamber 142, and the bore 120 distal to the piston 108 can be divided into a third chamber 144. For example, the plunger rod 106, the piston 108, and the end cap 128 can divide the bore 120 proximal to the piston 108 into the first chamber 140, and the first chamber 140 can be fluidly connected to the first inlet 122 and the microfluidic mixer 104. The plunger rod 106, the piston 108, and the end cap 128 can divide the bore 120 proximal to the piston 108 into the second chamber 142. The second chamber 142 can be fluidly connected to the second inlet 124 and the microfluidic mixer 104. The piston 108 can divide the bore 120 into the third chamber 144 distal to the piston 108. The plunger rod 106, the piston 108, and the end cap 128 can form a fluid-tight seal with the inner surface of the bore 120 so as to isolate fluid within the first chamber 140, the second chamber 142, and / or the third chamber 144. In an embodiment, the gaskets 130, 132 can form a fluid-tight seal and divide the bore 120 into the first chamber 140, the second chamber 142, and the third chamber 144. When connected, the first plug 134 and the second plug 136 can seal the fluid within the first chamber 140 and the second chamber 142, respectively. When connected, the seal component 138 can seal the fluid within the third chamber 144. In an embodiment, the bore 120 can be divided into three or more chambers proximal to the piston 108.

[0019] The volumes of the first chamber 140, the second chamber 142, and the third chamber 144 can change as the piston 108 displaces within the bore 120. For example, as the piston 108 displaces in the distal direction, the volumes of the first chamber 140 and the second chamber 142 can increase, and the volume of the third chamber 144 can decrease. Conversely, as the piston 108 displaces in the proximal direction, the volumes of the first chamber 140 and the second chamber 142 can decrease, and the volume of the third chamber 144 can increase. Although the volumes of the first chamber 140, the second chamber 142, and the third chamber 144 can change, the relative volume relationships among the first chamber 140, the second chamber 142, and the third chamber 144 can be maintained. For example, in an embodiment, the volume of the first chamber 140 and the volume of the second chamber 142 can remain equal to each other throughout the displacement of the piston 108. This can enable a 1:1 mixing ratio of the first fluid and the second fluid within the microfluidic mixer 104. Alternatively, in an embodiment, the volume of the first chamber 140 and the volume of the second chamber 142 can remain different by a fixed amount throughout the displacement of the piston 108. According to these embodiments, the syringe 100 can be adjusted to produce various different mixing ratios of the first fluid and the second fluid within the microfluidic mixer 104, such as 3:1 for example. The syringe 100 can be adjusted to produce different ratios, for example, by modifying the cross-sectional area of the chamber and / or by increasing or decreasing the axial geometry of the plunger rod 106.

[0020] In an embodiment, the end cap 128 may include an interface 146 that prevents rotation of the plunger rod 106 within the barrel 102 about the longitudinal axis of the plunger rod 106. For example, the interface 146 may have a shape complementary to the shape of the plunger rod 106, thereby enabling the plunger rod 106 to be rotationally coupled to the barrel 102. According to this configuration, the chambers of the bore 120 (e.g., the first chamber 140 and the second chamber 142) that are divided by the plunger rod 106 can be kept rotationally fixed, thereby improving and maintaining the intended fluid communication between those chambers and the microfluidic mixer 104.

[0021] In an embodiment, a structure of the syringe 100, such as the barrel 102, can be injection molded. Further or alternatively, a structure of the syringe 100, such as the microfluidic mixer 104, can be laser cut.

[0022] FIGS. 2-5 illustrate the use of the syringe 100 in which the syringe 100 generates a particle-based formulation from a first fluid and a second fluid. As shown in FIG. 2, the syringe 100 can be provided in a first configuration in which the plunger rod 106 is disposed in the proximal position. In the first configuration, the first inlet 122 can be fluidly connected to the first fluid source 202 via the first connector 206, and the second inlet 124 can be fluidly connected to the second fluid source 204 via the second connector 208.

[0023] As shown in FIG. 3, syringe 100 can be moved from the first arrangement to the second arrangement. Moving syringe 100 to the second arrangement can involve displacement of plunger rod 106 and piston 108 in the distal direction from the proximal position shown in FIG. 2 to the distal position shown in FIG. 3. This displacement in the distal direction can draw (i.e., fluidly communicate) the first fluid from the first fluid source 202 into the first chamber 140 through the first inlet 122, and can draw the second fluid from the second fluid source 204 into the second chamber 142 through the second inlet 124. As described above, piston 108, plunger rod 106, and end cap 128 can together seal both the first chamber 140 and the second chamber 142, and can prevent direct fluid communication between the first chamber 140 and the second chamber 142. Thus, the first fluid and the second fluid respectively contained within the first chamber 140 and the second chamber 142 do not mix in the second arrangement. In the second arrangement, and after the first fluid and the second fluid have been drawn into syringe 100, the first connector 206 and the second connector 208 can be removed, and the first plug 134 and the second plug 136 can be connected to the first inlet 122 and the second inlet 124 respectively to close the first inlet 122 and the second inlet 124.

[0024] As shown in FIG. 4, syringe 100 can be moved from a second arrangement to a third arrangement after the second arrangement. Moving syringe 100 to the third arrangement can involve displacement of plunger rod 106 and piston 108 in a proximal direction, returning from a distal position to a proximal position. This displacement in the proximal direction causes piston 108 to discharge the first fluid and the second fluid from the first chamber 140 and the second chamber 142 into the microfluidic mixer 104, respectively, and mix the first fluid and the second fluid into a particle-based formulation. For example, fluid communication between microfluidic channel 118 and first chamber 140 can be provided by first inlet 112. Fluid communication between microfluidic channel 118 and second chamber 142 can be provided by second inlet 114. Fluid communication between microfluidic channel 118 and third chamber 144 can be provided by outlet 116. First plug 134 and second plug 136 can prevent fluid from exiting first inlet 122 and second inlet 124 when piston 108 is displaced in the proximal direction. In addition or alternatively, first inlet 122 and / or second inlet 124 can include a one-way valve capable of preventing fluid from exiting first inlet 122 and / or second inlet 124. This displacement of piston 108 in the proximal direction reduces the volumes of first chamber 140 and second chamber 142, and discharges the first fluid and the second fluid from first chamber 140 and second chamber 142 through first inlet 112 and second inlet 114, respectively. This displacement of piston 108 in the proximal direction can also move the first fluid and the second fluid into microfluidic channel 118 through first inlet 112 and second inlet 114. In this case, the first fluid and the second fluid can be integrally mixed into a particle-based formulation within the geometry of microfluidic channel 118. This displacement of piston 108 can also discharge the particle-based formulation from microfluidic channel 118 into third chamber 144 through outlet 116, which can fluidly connect microfluidic mixer 104 and third chamber 144.

[0025] As shown in FIG. 5, syringe 100 can be moved from a third configuration to a fourth configuration. Moving syringe 100 to the fourth configuration may involve removing seal component 138. In an embodiment, removing seal component 138 can expose hollow needle 127 for the end use of the particle-based formulation. Alternatively, after seal component 138 is removed, outlet 126 can be connected to hollow needle 127, a fluid line, or any other structure intended to receive and / or transfer the particle-based formulation. After removal of seal component 138, moving syringe 100 to the fourth configuration may further involve another displacement of plunger rod 106 and piston 108 in the distal direction from a proximal position to a distal position. This displacement in the distal direction can cause the particle-based formulation to be discharged from third chamber 144 through outlet 126 that is in fluid communication with third chamber 144. Once discharged from syringe 100, the particle-based formulation can be used for any end use, including injection into a patient, experimentation, storage, etc. In an embodiment, the particle-based formulation formed by syringe 100 can be purified. For example, the particle-based formulation can be purified after exiting outlet 126 and before the particle-based formulation is transferred to a patient or end user.

[0026] In an embodiment, the displacement of plunger rod 106 and piston 108 can be performed manually and / or automatically. For example, plunger rod 106 and piston 108 can be displaced in response to a user manually pushing or pulling plunger rod 106. In an embodiment, a mechanical and / or electrical actuator can be connected to plunger rod 106, and the displacement of plunger rod 106 and piston 108 can be controlled directly or indirectly (i.e., using a controller) by the actuator. The actuator can include any one or all of a spring, a rubber band, a motor, a gear train, etc.

[0027] FIG. 6 shows a method 600 of generating a particle-based formulation using syringe 100. Method 600 may include, at step 602, connecting a first fluid source 202 to the first inlet 122 and connecting a second fluid source 204 to the second inlet 124. Prior to connecting the first fluid source 202 to the first inlet 122 and the second fluid source 204 to the second inlet 124, the first fluid source 202 and the second fluid source 204 can be stored at room temperature, such as a temperature of 10°C to 30°C. As described above, syringe 100 capable of generating a particle-based formulation using the first and second fluids stored at room temperature can simplify and reduce the costs associated with the generation of the particle-based formulation. The syringe 100 in step 602 may include any of the features / relationships described above with respect to the first arrangement and as shown in FIG. 2.

[0028] Method 600 may include, at step 604, displacing the plunger rod 106 and the piston 108 in the distal direction to draw a first fluid from the first fluid source 202 into the first chamber 140 through the first inlet 122 and to draw a second fluid from the second fluid source 204 into the second chamber 142 through the second inlet 124. As described above, in an embodiment, the first fluid may include lyophilized mRNA and the second fluid may include lyophilized lipid. Step 604 can be performed after step 602.

[0029] Method 600 may include, at step 606, displacing the plunger rod 106 and the piston 108 in the proximal direction to generate a particle-based formulation by discharging the first fluid from the first chamber 140 into the microfluidic mixer 104 and discharging the second fluid from the second chamber 142 into the microfluidic mixer 104. By displacing the plunger rod 106 and the piston 108 in the proximal direction, the particle-based formulation can be discharged from the microfluidic mixer 104 into the third chamber 144. The syringe 100 after step 606 may include any of the relationships / features described above with respect to the third arrangement and as shown in FIG. 4.

[0030] Method 600 may also include removing the seal component 138 from the outlet 126 after step 604 and before step 606. Method 600 may also include again displacing the plunger rod 106 and the piston 108 in the distal direction to discharge the particle-based formulation from the third chamber 144 through the outlet 126. Method 600 may include removing the seal component 138 (e.g., the tip cap) from the outlet 126 of the barrel 102 after displacing the plunger rod 106 and the piston 108 in the proximal direction. Method 600 may include attaching the hollow needle 127 to the outlet 126 of the barrel 102 before again displacing the plunger rod and the piston in the distal direction. After this second displacement, the syringe 100 may include any of the features / relationships described above with respect to the fourth configuration and shown in FIG. 5.

[0031] Method 600 may include removing the first fluid source 202 from the first inlet 122 and the second fluid source 204 from the second inlet 124, and connecting the first plug 134 to the first inlet 122 and the second plug 136 to the second inlet 124, after step 604 and before step 606. The syringe in this position may include any of the features / relationships described above with reference to the second configuration and shown in FIG. 3.

[0032] It will be understood that the foregoing description provides examples of the disclosed machines. However, other implementations of the present invention are contemplated in which the details may differ from those of the above-described examples. All references to the invention or its examples are intended to refer to the particular example being discussed at that time and are not intended to imply any limitation with respect to the more general scope of the present invention. All language indicating distinction and disparagement with respect to specific features is intended to indicate the lack of priority of those features, but not to completely exclude such features from the scope of the present invention unless otherwise indicated. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

1. A syringe for generating a particle-based formulation, a barrel, a bore extending between a proximal end and a distal end of the barrel, a first inlet at the proximal end configured to be fluidly connected to a first fluid source and the bore, a second inlet at the proximal end configured to be fluidly connected to a second fluid source and the bore, a barrel defining a microfluidic mixer fluidly connected to the bore and extending between the proximal end and the distal end, a seal fluidly sealing the proximal end of the barrel, a piston within the bore, wherein displacement of the piston in the distal direction is configured to draw a first fluid from the first fluid source into a first chamber of the syringe through the first inlet and draw a second fluid from the second fluid source into a second chamber of the syringe, and displacement of the piston in the proximal direction is configured to discharge the first fluid and the second fluid from the first chamber and the second chamber into the microfluidic mixer respectively, and generate a particle-based formulation by mixing the first fluid and the second fluid.

2. The microfluidic mixer, a first inlet fluidly connected to the first chamber and configured to receive the first fluid from the first chamber, a second inlet fluidly connected to the second chamber and configured to receive the second fluid from the second chamber, a microfluidic channel, and an outlet fluidly connected to the first inlet and the second inlet of the microfluidic mixer through the microfluidic channel. The syringe according to claim 1.

3. The syringe according to claim 2, further comprising a tip cap configured to seal an outlet of the barrel.

4. The piston divides the bore into a third chamber on the distal side of the piston, and the outlet of the microfluidic mixer is configured to be fluidly connected to the third chamber. The syringe according to claim 2.

5. The syringe according to claim 4, wherein the outlet includes a one-way valve that enables the particle-based formulation to exit from the outlet of the microfluidic mixer and prevents or restricts the particle-based formulation from re-entering the outlet of the microfluidic mixer from the third chamber.

6. The syringe according to claim 4, wherein the displacement of the piston in the proximal direction is configured to discharge the particle-based formulation from the outlet of the microfluidic mixer into the third chamber.

7. The displacement of the piston in the distal direction is the first displacement of the piston in the distal direction, After the first displacement of the piston in the distal direction and after the displacement of the piston in the proximal direction, a second displacement of the piston in the distal direction is configured to discharge the particle-based formulation through the outlet of the barrel, according to claim 1 syringe described.

8. The syringe further comprises a plunger rod attached to the piston, the plunger rod extending movably through the seal, The plunger rod, the piston, and the seal divide the bore on the proximal side of the piston into the first chamber, and the first chamber is in fluid connection with the first inlet and the microfluidic mixer, The plunger rod, the piston, and the seal divide the bore on the proximal side of the piston into the second chamber, and the second chamber is in fluid connection with the second inlet and the microfluidic mixer, according to claim 1 syringe described.

9. The syringe according to claim 8, wherein the plunger rod includes a gasket that prevents fluid communication between the first chamber and the second chamber.

10. The plunger rod extends through the interface of the seal, and the interface has a shape complementary to the shape of the plunger rod to prevent rotation of the plunger rod within the barrel, according to claim 8 syringe described.

11. The syringe according to claim 8, wherein the plunger rod is removably attached to the piston.

12. The first chamber has a first volume, and the second chamber has a second volume, The syringe according to claim 1, wherein the first volume and the second volume change in response to displacement of the piston within the bore.

13. The syringe according to claim 1, wherein the first inlet and the second inlet define corresponding Luer locks.

14. The syringe according to claim 1, further comprising a first plug configured to close the first inlet and a second plug configured to close the second inlet.

15. The syringe according to claim 1, wherein the first fluid comprises lyophilized mRNA and the second fluid comprises lyophilized lipid.

16. The syringe according to claim 1, further comprising a needle configured to be attached to an outlet of the barrel.

17. The syringe according to claim 1, wherein the seal defines an end cap.

18. A method of generating a particle-based formulation within a syringe, comprising: connecting a first fluid source to a first inlet of the syringe and a second fluid source to a second inlet of the syringe; displacing a piston of the syringe in a distal direction to draw a first fluid from the first fluid source into a first chamber of a barrel of the syringe through the first inlet and to draw a second fluid from the second fluid source into a second chamber of the barrel through the second inlet, wherein the first chamber and the second chamber are each located proximal to the piston; displacing the piston in a proximal direction to discharge the first fluid from the first chamber into a microfluidic mixer of the syringe and to discharge the second fluid from the second chamber into the microfluidic mixer of the syringe, thereby mixing the first fluid and the second fluid within the microfluidic mixer to generate the particle-based formulation.

19. The method according to claim 18, wherein the displacement of the piston in the proximal direction causes the particle-based formulation to be discharged from the microfluidic mixer into a third chamber of the barrel located distal to the piston.

20. The method according to claim 18, further comprising displacing the piston in the distal direction again to discharge the particle-based formulation from an outlet of the barrel. The method according to claim 18.

21. Further comprising attaching a needle to the outlet of the barrel before displacing the piston in the distal direction again. The method according to claim 20. **Claim 22** Further comprising removing a tip cap from the outlet of the barrel after displacing the piston in the proximal direction. The method according to claim 18. **Claim 23** Before displacing the piston in the proximal direction, removing the first fluid source from the first inlet and removing the second fluid source from the second inlet; Connecting a first plug to the first inlet and connecting a second plug to the second inlet; The method according to claim 18, further comprising. **Claim 24** The method according to claim 18, wherein the first fluid comprises lyophilized mRNA and the second fluid comprises lyophilized lipid.

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