Syringe for producing particle-based formulations

Abstract

A syringe and associated method for producing a particle-based formulation is described. The syringe includes a seal, a piston, and a barrel having a microfluidic mixer. Displacement of the piston in a distal direction is configured to draw a first fluid from a first fluid source into a first chamber of the barrel and a second fluid from a second fluid source into a second chamber of the barrel. Displacement of the piston in a proximal direction is configured to discharge the first fluid and the second fluid out of the first chamber and the second chamber, respectively, and into the microfluidic mixer to mix the first fluid and the second fluid into the particle-based formulation.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 391,409, filed on July 22, 2022, the disclosure of which is hereby incorporated by reference into this document. Technical Field

[0003] The present application relates generally to producing particle-based formulations, and in particular to syringes for producing particle-based formulations. Background Art

[0004] The production of particle-based formulations such as those for biomedical applications can be expensive and can involve complex, time-consuming steps. For example, cryogenic storage is necessary to retain the stability of some nanoparticle-based formulations or micron-based formulations, which can complicate the supply chain and increase the costs associated with particle-based formulations. In addition, current techniques for producing particle-based formulations can involve the use of complex equipment and multiple consumable mixing components that can take up laboratory space. These issues can limit or prevent point-of-care / point-of-use production of particle-based formulations.

[0005] Therefore, there is a need for systems and methods for reproducibly producing particle-based formulations with high precision in a combined process with fewer operating steps and lower costs. In addition, there is a need for systems and methods for producing particle-based formulations at the point of care / use and at or near room temperature. Summary of the invention

[0006] These needs are largely met by a syringe for producing a particle-based formulation. The syringe includes a barrel defining a hole extending between a proximal end and a distal end of the barrel; a first inlet located at the proximal end, the first inlet being configured to be fluidically connected to a first fluid source and the hole; a second inlet located at the proximal end, the second inlet being configured to be fluidically connected to a second fluid source and the hole; and a microfluidic mixer fluidly connected to the hole 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 located in the hole. The displacement of the piston toward the distal direction is configured to draw a first fluid from the first fluid source via the first inlet into a first chamber of the syringe, and is configured to 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 expel the first fluid and the second fluid out of the first chamber and the second chamber, respectively, and into the microfluidic mixer to mix the first fluid and the second fluid to produce a particle-based formulation.

[0007] Specific implementation may include one or more of the following features. The microfluidic mixer may include a first inlet, which is fluidically connected to the first chamber, wherein the first inlet is configured to receive the first fluid from the first chamber. The microfluidic mixer may include a second inlet, which is fluidically connected to the second chamber, wherein the second inlet is configured to receive the second fluid from the second chamber. The microfluidic mixer may include a microfluidic channel and an outlet, which is fluidically connected to the first inlet of the microfluidic mixer and the second inlet of the microfluidic mixer via the microfluidic channel. The syringe may include a tip cap configured to seal the outlet of the barrel. The piston may divide the hole into a third chamber at the far side of the piston, and the outlet of the microfluidic mixer is configured to be fluidically connected to the third chamber. The outlet may include a one-way valve, which allows a particle-based preparation to leave the outlet of the microfluidic mixer and prevents or limits the particle-based preparation from re-entering the outlet of the microfluidic mixer from the third chamber. The displacement of the piston toward the proximal direction is configured to discharge the particle-based preparation out of the outlet of the microfluidic mixer and into the third chamber. The displacement of the piston toward the distal direction is the first displacement of the piston toward the distal direction, and the second displacement of the piston toward the distal direction after the first displacement of the piston toward the distal direction and after the displacement of the piston toward the proximal direction is configured to discharge the preparation based on particles via the outlet of the barrel. The plunger rod, piston and seal divide the hole on the proximal side of the piston into the first chamber, and the first chamber is fluidically connected to the first inlet and the microfluid mixer. The plunger rod, piston and seal divide the hole on the proximal side of the piston into the second chamber, and the second chamber is fluidically connected to the second inlet and the microfluid mixer. The plunger rod may include a gasket that prevents the fluid from being communicated between the first chamber and the second chamber. The plunger rod extends through the joint of the seal, wherein the joint has a complementary shape relative to the shape of the plunger rod to prevent the rotation of the plunger rod in 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, wherein the first volume and the second volume change in response to the displacement of the piston in the hole. The first inlet and the second inlet define corresponding Luer locks. The syringe may include a first plug configured to plug the first inlet and a second plug configured to plug the second inlet. The first fluid may include freeze-dried mRNA, and the second fluid may include freeze-dried lipids. The syringe may include a needle configured to be attached to the outlet of the barrel. The seal defines an end cap.

[0008] On the other hand, a method for producing a particle-based preparation in a syringe is included. The method for producing includes connecting a first fluid source to a first inlet of a syringe and connecting a second fluid source to a second inlet of a syringe. The production also includes displacing the piston of the syringe toward a distal direction, so that a first fluid is drawn from the first fluid source into a first chamber of the barrel of the syringe via the first inlet, and a second fluid is drawn from the second fluid source into a second chamber of the barrel via the second inlet. The first chamber and the second chamber are each located near the piston. The production also includes displacing the piston toward a proximal direction, so that the first fluid is discharged from the first chamber and discharged into a microfluidic mixer of the syringe, and the second fluid is discharged from the second chamber and discharged into the microfluidic mixer of the syringe, thereby mixing the first fluid and the second fluid in the microfluidic mixer to produce a particle-based preparation.

[0009] The specific implementation of this other aspect may include one or more of the following features. The displacement of the piston toward the proximal direction discharges the particle-based formulation out of the microfluidic mixer and into a third chamber of the barrel located distal to the piston. The piston is displaced again toward the distal direction to discharge the particle-based formulation out of the outlet of the barrel. The needle is attached to the outlet of the barrel before the piston is displaced again toward the distal direction. The method may include removing the tip cap from the outlet of the barrel after the piston is displaced toward the proximal direction. The method may include removing the first fluid source from the first inlet and removing the second fluid source from the second inlet before the piston is displaced toward the proximal direction; and connecting the first plug to the first inlet and connecting the second plug to the second inlet. The first fluid may include freeze-dried mRNA, and the second fluid may include freeze-dried lipids.

[0010] Various additional features and advantages of the present invention will become apparent to those skilled in the art upon reading the following detailed description of illustrative embodiments in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The following detailed description is better understood when read in conjunction with the accompanying drawings.For purposes of illustration, various examples are shown in the drawings; however, the subject matter is not limited to the specific elements and instrumentalities disclosed.

[0012] In the attached picture:

[0013] Figure 1 A perspective view of a syringe is shown;

[0014] Figure 2 A device connected to a first fluid source and a second fluid source and connected to a plunger rod disposed in a proximal position is shown. Figure 1 syringe;

[0015] Figure 3 Shows Figure 1a syringe wherein the plunger rod is moved to a distal position and the first fluid source and the second fluid source are replaced by the first stopper and the second stopper, respectively;

[0016] Figure 4 Shows Figure 1 a syringe, wherein the plunger rod is again moved to a proximal position to mix the first fluid and the second fluid into a particle-based formulation within a microfluidic mixer of the syringe;

[0017] Figure 5 Shows Figure 1 The syringe comprises: a syringe in which the plunger rod is again moved to a distal position to expel the particle-based formulation from the syringe; and

[0018] Figure 6 A method of producing a particle-based formulation is shown. DETAILED DESCRIPTION

[0019] Figure 1 A syringe 100 for producing a particle-based formulation is shown. Figures 2 to 5 An example use of a syringe 100 is shown. The syringe 100 may include a barrel 102, which may define a microfluidic mixer 104, such as a microfluidic chip. The syringe 100 may also include a plunger rod 106, wherein a piston 108 is attached to the distal end of the plunger rod 106. Although a plunger rod 106 is described, there may be other ways to move the piston 108 within the barrel 102, and thus the syringe 100 may be provided without a plunger rod 102. In an embodiment, the plunger rod 106 may be removably attached to the piston 108. As described later with respect to Figures 2 to 5 Discussed in more detail, the displacement of plunger rod 106 and piston 108 toward distal direction to distal position can simultaneously draw the first fluid and the second fluid into syringe 100. Subsequent displacement of plunger rod 106 and piston 108 from distal position to proximal position toward proximal direction can discharge the first fluid and the second fluid into microfluid mixer 104, to mix the first fluid and the second fluid into a particle-based preparation. As used herein, the term "liquid" can refer to any free-flowing substance, and can include solid substances suspended in a free-flowing solution. The term "particle-based preparation" can include preparations of two or more substances, and can include nanoparticles and / or microparticles. Subsequent displacement of plunger rod 106 and piston 108 toward distal direction from proximal position to distal position can discharge particle-based preparations from syringe 100.

[0020] According to various aspects of the present invention, syringe 100 can allow the production of particle-based preparations at the point of use with minimal steps without the need for bulky external equipment. In an embodiment, each of the first fluid and the second fluid can be a freeze-dried component, and syringe 100 can be mixed with the reconstructed freeze-dried components stored at room temperature (e.g., at a temperature between 10°C and 30°C) to produce particle-based preparations, such as drugs, vaccines and other possibilities. For example, the first fluid and / or the second fluid may include any combination of polymers, lipids, combinations of lipids and polymers, small molecule drugs, proteins, nucleic acids, ASOs, gene editing preparations such as CRISPR / cas9, mRNA, siRNA, saRNA and other possibilities. In an embodiment, the first fluid may include freeze-dried mRNA, which may be reconstructed in a buffer. In an embodiment, the second fluid may be a freeze-dried lipid mixture, which may be reconstructed in an organic solvent (such as ethanol). Syringe 100 can be used for a variety of polymer-based nanoparticles and microparticles and for mRNA drugs or other materials containing small molecules. The syringe 100 can produce particle-based formulations with high precision and high repeatability, and can be used in biomedical applications to produce highly potent drugs, vaccines, etc. By eliminating foreign equipment and by allowing particle-based formulations to be produced at the point of use and at room temperature, the syringe 100 can significantly reduce the costs associated with the production of microparticle-based formulations and increase the accessibility of microparticle-based formulations.

[0021] Back to Figure 1 As previously discussed, the syringe 100 may include a barrel 102 that may define a microfluidic mixer 104. Figures 1 to 5In the embodiment shown, the barrel 102 can be translucent to allow visual inspection of the interior of the barrel 102. Additionally or alternatively, some or all of the barrel 102 can be opaque. In an embodiment, the microfluid mixer 104 can be formed integrally with the barrel 102. For example, the barrel 102 can include a planar area or a face area at the outer surface of the barrel 102, and the microfluid mixer 104 can be etched into the planar area. The barrel 102 can include a lid 110, which can cover the microfluid mixer 104 and seal it with the external environment around the syringe 100. In an embodiment, the lid 110 can be removable. Alternatively, the lid 110 can be fixedly fixed to the barrel 102. The microfluid mixer 104 can define 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 that can regulate the flow of fluid through the microfluidic mixer 104. For example, the outlet 116 may include a one-way valve that can allow the particle-based formulation to exit the outlet 116 and can prevent the particle-based formulation from re-entering the outlet 116. Additionally or alternatively, the first inlet 112 and / or the second inlet 114 may include a one-way valve that can prevent the fluid from exiting the microfluidic mixer 104 via the first inlet 112 and / or the second inlet 114. The one-way valves described in the present disclosure can be passive, such as duckbill valves, or active, such as stopcock valves.

[0022] In an embodiment, the syringe 100 may include two or more microfluidic mixers 104. The microfluidic mixers 104 may have the same features and may interface with other structures of the syringe 100, as discussed throughout this disclosure. In an alternative embodiment, the syringe 100 may have only one microfluidic mixer 104.

[0023] The barrel 102 may define a bore 120 extending between the proximal and distal ends of the barrel 102. For example, Figure 1 As shown, the barrel 102 may define a first inlet 122 and a second inlet 124, which may each be located at a proximal end of the barrel 102. For example and as Figure 5As shown, the barrel 102 may define an outlet 126, which may be located at the distal end of the barrel 102. The first inlet 122, the second inlet 124, and the outlet 126 may be fluidly connected to the hole 120. In an embodiment, any or all of the first inlet 122, the second inlet 124, and the outlet 126 may include a fitting, such as, for example, a Luer lock, which can connect any of the first inlet 122, the second inlet 124, and the outlet 126 to one or more other structures. For example and as Figure 2 As shown, the first inlet 122 can be fluidly connected to the first fluid source 202 and the second inlet 124 can be connected to the second fluid source 204 via respective first connectors 206 and second connectors 208. In an embodiment, the first fluid source 202 and the second fluid source 204 can, for example, define vials for containing the first fluid and the second fluid, respectively. In an embodiment, the syringe 100 can include more than two inlets and can be fluidly connected to more than two fluid sources to mix more than two fluids together into a particle-based formulation.

[0024] In an embodiment, the outlet 126 can be fluidly connected to a vial, needle, or other component. For example, the outlet 126 can be connected to a vial that collects the particle-based formulation for end-use application. Additionally or alternatively, in Figure 5 In embodiments, the outlet 126 can be fluidly connected to a hollow needle 127 that can inject the particle-based formulation for end-use applications. In embodiments, 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.

[0025] Some or all of the syringe 100 may sometimes be sealed from the external environment. For example, the syringe 100 may include a seal, such as an end cap 128, at the proximal end of the barrel 102. The plunger rod 106 may extend through the end cap 128 and, together with the end cap 128, may seal the proximal end of the barrel 102. In an embodiment, the plunger rod 106 may include a gasket 130, and / or the end cap 128 may include a gasket 132 that seals the proximal end of the barrel 102. The gasket 130 may be disposed on the shaft of the plunger rod 106. The syringe 100 may include a first plug 134 and a second plug 136, which may seal the first inlet 122 and the second inlet 124 from the external environment, respectively. The syringe 100 may include a sealing member 138, such as a tip cap for a Luer lock or a needle sleeve / needle shield, which may seal the outlet 126 of the barrel 102. Any or all of the end cap 128, plunger rod 106, piston 108, first stopper 134, second stopper 136, and sealing member 138 may be removably connected to the syringe 100 via any number of fittings or connections including, for example, snap fittings, threads, Luer locks, etc.

[0026] The bore 120 of the barrel 102 may be divided into any number of chambers. In response to the displacement of the plunger rod 106 and the piston 108, fluid may be isolated within the chambers and selectively communicated between the chambers. Figures 1 to 5 In the illustrated embodiment, the hole 120 proximal to the piston 108 can be divided into a first chamber 140 and a second chamber 142, and the hole 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 hole 120 proximal to the piston 108 into the first chamber 140, and the first chamber 140 can be fluidically 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 hole 120 proximal to the piston 108 into the second chamber 142. The second chamber 142 can be fluidically connected to the second inlet 124 and the microfluidic mixer 104. The piston 108 can divide the hole 120 into the third chamber 144 distal to the piston 108. The plunger rod 106, piston 108, and end cap 128 can form a fluid-tight seal with the inner surface of the bore 120 so that the fluid can be isolated in 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 can 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 in the first chamber 140 and the second chamber 142, respectively. When connected, the sealing member 138 can seal the fluid in the third chamber 144. In an embodiment, the bore 120 can be divided into more than two chambers proximal to the piston 108.

[0027] The volume of the first chamber 140, the second chamber 142, and the third chamber 144 can change as the piston 108 is displaced in the hole 120. For example, when the piston 108 is displaced toward the distal direction, the volume of the first chamber 140 and the second chamber 142 can increase, and the volume of the third chamber 144 can decrease. On the contrary, when the piston 108 is displaced toward the proximal direction, the volume of the first chamber 140 and the second chamber 142 can decrease, and the volume of the third chamber 144 can increase. Although the volume of the first chamber 140, the second chamber 142, and the third chamber 144 can change, the relative volume relationship between 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 relative to each other during the entire displacement of the piston 108. This can allow a 1:1 mixing ratio of the first fluid and the second fluid in the microfluidic mixer 104. Alternatively, in embodiments, the volume of the first chamber 140 and the volume of the second chamber 142 can remain at different fixed amounts throughout the displacement of the piston 108. According to these embodiments, the syringe 100 can be tuned to produce a variety of different mixing ratios of the first fluid and the second fluid within the microfluidic mixer 104, such as, for example, 3: 1. The syringe 100 can be tuned to produce different ratios by, for example, changing the cross-sectional area of ​​the chamber and / or by increasing or decreasing the axial geometry of the plunger rod 106.

[0028] In an embodiment, the end cap 128 may include a joint 146 that prevents the plunger rod 106 from rotating about the longitudinal axis of the plunger rod 106 within the barrel 102. For example, the joint 146 may have a complementary shape relative to the shape of the plunger rod 106 to rotationally interlock the plunger rod 106 relative to the barrel 102. According to this configuration, the chambers of the bore 120 divided by the plunger rod 106 (e.g., the first chamber 140 and the second chamber 142) can remain rotationally fixed, which can improve and maintain the desired fluid communication between the chambers and the microfluidic mixer 104.

[0029] In an embodiment, structures of the syringe 100, such as the barrel 102, may be injection molded. Additionally or alternatively, structures of the syringe 100, such as the microfluidic mixer 104, may be laser cut.

[0030] Figures 2 to 5 The use of the syringe 100 is shown, wherein the syringe 100 produces a particle-based formulation from a first fluid and a second fluid. Figure 2 As shown, the syringe 100 can be arranged in a first arrangement, wherein the plunger rod 106 is arranged in a proximal position. In the first arrangement, 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.

[0031] like Figure 3 As shown, the syringe 100 can be moved to the second arrangement after the first arrangement. Moving the syringe 100 to the second arrangement can involve the plunger rod 106 and the piston 108 moving in the distal direction from Figure 2 The proximal position shown is Figure 3 140 via the first inlet 122 and the second inlet 124. As discussed above, the piston 108, the plunger rod 106 and the end cap 128 can seal the first chamber 140 and the second chamber 142 together, and can prevent direct fluid communication between the first chamber 140 and the second chamber 142. Therefore, the first fluid and the second fluid contained in the first chamber 140 and the second chamber 142, respectively, do not mix in the second arrangement. In the second arrangement and after the first fluid and the second fluid are drawn into the 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 plug the first inlet 122 and the second inlet 124.

[0032] like Figure 4As shown, the syringe 100 can be moved to the third arrangement after the second arrangement.Moving the syringe 100 to the third arrangement may involve the displacement of the plunger rod 106 and the piston 108 from the distal position and returning to the proximal position toward the proximal direction.This displacement toward the proximal direction can cause the piston 108 to discharge the first fluid and the second fluid respectively from the first chamber 140 and the second chamber 142 and discharge into the microfluid mixer 104, so that the first fluid and the second fluid are mixed into a particle-based formulation.For example, the fluid communication between the microfluidic channel 118 and the first chamber 140 can be provided by the first inlet 112.The fluid communication between the microfluidic channel 118 and the second chamber 142 can be provided by the second inlet 114.The fluid communication between the microfluidic channel 118 and the third chamber 144 can be provided by the outlet 116.When the piston 108 is displaced toward the proximal direction, the first plug 134 and the second plug 136 can prevent the fluid from leaving the first inlet 122 and the second inlet 124. Additionally or alternatively, the first inlet 122 and / or the second inlet 124 may include a one-way valve that can prevent the fluid from leaving the first inlet 122 and / or the second inlet 124. Such displacement of the piston 108 toward the proximal direction can reduce the volume of the first chamber 140 and the second chamber 142 to discharge the first fluid and the second fluid from the first chamber 140 and the second chamber 142 via the first inlet 112 and the second inlet 114, respectively. Such displacement of the piston 108 toward the proximal direction can also drive the first fluid and the second fluid through the first inlet 112 and the second inlet 114 and into the microfluidic channel 118, wherein the first fluid and the second fluid can be mixed together into a particle-based formulation within the geometry of the microfluidic channel 118. Such displacement of the piston 108 can also discharge the particle-based formulation from the microfluidic channel 118 and discharge it into the third chamber 144 via the outlet 116, which can fluidly connect the microfluidic mixer 104 and the third chamber 144.

[0033] like Figure 5As shown, the syringe 100 can be moved to the fourth arrangement after the third arrangement. Moving the syringe 100 to the fourth arrangement may involve removing the sealing member 138. In an embodiment, removing the sealing member 138 may reveal the hollow needle 127 for the final use application of the particle-based preparation. Alternatively, after the sealing member 138 is removed, the outlet 126 may be connected to the hollow needle 127, a fluid line or any other structure intended to receive and / or transfer the particle-based preparation. After the removal of the sealing member 138, moving the syringe 100 to the fourth arrangement may further involve another displacement of the plunger rod 106 and the piston 108 from the proximal position to the distal position toward the distal direction. This displacement toward the distal direction can discharge the particle-based preparation from the third chamber 144 via the outlet 126, which is fluidly connected to the third chamber 144. Once discharged from the syringe 100, the particle-based preparation can be used for any final use, including injection into a patient, experiment, storage, etc. In an embodiment, the particle-based preparation formed by the syringe 100 can be purified. For example, the particle-based formulation may be purified after exiting the outlet 126 and before the particle-based formulation is transferred to a patient or end user.

[0034] In an embodiment, the displacement of the plunger rod 106 and the piston 108 can be performed manually and / or automatically. For example, the plunger rod 106 and the piston 108 can be displaced in response to a user manually pushing or pulling the plunger rod 106. In an embodiment, a mechanical actuator and / or an electronic actuator can be connected to the plunger rod 106, and the displacement of the plunger rod 106 and the 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.

[0035] Figure 6 A method 600 for producing a particle-based formulation using the syringe 100 is shown. The method 600 may include, at step 602, connecting the first fluid source 202 to the first inlet 122 and connecting the second fluid source 204 to the second inlet 124. Prior to connecting the first fluid source 202 to the first inlet 122 and connecting the second fluid source 204 to the second inlet 124, the first fluid source 202 and the second fluid source 204 may be stored at room temperature, such as a temperature between 10° C. and 30° C. As previously discussed, a syringe 100 that can produce a particle-based formulation using the first fluid and the second fluid stored at room temperature can simplify and reduce costs associated with the production of particle-based formulations. The syringe 100 may include, at step 602, as discussed above with respect to the first arrangement and as described above with respect to the first arrangement. Figure 2 Any of the features / relationships depicted in .

[0036] The method 600 may include, at step 604, displacing the plunger rod 106 and the piston 108 in the distal direction to draw the first fluid from the first fluid source 202 into the first chamber 140 via the first inlet 122, and draw the second fluid from the second fluid source 204 into the second chamber 142 via the second inlet 124. As discussed above, in embodiments, the first fluid may include lyophilized mRNA, and the second fluid may include lyophilized lipids. Step 604 may be performed after step 602.

[0037] The method 600 may include, at step 606, displacing the plunger rod 106 and the piston 108 in a proximal direction to expel the first fluid from the first chamber 140 and into the microfluidic mixer 104, and the second fluid from the second chamber 142 and into the microfluidic mixer 104, thereby producing a particle-based formulation. The displacement of the plunger rod 106 and the piston 108 in the proximal direction may expel the particle-based formulation out of the microfluidic mixer 104 and into the third chamber 144. After step 606, the syringe 100 may include the previously discussed third arrangement and as described above. Figure 4 Any of the relationships / characteristics depicted in .

[0038] The method 600 may also include removing the sealing member 138 from the outlet 126 after step 604 and before step 606. The method 600 may also include displacing the plunger rod 106 and the piston 108 in the distal direction again to discharge the particle-based formulation from the third chamber 144 via the outlet 126. The method 600 may include, after displacing the plunger rod 106 and the piston 108 in the proximal direction, removing the sealing member 138 (e.g., the tip cap) from the outlet 126 of the barrel 102. The method 600 may include, before displacing the plunger rod and the piston in the distal direction again, attaching the hollow needle 127 to the outlet 126 of the barrel 102. After this re-displacement, the syringe 100 may include the previously discussed fourth arrangement and as described above. Figure 5 Any of the features / relationships depicted in .

[0039] The method 600 may include, after step 604 and before step 606, removing the first fluid source 202 from the first inlet 122 and removing 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. The syringe in this position may include the previously discussed with reference to the second arrangement and as described above. Figure 3 Any of the relationships / characteristics depicted in .

[0040] It should be understood that the foregoing description provides examples of the disclosed machines. However, it is contemplated that other specific implementations of the present invention may differ from the foregoing examples in detail. All references to the present invention or its examples are intended to reference the specific examples being discussed at this time, and are not intended to imply any limitation on the scope of the present invention more generally. All language regarding the distinction and disparagement of certain features is intended to indicate that those features are non-preferred, but are not completely excluded 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 clearly contradictory to the context.

Claims

1. A syringe for producing a particle-based formulation, the syringe comprising: A cylinder, the cylinder defining: a bore extending between a proximal end and a distal end of the barrel; a first inlet located at the proximal end, the first inlet configured to be fluidly connected to a first fluid source and the aperture; a second inlet located at the proximal end, the second inlet configured to be fluidly connected to a second fluid source and the aperture; and a microfluidic mixer fluidly connected to the aperture and extending between the proximal end and the distal end; a seal that fluidly seals the proximal end of the barrel; and a piston, the piston being located in the hole; wherein the displacement of the piston in the distal direction is configured to draw a first fluid from the first fluid source into the first chamber of the syringe via the first inlet, and is configured to draw a second fluid from the second fluid source into the second chamber of the syringe, and wherein displacement of the piston in the proximal direction is configured to discharge the first fluid and the second fluid out of the first chamber and the second chamber, respectively, and into the microfluidic mixer to mix the first fluid and the second fluid to produce a particle-based formulation.

2. The syringe of claim 1, wherein the microfluidic mixer comprises: a first inlet fluidly connected to the first chamber, wherein the first inlet is configured to receive the first fluid from the first chamber; a second inlet fluidly connected to the second chamber, wherein the second inlet is configured to receive the second fluid from the second chamber; Microfluidic channels; and An outlet is fluidly connected to the first inlet of the microfluidic mixer and the second inlet of the microfluidic mixer via the microfluidic channel.

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

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

5. The syringe of claim 4, wherein the outlet comprises a one-way valve that allows the particle-based formulation to exit 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 of claim 4, wherein the displacement of the piston toward the proximal direction is configured to expel the particle-based formulation out of the outlet of the microfluidic mixer and into the third chamber.

7. The syringe of claim 1, wherein the displacement of the piston toward the distal direction is a first displacement of the piston toward the distal direction, and wherein a second displacement of the piston towards the distal direction subsequent to the first displacement of the piston towards the distal direction and subsequent to the displacement of the piston towards the proximal direction is configured to expel the particle-based formulation via the outlet of the barrel.

8. The syringe of claim 1 further comprising a plunger rod attached to said piston, said plunger rod movably extending through said seal, wherein the plunger rod, the piston and the seal divide the hole proximal to the piston into the first chamber, and the first chamber is fluidically connected to the first inlet and the microfluidic mixer, and The plunger rod, the piston and the seal divide the hole on the proximal side of the piston into the second chamber, and the second chamber is fluidically connected to the second inlet and the microfluidic mixer.

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

10. The syringe of claim 8, wherein the plunger rod extends through an engagement portion of the seal, wherein the engagement portion has a complementary shape relative to a shape of the plunger rod to prevent rotation of the plunger rod within the barrel.

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

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

13. The syringe of claim 1, wherein the first inlet and the second inlet define respective Luer locks.

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

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

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

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

18. A method of producing a particle-based formulation in a syringe, the method comprising: connecting a first fluid source to a first inlet of the syringe and connecting 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 via the first inlet, and to draw a second fluid from the second fluid source into a second chamber of the barrel via the second inlet, the first chamber and the second chamber being each located proximal to the piston; as well as The piston is displaced in a proximal direction to expel the first fluid from the first chamber and into a microfluidic mixer of the syringe, and the second fluid from the second chamber and into the microfluidic mixer of the syringe, thereby mixing the first fluid and the second fluid in the microfluidic mixer to produce the particle-based formulation.

19. The method of claim 18, wherein displacement of the piston in the proximal direction expels the particle-based formulation out of the microfluidic mixer and into a third chamber of the barrel distal to the piston.

20. The method of claim 18, further comprising: The piston is displaced again toward the distal direction to expel the particle-based formulation out of the outlet of the barrel.

21. The method according to claim 20, further comprising: A needle is attached to the outlet of the barrel before displacing the piston again towards the distal direction.

22. The method of claim 18, further comprising: The tip cap is removed from the outlet of the barrel after displacing the piston in the proximal direction.

23. The method of claim 18, further comprising: 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; as well as A first plug is connected to the first inlet and a second plug is connected to the second inlet.

24. The method of claim 18, wherein the first fluid comprises lyophilized mRNA and the second fluid comprises lyophilized lipid.

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