Adapter and method for mixing the components of a compound drug via the adapter

Abstract

It provides a consistent, safe and convenient method of mixing ingredients for injection. An adapter for connecting one or more storage containers to a syringe is described. The adapter includes a first port providing a connection with a first container volume, a second port providing a connection with a second container volume, and a third port providing a connection to a syringe. The adapter further includes a mixing channel extending from a first end to a second end in fluid communication with the third port. The mixing channel includes a serpentine path along at least a portion of its length. The mixing channel allows two components of a combination drug to mix through the mixing channel to form a combination drug. Also disclosed are systems including such adapters, methods of mixing two components of a combination drug through such adapters, and methods of manufacturing such adapters.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 251,880, filed Oct. 4, 2021, the disclosure of which is incorporated herein by reference.

[0002] (Field of the Invention) The present disclosure relates to an adapter for connecting one or more storage containers to a syringe, a system comprising such an adapter, a method of mixing components of a composite drug via such an adapter, and a method of manufacturing such an adapter.

Background Art

[0003] Recent developments in immunology include newly approved messenger RNA - lipid nanoparticle (mRNA - LNP) vaccines. Messenger RNA (mRNA) technology has the advantage that it does not require a complete re - evaluation of the Chemical & Manufacturing Control (CMC) of vaccine production and can quickly adapt to new antigen designs by changing the mRNA sequence. However, mRNA provided alone is not readily absorbed or effectively delivered to human immune cells and has unstable chemical and physical properties and is thus not effective for use as a vaccine. Recent developments have shown that when mRNA is encapsulated within a lipid nanoparticle (LNP) vector, the absorption and stability of mRNA can be increased to effective levels.

[0004] The preparation of mRNA - LNP vaccines is achieved by mixing ethanol - dissolved lipids with RNA in water under tightly controlled conditions. Such mixing is often performed in a laboratory using equipment that is often inappropriate for large - scale distribution (e.g., due to their low durability, high cost, high complexity, low consistency between lots and / or large variability between batches).

[0005] mRNA-LNPs have a limited shelf life at room temperature. Therefore, to extend their shelf life, mRNA-LNP vaccines must be stored at extremely low temperatures (typically -20 to -80 degrees Celsius). This presents a problem because cryogenic distribution is expensive and difficult to transport. In addition, there is a risk that mRNA-LNP vaccines will be discarded if, for example, the cryogenic environment at any stage of the distribution network becomes unusable.

[0006] Non-messenger RNA drugs, such as RNAi, siRNA, and other oligonucleotides, are also known and can be formed into lipid nanoparticle compositions (RNA-LNPs). RNA-LNP drugs can be chemically modified to improve their stability and shelf life at room temperature (such chemical modifications are not possible with mRNA-LNP technologies, which require interaction with cellular proteins to function properly). Chemical modification of RNA-LNPs can be difficult and expensive to achieve, but is nevertheless often preferred to avoid the significant distribution costs associated with unmodified RNA-LNP drugs, which must also be kept at very low temperatures, as well as the difficulties associated with managing drug efficacy over time due to their limited molecular half-life.

[0007] In short, the low-temperature requirements for mRNA-LNPs and RNA-LNP drugs present a major challenge for their distribution and development.

[0008] Other problems associated with known systems for generating nanoparticle compositions include limitations in scale, utility, and / or reliability. Repeated stirring of bulk RNA and lipid fluid mixtures using pipettes or syringes is known to result in mRNA-LNP (or RNA-LNP) formation. However, such systems are often difficult to use effectively, consistently, and efficiently. Reliably obtaining mRNA and RNA lipid nanoparticle compositions on a sufficient scale and efficiently remains a challenge. [Overview of the Initiative]

[0009] One general aspect of the present invention relates to an adapter. The adapter includes a first port configured to connect to a first vessel, a second port configured to connect to a second vessel, and a third port configured to connect to a third vessel. The adapter may further include a mixing channel extending from the first end to the second end, which is in fluid communication (i.e., capable of allowing fluid to flow) to the third port, and the mixing channel may include a meandering path along the longitudinal axis of the adapter.

[0010] The adapter's implementation may include one or more of the following features: An adapter in which the mixing channel is a microfluidic channel. The mixing channel may include dimples. The mixing channel may include a cylindrical path, and the dimples extend radially outward into the body of the adapter beyond the path. A meandering path extends in and out of the dimples and path along the longitudinal axis. The dimples surround the path. The dimples are arranged as a collection of dimples extending along the longitudinal axis. Each collection of dimples includes two circumferential rows of dimples that are angularly offset from each other around the longitudinal axis of the adapter. The mixing channel has an internal dimension of 20 to 200 μm. The mixing channel may include a constriction, which is a portion of the mixing channel having a smaller internal dimension than the preceding and / or succeeding portions of the mixing channel. The adapter may include a first through channel connecting a first port to the mixing channel, and a second through channel connecting a second port to the mixing channel. The meandering path is configured to induce localized changes in the direction of the fluid flow as it moves through the mixing channel. The adapter may include a one-way valve connected to a second port. The third port is configured to communicate with a third vessel in two directions. The third port may include at least one of a rubber diaphragm configured to be punctured by a needle, or a fitting configured to attach the third vessel to the third port, the fitting being a Luer taper fitting if necessary. The mixing channel may include at least one bend between the continuously connected channel portions, the angle between the continuously connected substantially straight channel portions being at least one of less than 120 degrees, less than 100 degrees, 90 degrees, or less than 90 degrees. The at least one bend may include one of a square joint between the continuously connected channel portions, a triangular joint between the continuously connected channel portions, or a sawtooth joint between the continuously connected channel portions. At least one bend may include at least one of two bends, four bends, ten bends, or more than ten bends. A mixed channel may include 40 or fewer bends.The adapter may include multiple mixing channels, each mixing channel connecting a first and second passage channel to a third port. The adapter may include further first and second passage channels, each connecting to the third port via a mixing channel. The third container is a syringe. The first and second containers are constant-volume containers. The first container holds an organic compound in at least 25% alcohol, the organic compound may be a lipid if necessary. The second container holds lyophilized anhydrous RNA. The first and second containers are detachably connected to the first and second ports, respectively. The third container is a syringe connected to the third port, the syringe holding a buffer.

[0011] Another general aspect of the present disclosure includes a method for mixing two components of a compound drug via an adapter. The adapter includes a first port connected to a first container holding a first component of the two components, a second port connected to a second container holding a second component of the two components, a third port configured to be connected to a syringe, a mixing channel extending from a first end to a second end and in fluid communication with the third port, a first through channel connecting the first port to the mixing channel, and a second through channel connecting the second port to the mixing channel, the mixing channel may include a meandering path along the longitudinal axis of the adapter. The method includes the steps of connecting a syringe, which may include a plunger, to the third port, and pulling the plunger. By pulling the plunger, the first component is drawn from the first container into the first through channel, and the second component is drawn from the second container into the second through channel. When the plunger is pulled, the first and second components are further drawn into the syringe through the mixing channel.

[0012] The implementation may include one or more of the following features: a method in which the first component is an organic compound in at least a 25% alcohol solution and the second component is an anhydrous pharmaceutical product; and when the plunger is pushed down, at least a portion of the aqueous buffer is transferred into the second container. The method may also include the steps of connecting the first container to the first port and connecting the second container to the second port, before connecting the syringe to the third port.

[0013] Another general aspect of the present disclosure includes a method for manufacturing an adapter. The method includes the step of forming a first recess in a first polymer component. The method also includes the step of fusing the first polymer component to a second polymer component such that the first recess defines a mixing channel extending from a first end to a second end. The mixing channel may include a meandering path along the longitudinal axis of the adapter.

[0014] The implementation configuration may include one or more of the following features: A manufacturing method which may include a first discontinuous depression. The method may further include the step of forming a second discontinuous depression in a second polymer component. The step of fusing the first polymer component to the second polymer component may include the step of offsetting the first discontinuous depression and the second discontinuous depression relative to each other so that the second discontinuous depression defines a mixing channel. The manufacturing method may include the step of offsetting the first polymer component and the second polymer component by 100 to 200 μm. The first discontinuous depression and the second discontinuous depression are formed by injection molding or compression molding. [Brief explanation of the drawing]

[0015] Specific embodiments of this disclosure are described in the following detailed description with reference to the accompanying drawings, merely as examples. [Figure 1A] This figure shows a cross-sectional view of an exemplary system as described in this disclosure. [Figure 1B] This figure shows a cross-sectional view of another exemplary system as described in this disclosure. [Figure 1C]A diagram showing how the mixed channel of FIG. 1A is formed according to the first method. [Figure 1D] A diagram showing how the mixed channel of FIG. 1B is formed according to the second method. [Figure 1E] A diagram showing another method of forming a mixed channel according to the present disclosure. [Figure 1F] A diagram showing yet another method of forming a mixed channel according to the present disclosure. [Figure 2A] A diagram showing a first example of a mixed channel from an adapter according to FIG. 1A or FIG. 1B. [Figure 2B] A diagram showing a second example of a mixed channel from an adapter according to FIG. 1A or FIG. 1B. [Figure 2C] A diagram showing a third example of a mixed channel from an adapter according to FIG. 1A or FIG. 1B. [Figure 2D] Shows a fourth example of a mixed channel from an adapter according to FIG. 1A or FIG. 1B. [Figure 2E] Shows a fifth example of a mixed channel from an adapter according to FIG. 1B. [Figure 2F] Shows a sixth example of a mixed channel from an adapter according to FIG. 1B. [Figure 3] A diagram showing a second end of a mixed channel according to any of FIGS. 2A - 2C, coupled to a first container and a second container according to FIG. 1A or FIG. 1B. [Figure 4] A diagram showing a third port of an adapter according to FIG. 1A or FIG. 1B, connected to a syringe. [Figure 5A] A flowchart showing an exemplary method of mixing components of a compound drug using an adapter according to FIG. 1A or FIG. 1B. [Figure 5B] A flowchart showing another exemplary method of mixing components of a compound drug using an adapter according to FIG. 1A or FIG. 1B. [Figure 6A] A diagram showing the operation of the system of FIG. 1A in response to the plunger of the syringe being pushed down. [Figure 6B]A diagram showing the operation of the system of FIG. 1A in response to pulling the plunger of the syringe. [Figure 7] A flowchart showing an exemplary manufacturing method of an adapter according to FIG. 1A or FIG. 1B. [Figure 8] A diagram showing an exemplary core pin used to manufacture an adapter according to the present disclosure. [Figure 9] A diagram showing an exemplary integrated adapter according to the present disclosure. [Figure 10] A diagram showing a perspective view of an adapter according to the present disclosure. [Figure 11A] A diagram showing a top view of the adapter of FIG. 10. [Figure 11B] A diagram showing a cross-sectional view of the adapter of FIG. 11A. [Figure 11C] A diagram showing an enlarged view of a region of the adapter of FIG. 11B. The same reference numerals are used for similar components throughout the drawings.

MODE FOR CARRYING OUT THE INVENTION

[0016] FIG. 1A shows a system 100a for mixing the contents of two containers 104, 106 by an adapter 102a and a container 108 (e.g., a syringe). FIG. 1B shows a system 100b for mixing the contents of two containers 108, 106 by another adapter 102b and a container 104.

[0017] FIG. 1A shows an adapter 102a connected to a first container 104, a second container 106, and a third container 108. The containers 104, 106 and / or the third container 108 can be connected to the adapter 102a when the container and / or syringe is in fluid communication with the adapter 102a. The adapter 102a further includes a mixing channel 120a having a first end in fluid communication with the third container 108 and a second end in fluid communication with the first container 104 and the second container 106.

[0018] The adapter 102a in Figure 1A can be formed from two fused parts 110a and 112a, each of which may be a polymer or glass part. Alternatively, the adapter 102a may be formed as a single, integrated part, for example, by injection molding or 3D printing. To enhance the ease with which the fluids to be mixed flow through the adapter, a low surface energy material can be used for at least a portion of the adapter. For example, parts 110a and 112a can be formed or coated with a low surface energy material such as ethylene tetrafluoroethylene (ETFE). Other low surface energy materials, such as fluoropolymer materials other than ETFE, may also be used. Alternatively, the surfaces of parts 110a and 112a that form the inner surface of the mixing channel can be treated to reduce the surface energy of the walls of the mixing channel. While low surface energy materials may offer additional advantages in some embodiments, they are merely optional features for the inventions of this disclosure.

[0019] In adapter 102a of Figure 1A, the mixing channel 120a can be defined by a recess formed (e.g., by molding or engraving) in one or both of parts 110a and 112a. Figure 1C shows an arrangement in which the mixing channel is formed by creating a recess 111 in one of parts 110a, 112a. This arrangement can be used to form the system shown in Figure 1A. As shown in Figure 1C, the recess 111 can be formed in only one of parts 110a, 112a, where the recess 111 takes the form of an open channel in part 110a. The other part (here 112a) does not contain a channel. Instead, part 112a has a substantially flat surface, and when part 112a is stacked on and sealed (or fused) with part 110a, the open channel is closed to form the mixing channel shown in Figure 1A. The recess can be molded as a channel as shown in any one of Figures 2A-2D.

[0020] Figure 1B shows an embodiment of 102b connected to the first container 104, the second container 106, and the third container 108. Similar to adapter 102a in Figure 1A, adapter 102b includes a mixing channel 120b (circularly shown) having a first end that fluidly communicates with the third container 108b and a second end that fluidly communicates with the first container 104 and the second container 106.

[0021] The adapter 102b in Figure 1B can also be formed from two parts 110b and 112b fused together, each of which can be a polymer or glass part. However, in contrast to the adapter 102a in Figure 1A, the mixing channel 120b can be defined by a series of depressions (e.g., made by molding or engraving) in each of the parts 110b and 112b. These depressions form a continuous channel when the two parts 110b and 112b are fused together, and the channel is offset from one another so that it comprises the mixing channel. In some embodiments, the depressions may be discontinuous. In addition, or instead, some or all of the depressions may be formed in a continuous pattern. Figure 1D shows an arrangement in which the mixing channel is formed by generating discontinuous depressions 111a, 111b in each of the parts 110b and 112b.

[0022] As shown in Figure 1D, the depressions may include a series of discontinuous depressions or grooves, which form broken open channels in each of the parts 110b and 112b. Each of the broken channel segments is offset from, but overlaps with, the corresponding broken channel segment on the other part. In this way, when the first and second parts are joined together, the discontinuous channel segments of the first and second parts 110b and 112b are in fluid communication with each other to form a meandering mixed channel, as shown in Figure 1B. Meandering, as used herein, can have a simple and ordinary meaning and may be used to describe a mixed channel that includes a path that changes direction itself, or a feature (e.g., a dimple in Figure 2F) that deviates from the path so that some or all of the fluid changes direction. An example of such offset depressions is shown in Figure 2E, which will be described in more detail later.

[0023] Two further methods for forming an adapter from the first and second components are schematically shown in Figures 1E and 1F.

[0024] The configuration shown in Figure 1E is similar to the configuration shown in Figure 1D, in that a discontinuous recess 111a' is formed in the first component 110b' and a second discontinuous recess 111b' is formed in the second component 112b'. Rather than a broken channel (as shown in Figure 1D), the configuration in Figure 1D includes multiple adjacent but spaced-out recesses. The recesses in the first component are offset from the recesses in the second component, and when the components are sealed together, the recesses in the first component overlap with the recesses in the second component, enabling continuous fluid communication through the channel formed in the completed adapter.

[0025] The configuration shown in Figure 1F differs from the configurations shown in Figures 1C to 1E. In the configuration shown in Figure 1F, discontinuous recesses 111a'' and 111b'' are formed in parts 110b'' and 112b'', respectively. However, each discontinuous recess is in the form of a square or U-shaped channel segment with closed ends. The segments are offset from each other so that when the first and second parts are sealed together, the channel segments on the opposing parts are in fluid communication with each other and thus form a meandering path through the adapter. Note that in the embodiment shown in Figure 1F, the fluid flow path extends in two planes, and the U-shaped segments provide a channel segment extending in the first plane, while the overlapping portion of the segments provides an extension of the mixing channel extending in the second plane perpendicular to the first plane. This can further improve mixing by providing a more meandering path for the fluid to travel as it moves through the mixing channel.

[0026] Figures 1C to 1F show adapter structures in which two components are sealed together in an opposing relationship, but it will be understood that three or more components may be used. Furthermore, one or both of the components may be coated, for example, with a film so that at least one (or two or more, if necessary) layer of the film is placed between the first and second components. Advantages of applying one or more layers of film include a reduction in surface energy within the mixing channel, improved sealing of the first and second components, and / or deactivation of the inner surface of the mixing channel.

[0027] The method for forming adapters 102a and 102b will be described in more detail later with reference to Figure 7.

[0028] Returning to Figures 1A and 1B, the functionality of the mixing channel 120b of adapter 102b is substantially the same as that of the mixing channel 120a of adapter 102a. In particular, both mixing channels 120a and 120b are positioned to generate turbulence in the fluid flowing through them. Descriptions of mixing capacity, function, input, output, etc., apply equally to mixing channels 120a and 120b. The following description refers to adapter 102a, but it applies equally to adapter 102b and should be read as such.

[0029] Adapter 102a can be configured to connect to multiple containers, such as two or three or more containers. Therefore, any reference to two containers in this specification should be interpreted as including three or more containers. Each container 104, 106 may be a vial suitable for storing a drug or component of a compound drug. For example, the first container 104 may store an RNA component (such as an mRNA component, siRNA component, RNAi component, or microRNA component), and the second container 106 may store an alcohol-soluble (e.g., ethanol-soluble) lipid component to be mixed with the RNA component. Any reference to RNA or mRNA in this specification should be interpreted as meaning any type of RNA, including those outlined above. Containers 104, 106 are connected to adapter 102a at their respective container ports 114 and 116 (sometimes referred to herein as the first port 114 and the second port 116). In other words, the first container 104 is connected to the first port 114 of the adapter 102a, and the second container 106 is connected to the second port 116 of the adapter 102a.

[0030] Furthermore, ports 114 and 116 can be configured to allow temporary or detachable connection to the respective vessels 104 and 106. For example, one or both of the first port 114 and the second port 116 may have threaded ports, and the openings of the first vessel 104 and / or the second vessel 106 may have corresponding threads, so that the respective vessels can be connected to the ports or arranged to be in fluid communication with the ports by engaging the threaded ports with the threads of the corresponding openings. It will be understood that one or both of the first port 114 and the second port 116 may have a detachable coupling mechanism as described in International Publication 2011 / 077434. The disclosure of International Publication 2011 / 077434 is incorporated herein by reference. Since the adapter 102a can be configured to connect to any number of vessels in some embodiments, the adapter may accordingly have the same number of ports as the vessels for connecting to each of the vessels. Furthermore, one or more ports may include one-way valves positioned to allow fluid flow into the adapter and to restrict or substantially prevent fluid flow from the adapter. The ports for connecting the adapter to each container will be described in more detail below with respect to Figure 3.

[0031] Returning to Figure 1A, the container 108 may be any type of medical syringe, or any type of reciprocating pump or container suitable for containing a compound drug. The container 108 can be connected to the adapter 102a through a third port 118 of the adapter 102a (hereinafter referred to as the "syringe port" or simply the "port"). In most embodiments, the third port 118 is configured to provide a temporary or removable connection between the container 108 and the adapter 102a, and in some embodiments, the third port 118 of the adapter 102a may allow bidirectional fluid communication with the syringe. An exemplary third port 118 includes a rubber diaphragm configured to be punctured by a needle or a Luer-lock tapered fitting. The third port is described in more detail below with respect to Figure 4.

[0032] Continuing to refer to Figure 1A, the adapter 102a includes a mixing channel 120a extending from a first end that fluid-communicates with the third port 118 to a second end that fluid-communicates with the first port 114 and the second port 116. In some embodiments, multiple mixing channels may be provided, if necessary, in parallel, each enabling fluid communication from the third port 118 to the first port 114 and the second port 116. Providing multiple mixing channels has the advantage of increasing the overall throughput of the adapter.

[0033] The mixing channel 120a is configured to facilitate the mixing of the fluid flowing through the mixing channel by inducing turbulence within such fluid. The mixing channel 120a includes a meandering path. The meandering path may include, for example, baffles, bends, curves, depressions, dimples, or a combination thereof, to generate turbulence in the fluid flowing through the channel. Figures 2A-E depict the geometric shape, dimensions, configuration, and function of an exemplary mixing channel.

[0034] Referring to Figure 1A, the mixing channel 120a does not necessarily have direct fluid communication with the first port 114 or the second port 116. Rather, the mixing channel 120a can have fluid communication with the first port 114 and the second port 116 via the first through channel 122 and the second through channel 124, respectively. That is, the first through channel 122 may extend from the second end of the mixing channel 120a to the first port 114, and the second through channel 124 may extend from the second end of the mixing channel 120a to the second port 116. The through channels will be described in more detail below with reference to Figure 3.

[0035] Possible uses of system 100a in Figure 1A and system 100b in Figure 1B are for mixing the components of a compound drug for the formation of a compound drug. Here, the components are in a state that can be stored at room temperature and may be provided in separate containers 104, 106. Embodiments of adapters 102a and 102b have two connector ports 114 and 116 and are therefore suitable for mixing two such components. When three or more components are to be mixed, it is understood that three or more containers may be provided, each of which may contain at least one component. Adapters having three or more container ports may be used in such situations as well. Furthermore, any number of components can be provided in an unmixed state in a single container.

[0036] To mix the components, a first container 104 and a second container 106 are connected to a first port 114 and a second port 116, respectively, and a container 108 (e.g., a syringe) is connected to a third port 118. In embodiments where container 108 is a syringe, the plunger of the syringe can be pulled to induce a pressure difference at the orifice (inlet) of container 108. This pressure difference extends from the orifice of the third container 108 at the first end of the mixing channel 120a to the second end of the mixing channel 120a to which the first container 104 and the second container 106 are fluidly connected. As a result, when the plunger is pulled, the components are drawn out of the first container 104 and the second container 106, enter the mixing channel 120a through the first and second through channels 122, 124 (if present), enter the third port 118 through the mixing channel, and enter the third container 108. When the components collectively pass through the meandering mixing channel, turbulence is induced in the fluid flow, and therefore the components transition from a non-mixed state to a mixed state. As a result, the complex drug is formed by the components collectively passing through the mixing channel 120a.

[0037] In some embodiments, at least one of the components can be contained in a container in a storage state, such as lyophilized, solid, or otherwise in a stable state suitable for medium- or long-term storage. The component can then be reconstituted from its stored state to its prepared state by filling the third container 108 with a reconstituter (such as an aqueous buffer or neutralizer) before connecting the third container 108 to the third port 118, and by pushing in the plunger of a syringe before pulling the plunger of the third container 108 as described above, thereby transferring the reconstituter to the container containing the stored component. This reconstitutes the stored component with the reconstituter, achieving the prepared state of the component. The prepared state is a state in which the component is mixable in a mixing channel or otherwise ready for final use in a compound drug. In these embodiments, a port not connected to a container containing the component in its stored state may include a one-way valve configured to prevent the reconstituter from passing through the port when the plunger of the syringe is pushed in.

[0038] Next, the plunger of the syringe (i.e., the third container 108) can be pulled, drawing the prepared components from the first container 104 and the second container 106 into the mixing channels 120a and 120b, respectively, and through the mixing channels 120a and 120b into the third container 108. Turbulence is induced in the mixture as the prepared components pass through the mixing channels, which may have the effect of transferring the solution from a mixture of components to a compound drug. In other embodiments, the first container 104 and the second container 106 may be syringes, one of which contains the prepared components. Mixing can be induced in a similar manner within the mixing channels 120a and 120b, but the force driving the fluid may arise from simultaneously pushing the plungers of the syringes forming the first container 104 and the second container 106.

[0039] Therefore, the systems 100a and 100b in Figures 1A and 1B can be used to form an RNA-LNP (e.g., mRNA-LNP) complex that can be readily injected by mixing RNA and lipid components dissolved in ethanol via the methods outlined above. Here, the RNA is provided in the first container 104 either in storage condition (e.g., lyophilized RNA or mRNA, or in solution, e.g., RNA or mRNA in aqueous solution) or in a prepared condition, and the ethanol-soluble lipids are provided in the second container 106.

[0040] An exemplary method of using adapter 102a will be described in more detail below with reference to Figures 5, 6A, and 6B.

[0041] Figures 2A to 2E show exemplary embodiments of mixing channels in adapters according to the present disclosure in side views. The mixing channels in Figures 2A to 2D are located within the adapter 102a of Figure 1A and include a meandering path that meanders in a plane parallel to the interface between the first component 110a and the second component 112a. The mixing channel in Figure 2E is located within the adapter 102b of Figure 1B and includes a meandering path that meanders in a plane perpendicular to the interface between the first component 110b and the second component 112b. The mixing channel in Figure 2F forms a meandering path located within the adapter 102b of Figure 2B, allowing fluid to flow into and out of the path of the mixing channel 120b. The cross-section of the mixing channel (i.e., perpendicular to the diagrams shown in Figures 2A to 2E) may be substantially any shape, such as circular, square, or rectangular.

[0042] Each mixing channel has a path along which a fluid (typically a liquid) can flow. The path is a meandering path containing many bends 202a, 204a, 202b, 204b, 202c, 204c, 202d, 204d, 202e, 204e. As the fluid passes through the bends, a local change is induced in the direction of the fluid flow. Thus, as the fluid passes through the bends, the degree of turbulence in the fluid flow (i.e., the Reynolds number) increases. As the degree of turbulence increases, the flow parallelism between the components of the fluid decreases, and therefore the degree of mixing can be increased. As a result, increasing the turbulence of the fluid in the mixing channel can promote the mixing of the components of that fluid.

[0043] The degree to which turbulence increases upon passage through a bend depends on the geometry of the bend. Therefore, the geometry of the bend can be selected according to the degree of turbulence required to achieve the mixing ratio required for any given adapter application. Sharp bends, such as those shown in Figures 2A-2C and 2E (defined herein as bends with discontinuous gradients forming an angle, or bends with a small radius of curvature (e.g., about the same as the channel width), or bends with a large deviation from the direction of the bend relative to the distance projected in the direction before the bend), cause a greater increase in turbulence than smooth bends (such as those with a continuous gradient as shown in Figure 2D). Therefore, the sharper the bend, the greater the increase in turbulence at the bend, and the smoother the bend, the smaller the increase in turbulence at the bend. In one configuration, the angle can change by 90 degrees over a distance of 10 μm or less at a bend between adjacent channel sections. Similarly, the angle of the bend (i.e., the angle between continuously connected, substantially straight channel sections) influences the increase in turbulence across the bend, and bends with smaller angles (such as the 90-degree joints 202a, 204a or the acute joints 202b, 204b depicted in Figures 2A and 2B) can promote turbulence more effectively than bends with larger angles (such as the obtuse-angle bends of joints 202c, 204c, 202d, and 204d depicted in Figures 2C and 2D). A channel section can be said to be substantially straight when it has a curvature close to zero.

[0044] Therefore, for applications where a higher degree of turbulence is required to achieve the desired mixing (e.g., when lipid nanostructures are formed), steeper and / or tighter angle bends can be selected. Conversely, for applications where only a low degree of turbulence is required to achieve the desired mixing, or where small flow fluctuations are required to maintain specific physical properties of the components during mixing, blunter and / or gentler angle bends can be selected. Additionally, blunter bends can be selected for ease of manufacture, as they are easier to produce more consistently. Suitable bend angles include any bend angle of 120 degrees or less.

[0045] A single bend is unlikely to provide a sufficient increase in turbulence to transition the fluid flow from a completely laminar state to a completely turbulent state. In other words, a single bend is unlikely to provide a sufficient increase in turbulence to transition the fluid from a non-mixed state to a desired mixed state. Therefore, a mixing channel includes multiple bends, each of which slightly increases the turbulence of the fluid. In this way, the turbulence increases significantly throughout the mixing channel, making it possible for the fluid to transition from a non-mixed state to a mixed state. The more bends there are, the greater the degree of mixing across the mixing channel. However, as the number of bends increases, so does the resistance to the fluid flow through the mixing channel. Therefore, the number of bends is selected to achieve the desired degree of mixing while avoiding resistance that makes it impossible to move the syringe by hand. With this in mind, in one implementation, the inventors have found that an arrangement of 10 to 40 bends is particularly useful for generating mRNA-LNP or RNA-LNP compositions. However, as the reader will understand, different numbers of bends may be used depending on the circumstances.

[0046] In some embodiments, the sides of the mixing channel contain or are coated with a low surface energy material, such as a low surface energy polymer or low surface energy glass, to ensure low bonding between the fluid in the mixing channel and the sides of the mixing channel. An example of a suitable material for at least the inner wall of the mixing channel is ETFE. Forming the sides of the mixing channel with a low surface energy material can reduce the loss of components across the mixing channel during use. This can therefore allow the adapter to operate more efficiently.

[0047] The mixing channel is a microfluidic path designed to reduce the influence of volume forces on fluid flow. Furthermore, the microfluidic path can increase the velocity of the fluid flowing through the mixing channel (compared to paths with larger cross-sectional areas), thereby further improving mixing. Higher fluid velocities through the mixing channel result in greater induced turbulence, and therefore, a higher degree of turbulence induced across the mixing channel. The velocity also depends on the force pulling the syringe plunger.

[0048] In at least some embodiments, the microfluidic path may include one or more constrictions 220, 222, 224, 226 having smaller cross-sectional areas than the microfluidic channel portions on either side thereof (in other words, the preceding channel portion and the succeeding channel portion). The constrictions can increase the fluid velocity through which the fluid passes, further improving mixing. The microfluidic path may include one or more constrictions.

[0049] Therefore, the fluid path may include internal dimensions (or, if the mixing channel has a circular cross-sectional area, the inner diameter) of 10 μm to 1 millimeter or less, and if necessary, 200 μm to 800 μm, 400 μm to 600 μm, 600 μm to 700 μm, or 20 μm to 100 μm. At these scales, the effect of bends on fluid turbulence, especially the effect of sharp bends, can be amplified, and mixing is increased compared to fluid paths with larger internal dimensions.

[0050] As described above in relation to Figures 1A and 1B, it is conceivable that adapters 102a and 102b may have multiple mixing channels. Using multiple mixing channels can increase the total volume, flow rate, and throughput of fluid that adapters 102a and 102b can handle as a whole. Each mixing channel within the multiple mixing channels may be provided in parallel and with substantially the same geometry. Alternatively, each mixing channel may have a different geometry or configuration.

[0051] As depicted in Figure 2A, the mixed channel may comprise a series of steep, square (i.e., 90-degree) joints 202a, 204a between continuously connected, substantially straight channel portions 206a, 208a. A joint can be considered steep if, for example, it includes a discontinuous gradient in a curved section. Each of the joints in Figure 2A is connected at an angle θa, where θa is equal to or substantially equal to 90 degrees.

[0052] In the embodiment shown in Figure 2A, a continuously connected, substantially linear channel section includes a lateral section 206a with length Ya extending vertically and a longitudinal section 208a with length Xa extending horizontally. The lateral section 206a and the longitudinal section 208a alternate positions. The values ​​of Xa and Ya may be substantially equal or different. Typically, Xa and / or Ya may be 100 to 200 μm, and Xa may be shorter than Ya to allow for further turbulence as the channel cross-sectional area changes. In other embodiments, Ya may be shorter than Xa to achieve a similar effect.

[0053] Each mixing channel may have a constant internal dimension (e.g., the inner diameter of the cross-section or the width inside it), but preferably, it has at least two alternating internal dimensions such that the cross-sectional area of ​​the channel changes along its length. For example, a portion of length Xa may have an internal dimension dXa, and a portion of length Ya may have an internal dimension dYa. Preferably, dXa is less than dYa. For example, the internal dimension dXa can be about 50 μm or less, and dYa can be about 100 μm or less. dXa and / or dYa may be 20 μm or more. By having at least two alternating internal dimensions in the mixing channel, the fluid flowing through the mixing channel repeatedly accelerates and decelerates. Thus, a further degree of turbulence is induced across the channel.

[0054] As shown in Figures 2B and 2C, the mixed channel may include a series of sharp or sharp obtuse angle joints 202b, 204b, 202c, and 204d between continuously connected substantially straight channel portions. In these embodiments, the continuously connected substantially straight channel portions may have the same or substantially the same dimensions as Xa and Ya described above.

[0055] As shown in the illustration, the embodiment in Figure 2B has sawtooth joints 202b, 204b between continuously connected substantially straight channel portions. Each of these joints connects the continuous substantially straight channel portions at an angle θb, where θb is less than 90 degrees.

[0056] As illustrated, the embodiment in Figure 2C has triangular joints 202c, 204c between associated, continuously connected, substantially straight channel portions. Each of these joints connects the continuous, substantially straight channel portions at an angle θc, where θc is greater than 90 degrees and less than 120 degrees.

[0057] Figure 2D shows an exemplary mixed channel including a series of smooth joints 202d, 204d, distinct from the abrupt joints of Figures 2A-2C. A joint may be considered smooth if, for example, there are substantially no discontinuities in the joint's gradient (or unless the joint is considered abrupt). Each of these smooth joints connects substantially straight channel portions that are continuous at an angle θd, where θd may be less than 90 degrees, 90 degrees, or less than 120 degrees.

[0058] Similar to the embodiment shown in Figure 2A, the mixing channels in Figures 2B to 2D may have a constant internal dimension, but preferably each has at least two alternating internal dimensions db1 and db2, dc1 and dc2, and dd1 and dd2. For example, in some embodiments, the internal dimensions db1, dc1, and dd1 may be 100 μm or less, and db2, dc2, and dd2 may be 100 μm or more.

[0059] Figure 2E illustrates an example of a mixing channel used in the adapter of Figure 1B (however, the adapter of Figure 1B is not limited to this). This mixing channel is formed by the fusion of parts 210 and 212 at the interface 214. Part 210 includes a series of discontinuous depressions 216 formed on its surface, and part 212 includes a series of discontinuous depressions 218 formed on its surface. When the surfaces of parts 210 and 212 are joined together, a series of fluid-connected internal cavities offset along the interface 214 are obtained, as shown in Figure 2E, thereby forming a mixing channel. The depressions 216 have a depth equal to or substantially equal to Ye1. The depressions 218 have a depth equal to or substantially equal to Ye2. Similarly, each of the depressions 216 and 218 may have a width equal to or substantially equal to Xe, where Xe may be 100 to 200 μm. Ye1 and Ye2 may be substantially the same as each other and may be 50 to 100 μm in size. In other embodiments, the dimensions of Xe, Ye1, and Ye2 may be variable along the length of the mixing channel, for example, to form a constriction.

[0060] In the embodiment shown in Figure 2E, the fluid path defined by the mixing channel is formed by shifting each series of discontinuous depressions by an offset amount Δ, thereby forming the internal dimension de of the mixing channel. For example, Δ can be 20 to 200 μm. In the embodiment, depressions 216 and 218 may be rectangular or form a herringbone pattern.

[0061] Figure 2F shows an example 120b of a mixing channel used in the adapter 102b of Figure 1B (however, the adapter in Figure 1B is not limited thereto). The mixing channel 120b may include several dimples 230. The dimples 230 may be formed in the body of the adapter 102b. For example, the dimples 230 may be formed in parts 210 and 212. The mixing channel 120b may include a path 232 extending along the longitudinal axis of the adapter 102b. The path 232 may be cylindrical and may have a diameter 234. In embodiments, the diameter 234 is 10 μm to 1 mm or less, and may be 200 μm to 800 μm, 400 μm to 600 μm, 600 μm to 700 μm, or 20 μm to 100 μm if necessary. Alternatively, the diameter 234 may be 0.3 mm or more. The diameter 234 may be constant along the longitudinal axis of the adapter 102b, or it may vary along the longitudinal axis of the adapter 102b. The diameter of the dimple 230 is, for example, less than 400 μm, and may be 280 μm to 325 μm if necessary. The dimple 230 protrudes from the path 232. Since the dimple 230 is recessed toward the body of the adapter 102b, it extends radially outward beyond the path 232. The dimple 230 is divided into two sets 230a and 230b along the longitudinal axis of the adapter 102b. Each of the sets 230a and 230b has a length of approximately 700 μm along the longitudinal axis of the adapter 102b. Each of the sets 230a and 230b contains at least two rows of circumferentially aligned dimples 230. Between these two rows of dimples 230, there is an angle difference around the longitudinal axis of the adapter 102b.

[0062] In embodiments, the dimples 230 can extend radially outward beyond the diameter 234 of the path 232. Therefore, with this configuration, the fluid flowing through the path 232 can follow meandering paths extending both inside and outside the dimples 230 and the path 232. Thus, by constructing an obstruction shape for the fluid using the path 232 and the dimples 230, turbulence can be intentionally generated, allowing for the mixing of materials forming the fluid flowing through it. The size, shape, orientation, location, and pattern of this obstruction shape for the fluid can be adjusted so that the turbulence pattern follows a predictable pattern. In embodiments, the dimples 230 can be formed along the entire length of the path 232. In embodiments, the dimples 230 can be formed surrounding the path 232 (e.g., upward, downward, laterally, circumferentially, etc.). This configuration can improve mixing efficiency.

[0063] The mixing channel 120b can be formed by fusing parts 210 and 212 at the interface 214. Alternatively, the mixing channel 120b can be formed as a single part using 3D printing or injection molding, as described later in this specification.

[0064] Figure 3 shows the second end 300 of the mixing channel 302, and in particular, the connection between the mixing channel 302, the first container 304, and the second container 306. As the reader will understand, any of the mixing channels shown in Figures 2A to 2E may have a second end arranged as shown in Figure 3.

[0065] The second end 300 of the mixing channel 302 is coupled to the first port 308 and the second port 310 to allow fluid to flow back and forth. As shown in the figure, the first port 308 and / or the second port 310 are offset from the endpoint 318 of the second end 300. Each of the first port 308 and the second port 310 is configured to be connectable to the first vessel 304 and the second vessel 306. In this way, each of the first port 308 and the second port 310, when connected to the first vessel 304 and the second vessel 306, respectively, is configured to provide a conduit between the internal space of each vessel and the mixing channel 302 of the adapter. Thus, the first port 308 and the second port 310 can establish fluid communication between the first vessel 304, the second vessel 306, and the mixing channel 302, respectively.

[0066] The first port 308 and the second port 310 can be permanently attached to the first container 304 and the second container 306, in which case the first container 304 and the second container 306 may be provided with alternative inputs to allow refilling. Alternatively, the first port 308 and the second port 310 may be detachably or temporarily connected to the first container 304 and the second container 306, respectively. This allows the first container 304 and the second container 306 to be refilled or replaced from the outside, and / or the adapter to be reusable.

[0067] Removable or temporary connections can also be achieved by constructing the ports using any of the conventional mechanical fastening means. For example, the openings of the first port 308 and the second port 310 may be fitted with female threads, and the openings of the first container 304 and the second container 306 may be fitted with corresponding male threads. In this way, the female and male threads can be engaged to connect the first container 304 and the second container 306 to the first port 308 and the second port 310, respectively. As another example, the first port 308 and the second port 310 may be removablely connected to the first container 304 and the second container 306 by using a push-in coupling mechanism. These connections are maintained by friction between the outside of the opening of the first container 304 and the inside of the opening of the first port 308, and between the outside of the opening of the second container 306 and the inside of the opening of the second port 310. Preferably, the first port 308 and the second port 310 include, for example, a vented vial adapter disclosed in U.S. Patent No. 8,753,325. This adapter facilitates the extraction of fluid from the vial into the system by drawing air into the vial. The disclosure of U.S. Patent No. 8,753,325 is incorporated herein by reference.

[0068] At least one of ports 308, 310 may further comprise a one-way valve 312. The one-way valve can be any valve suitable for allowing fluid to flow from the second vessel 306 to the mixing channel 302, while restricting or substantially preventing fluid from flowing in the opposite direction. The advantage of including a one-way valve 312 in at least one port is that it prevents the reconstituter from entering a vessel that does not contain the stored components, as will be discussed in relation to Figures 1A and 1B above and Figures 5 and 6A below.

[0069] If necessary, the second end 300 of the mixing channel 302 may further comprise a first through channel 314 and a second through channel 316 extending into the mixing channel 302 from the first port 308 and the second port 310, respectively. Each of the through channels 314, 316 provides a conduit for fluid communication between each of the ports 308, 310 and the mixing channel 302. The first through channel 314 includes a first end at the first port 308 and a second end fluidly connected to the mixing channel 302. The second through channel 316 includes a first end at the second port 310 and a second end fluidly connected to the mixing channel 302. In some embodiments, the second end of the first through channel 314 may join the mixing channel 302 at substantially the same location where the second end of the second through channel 316 joins the mixing channel 302. However, in some embodiments (such as those shown in Figure 3), the second end of the first through channel 314 may merge into the mixing channel at a location offset from where the second end of the second through channel 316 merges with the mixing channel 302. This offset may be due to at least one or two bends. By providing such an offset, for example, a region with a hydrophobic surface may be provided in the mixing channel, thereby providing resistance to the fluid moving towards the first container 304 and reducing its entry into the first container 304. The offset can further provide the advantage of making the adapter simpler in structure, more efficient, and more cost-effective to manufacture.

[0070] Figure 4 shows the syringe port 404 to which syringe 402 is connected.

[0071] Syringe 402 may be any conventional syringe or reciprocating pump, as long as it is suitable for use in a pharmaceutical setting. The syringe particularly includes a plunger 406 (or piston). The plunger fits securely into the barrel (syringe barrel) 408 and changes the volume of the internal space 410 of the syringe. The syringe further includes an orifice 412 on the opposite side of the plunger, to which a needle 414 can be attached. Alternatively, the orifice 412 may be contained within a Luer lock tip.

[0072] The connection between the syringe port 404 (or "third port") and the syringe may be any manner suitable for the internal space 410 of the syringe to communicate fluidly with the mixing channel through the syringe port 404. Thus, the syringe port may comprise any fitting configured to attach the syringe to the third port. For example, if the needle 414 is attached to the orifice 412 of the syringe (as shown in Figure 4), the third port may include a rubber diaphragm 416 suitable for repeated punctures with the needle. Alternatively, if the orifice 412 is contained within a Luer-lock tip, the fitting of the syringe port 404 may include a Luer taper fitting.

[0073] This disclosure also includes a method for mixing two components of a compound drug via one of the adapters disclosed herein. The method includes the steps of connecting a syringe equipped with a plunger to a third port and pulling the plunger. By pulling the plunger, the first component is drawn from the first container into the first passage channel and the second component is drawn from the second container into the second passage channel. Further pulling of the plunger draws the first and second components into the syringe via the mixing channel.

[0074] In this method, the first component may be an organic compound in at least a 25% alcohol solution, and the second component may be an anhydrous pharmaceutical product. The syringe may initially hold a reconstituter (such as an aqueous buffer solution), in which case the method further includes a step of pushing the plunger in before pulling the plunger, the step of pushing the plunger in transferring at least a portion of the reconstituter into the second container.

[0075] In some embodiments, the method further includes the steps of connecting a first container to a first port and connecting a second container to a second port of the adapter, before connecting a syringe to a third port of the adapter.

[0076] Figure 5A shows a flowchart of an exemplary embodiment of method 500a outlined above for mixing the components of a compound drug via one of the adapters described herein. Figure 5B shows an alternative exemplary embodiment of method 500b outlined above for mixing the components of a compound drug, wherein one of the containers contains the already reconstituted product. Steps indicated by dashed lines are optional and can be omitted, and the order of non-causal steps can be changed.

[0077] In step 502a, containers 104 and 106 are connected to ports 114 and 116 of the adapter. Containers 104 and 106 can contain lyophilized RNA that has not yet been reconstituted. This connection can be made by any of the methods of connecting the containers to the ports described herein. Alternatively, the containers may already be provided connected to the ports of the adapter, in which case this step can be omitted.

[0078] In step 504, the syringe is connected to the third port (or "syringe port") of the adapter. This connection may be made by any of the methods of connecting the syringe to the syringe port described herein. The syringe may be substantially empty when connected to the adapter, or the plunger of the syringe may already be advanced. Alternatively, the syringe may contain a reconstituter (such as an aqueous buffer or neutralizer) in its internal space when connected to the adapter.

[0079] If the syringe contains the reconstituted agent, follow method 500a in Figure 5A. In step 506a, push the plunger of the syringe so that the reconstituted agent is delivered through the adapter into at least one of the containers. If the syringe is substantially empty when connected to the adapter and the plunger of the syringe has been pushed in beforehand (e.g., in step 502b), this step can be omitted and method 500b in Figure 5B can be followed.

[0080] The effect of pushing the plunger in step 506a is illustrated in Figure 6A. Figure 6A shows a system 600 comprising an adapter 602 (such as any of the adapters described herein), a first container 604, a second container 606, and a syringe 608. When the plunger of the syringe 608 is pushed in, the reconstituter 632 flows out of the orifice of the syringe, through the mixing channel 612, and along the path defined by the mixing channel, into the first container 604 containing the first component 628a of the compound drug in storage. The first component 628a is then reconstituted by the reconstituter 632 within the first container 604.

[0081] The second port 616 shown in Figure 6A includes a one-way valve 622 that is directed to block or substantially prevent the fluid from passing from the mixing channel 612 to the second container 606. Therefore, even if the reconstituter 632 flows into the second port 616, it does not flow into the second container 606. In other embodiments, the one-way valve 622 is not present at the second port. In that case, the reconstituter 632 can flow into the second container through the second port 616. The second container contains the component 630 of the compound drug. In this embodiment, the component 630 contained in the second container 606 is, for example, a solution with a higher concentration than necessary. Therefore, the component 630 can withstand dilution by the reconstituter 632.

[0082] In step 508, the syringe plunger is pulled, drawing the unmixed components from containers 604 and 606 through the adapter into the syringe. The mixing channel in the adapter induces turbulence in the fluid flow, so that the components are mixed to the desired extent by the time they reach the syringe. Figure 5B shows an alternative operation, in which the contents of container 604 may be reconstituted or not lyophilized before container 604 is attached to the adapter. In step 502b, the syringe plunger is pushed in. This is in preparation for ensuring that the contents of containers 604 and 606 are drawn out after they are connected to the adapter in step 504. If containers 604 and 606 are not yet connected to the adapter, they are connected in step 506b. Finally, the plunger is pulled in step 508.

[0083] The effect of pulling the plunger in step 508 is shown in Figure 6B, which shows a system 600 comprising an adapter 602, a first container 604, a second container 606, and a syringe 608. This system is the same as that shown in Figure 6A. When the plunger of syringe 608 is pulled, a pressure difference is induced in the orifice of the syringe. This pressure difference then propagates through the syringe port 610, through the mixing channel 612, to the first container 604 via the first port 614 and the first through channel 618 (if present), and to the second container 606 via the second port 616 and the second through channel 620 (if present). As a result, the first component 628b (in this prepared state) is drawn from the first vessel 604 into the mixing channel 612 at or substantially near the second end 624 of the mixing channel 612 (through the first port 614 and the first through channel 618, if present). Similarly, the second component 630 is drawn from the second vessel 606 into the mixing channel 612 at or substantially near the second end 624 of the mixing channel 612 (through the second port 616 and the second through channel 620, if present).

[0084] Next, the first component 628b and the second component 630 are drawn along the path defined by the mixing channel 612, from the second end 624 of the mixing channel 612 through the mixing channel 612 to the first end 626 of the mixing channel 612. Here, the mixing channel 612 comprises several bends and is configured in one of the ways described with respect to Figures 2A-E.

[0085] Initially, at the second end 624 of the mixing channel 612, the first component 628b and the second component 630 are in a non-mixed state. Next, as the first component 628b and the second component 630 pass through each bend in the mixing channel, they gradually transition from a non-mixed state to a mixed state, as described with respect to Figures 2A to 2E.

[0086] From the first end 626 of the mixing channel 612, the first component 628b and the second component 630 are drawn into the syringe through the syringe port 610 as a compound drug. In some embodiments, the compound drug is drawn into the syringe in a ready-to-use state. In other embodiments, the compound drug drawn into the syringe requires further dilution before use. In some of these other embodiments, the plunger does not need to be pushed in its entirety in step 506, in which case a portion of the reconstituter 632 remains inside the syringe 608. This remaining reconstituter 632 dilutes the compound drug in the syringe 608. As a result, the compound drug in the syringe 608 becomes ready to use.

[0087] Considering specific examples of forming mRNA-LNP complexes, mRNA-LNP (or RNA-LNP) complexes may be formed by mixing a first component of mRNA (or RNA) in a first container 604 with a second component of lipids dissolved in a 25% or greater alcohol solution in a second container 606, via one of the adapters disclosed herein.

[0088] In some embodiments, the first component includes a pre-prepared mRNA (or RNA) in a prepared state that has been reconstituted before being contained in the first container 604. In these embodiments, it is not necessary to introduce a reconstituter, and step 506 can be omitted from method 500. Also, the one-way valve 622 may not be provided.

[0089] In other embodiments, the first component comprises stored mRNA (or RNA) that requires reconstitution before use. For example, the mRNA (or RNA) may be lyophilized mRNA (or lyophilized RNA), in which case the reconstitution agent, introduced by pushing the plunger of the syringe, may be an aqueous buffer. Alternatively, the mRNA (or RNA) may be dissolved in a liquid that requires neutralization before use, in which case the reconstitution agent may be a neutralizing agent.

[0090] In these embodiments, a one-way valve 622 may be provided. In this case, the second component (i.e., lipids dissolved in the alcohol solution) does not need to be specially prepared to withstand the neutralizing agent. However, if the second component contains lipids dissolved in an alcohol solution of more than 25%, preferably 40-100%, the one-way valve 622 may be omitted. This concentration allows the second component to withstand dilution with the reconstituter without affecting the quality of the resulting mRNA-LNP complex drug.

[0091] Figure 7 shows a flowchart of an example 700 of a method for manufacturing an adapter, such as adapter 102a of system 100a in Figure 1A or adapter 102b of system 100b in Figure 1B. Steps shown by dashed lines are optional and can be omitted. Method 700 begins in step 702 by forming a first recess in a first part (e.g., part 110a in Figure 1A or part 110b in Figure 1B). Next, in step 704, a second recess is formed in a second part (e.g., part 112a in Figure 1A or part 112b in Figure 1B). Finally, in step 706, the first part is fused to the second part.

[0092] The first recesses, and second recesses if necessary, define mixing channels 120a, 120b when the first component is fused to the second component. In addition to, or separately, these recesses may define a first through channel 122 and / or a second through channel 124 when the first component is fused to the second component. The adapter may further have multiple mixing channels, in which case two or more first recesses are formed in the first component in step 702 and two or more second recesses are formed in the second component in step 704. If multiple mixing channels are provided, they may be in communication at multiple locations along the longitudinal direction. This allows fluid to move from one channel to another.

[0093] In the embodiment relating to the adapter in Figure 1A, the first recess, and a second recess if necessary, includes a continuous recess having a geometric shape and configuration such as those described for the mixing channel in any of Figures 2A to 2D. Thus, the mixing channel 120a defined by the recess has a meandering path that curves in a plane parallel to the interface between the first and second parts. If the first recess in the first part formed in step 702 is the same size as, or substantially the same size as, the entire cross-section of the mixing channel, step 704 can be omitted. In this case, the second part fuses to the first part without itself having a second recess. This has the advantage that the microfluidic path can be formed in a (single) structural component, which may not need to be connected to, for example, a syringe or container. Thus, the manufacturing of the adapter can be simplified and costs can be reduced. In addition, step 704 ensures that the first recess formed in step 702 is the same size as, or substantially the same size as, a portion of the cross-section of the mixing channel (e.g., substantially half of the entire cross-section). In this case, the second recess formed in step 704 is the same size as, or substantially the same size as, the remaining portion of the cross-section of the mixing channel (e.g., substantially half of the cross-section). In step 706, the first part is fused to the second part with the first and second recesses aligned.

[0094] On the other hand, in the embodiment relating to the adapter in Figure 1B, each of the first and second recesses comprises a discontinuous recess. The discontinuous recess is, for example, a straight arrangement of separate recesses extending in the direction of the mixing channel 120b. In these embodiments, the fusion of the first part to the second part in step 706 includes the step of shifting the first discontinuous recess by a selected amount from the second discontinuous recess so that the first and second discontinuous recesses collectively form a mixing channel when the parts are fused. This is shown in Figure 2E, where portion 210b is fused to portion 212b, and discontinuous recess 216 is shifted from discontinuous recess 218 to form a mixing channel. In one example, the shift between the first and second discontinuous recesses is 20 to 200 μm. The geometry and configuration of these mixing channels may be any of those described in relation to Figures 2A-2D or Figure 2E, but in some embodiments relating to Figure 1B, the mixing channel has a meandering path that curves in a plane parallel to the interface between the first part 110b and the second part 112b.

[0095] Each component can be formed from substantially any material, but preferably from a low surface energy material, at least for the reasons mentioned above. Each component may be conical in shape, as shown in Figures 1A and 1B. For example, each component may be an injection-molded or compression-molded polymer component. Alternatively, each component can be formed from a glass material or another substrate by pressing, etching, or laser engraving. In these scenarios, the first and / or second recesses can be formed in the first and / or second components by injection molding or compression molding, bonding a laser-cut polymer film onto an injection-molded or compression-molded component, bonding a micro-molded component onto an injection-molded or compression-molded component, engraving a recess into a component or part of a component overmolded into a polymer adapter, or overmolding a capillary tube into a polymer adapter. Each of these methods for forming the recesses can provide durable adapters with desirable material properties on an industrially effective scale and at low cost. Alternatively, microfluidic pathways surrounded by a film may be formed by forming depressions on either or each of the components in a film laminated on a rigid component. For example, in the embodiment shown in Figure 1B, the film may have a structure in which holes are continuously perforated or embossed at 200 μm intervals. This method allows for the easy and low-cost manufacturing of microfluidic pathways.

[0096] The first component and / or the second component may have any of the structures of the first port 114, the second port 116, the third port 118, and / or other components of the adapter. Alternatively, the first port 114, the second port 116, and / or the third port 118 may be coupled to the first component and / or the second component before step 706. Alternatively, the first port 114, the second port 116, and / or the third port 118 may be coupled to the adapter at the interface between the first component and the second component during fusion bonding in step 706.

[0097] As described above, the mixing channel 120b of the adapter 102b can be formed as a single part using injection molding or 3D printing. In embodiments, the mixing channel 120b can be formed as a single part using injection molding such as liquid silicone rubber injection molding or thermoplastic elastomer injection molding. For example, as shown in Figure 8, the core pin 800 can be used in an injection molding die to form the mixing channel 120b of the adapter 102b in a single part by injecting a liquid (e.g., silicone rubber, thermoplastic elastomer, etc.) into the mold around the core pin 800. The core pin 800 may include a cylindrical rod 832 for forming the path 232 of the mixing channel 120b. The core pin 800 may include projections 830 extending radially outward from the cylindrical rod 832 to form the dimples 230 of the mixing channel 120b. The core pin 800 can be formed from a flexible elastic material such as an elastomer that can deform when the core pin 800 is removed from the molded adapter 102b. The adapter 102b can be released from the core pin 800 (for example, using a strategically positioned air ejector system), and / or the core pin 800 can be pulled out from the adapter 102b after molding. Since the core pin 800 is formed from a flexible elastic material, the core pin 800 can be separated from the molded adapter 102b without damaging the core pin 800 or the adapter 102b. Figure 9 shows an embodiment of the adapter 102b formed from injection molding, which is formed in a single, integral part of the adapter 102b and includes a mixed channel 120b having the dimples 230 and paths 232 described above with reference to Figure 2F.

[0098] Figures 10-11C show other diagrams of the system 100b described above. The system 100b shown in Figures 10-11C and described below may include any of the features described above with respect to either system 100a or system 100b, and vice versa. For example, system 100b may include an adapter 102b, a first port 114, a second port 116, and a third port 118. The adapter 102b may be formed from a first part 110b and a second part 112b, which can be fastened together with a fastener. The first part 110b and the second part 112b may be injection molded and may include two-shot sealing features such as a gasket 136. The first part 110b and the second part 112b may be formed from metal (e.g., aluminum) or plastic (e.g., polyethylene terephthalate), among other possible materials. A mixing channel 120b can be formed between the first component 110b and the second component 112b. That is, the geometric shapes formed on each of the first component 110b and the second component 112b can define the mixing channel 120b. System 100b may be reusable.

[0099] According to a first aspect of this disclosure, an adapter is provided for connecting one or more storage containers to a syringe. The adapter comprises a first port configured to provide connection to a first container, a second port configured to provide connection to a second container, and a third port configured to provide connection to a syringe. The adapter further comprises a mixing channel extending from a first end, which is in fluid communication with the third port, to the second end. The mixing channel includes a meandering path along at least a portion of its length. By providing a meandering path within the adapter, it is possible to mix components supplied from separate containers as they are drawn into the syringe through the adapter using turbulence induced by the fluid flow through the mixing channel. This can provide consistency, safety, and convenience to a method of mixing components for injection.

[0100] If necessary, the mixing channel is a microfluidic mixing channel and may have an internal dimension (e.g., a first internal dimension) of 20 to 200 μm, preferably 20 to 100 μm, more preferably 20 to 50 μm, and more preferably about 50 μm. In addition, the mixing channel may have a second internal dimension (e.g., within a portion of the mixing channel) that is larger than the first internal dimension. For example, the second internal dimension can be 20 to 500 μm, preferably 50 to 200 μm, more preferably 50 μm or more, more preferably 100 μm or more, and more preferably greater than or equal to the first internal dimension. In other words, the cross-sectional area of ​​the channel may vary along its length.

[0101] In some embodiments, the mixing channel includes a constriction, which is a portion of the mixing channel having a smaller internal dimension than the preceding and succeeding portions of the mixing channel. In other words, the constriction is a portion of the mixing channel that is thinner than the portions of the mixing channel on either side of it. The constriction may be formed as a pinch point along the length of the channel, or by alternating the cross-sectional area between a larger cross-sectional area (e.g., for a channel segment extending in a first direction) and a smaller cross-sectional area (e.g., for a channel segment extending in a second direction). Mixing can be further improved by introducing one or more constrictions along the length of the path through which the fluid travels.

[0102] Furthermore, in some embodiments, the meandering path is configured to induce localized changes in the flow direction of the liquid moving through the mixing channel.

[0103] In some embodiments, the adapter further comprises a first through channel extending from a first end fluid-communicating with a first port to a second end fluid-communicating with a mixing channel, and a second through channel extending from the first end fluid-communicating with a second port to a second end fluid-communicating with a mixing channel. The through channels may be configured to deliver fluid from the container volume to the mixing channel.

[0104] In some embodiments, the first and second through channels have substantially the same volume. In other embodiments, the first and second through channels have substantially different volumes. The first and second through channels may be joined to the mixing channel at the same point. Alternatively, the joint between the first through channel and the mixing channel and the joint between the second through channel and the mixing channel may be offset from each other. A one-way valve can be provided between the two joints to prevent fluid flow (in at least one direction) between the first and second through channels.

[0105] The adapter may be provided with a one-way valve at the second port or between the second port and the mixing channel. Alternatively, the one-way valve does not need to be provided at the second port or between the second port and the mixing channel. In addition, or alternatively, the adapter may further be provided with a one-way valve at the first port or between the first port and the mixing channel.

[0106] The third port may be configured to communicate with the syringe in both directions. For example, the third port may include a rubber diaphragm configured to be punctured by a needle. Alternatively, the third port may include a fitting, such as a Luer taper fitting, configured to attach the syringe to the third port.

[0107] In some embodiments, the mixing channel may have at least one bend between continuously connected channel sections (e.g., continuously connected substantially straight channel sections). The angle between the continuously connected substantially straight channel sections may be less than 120 degrees, more preferably less than 100 degrees, and most preferably 95 degrees or less. In one example, the angle between the continuously connected channel sections is 90 degrees, and as a result, at least one bend forms a square joint between the continuously connected channel sections. In other embodiments, a triangular joint can be formed between the continuously connected channel sections, or a sawtooth joint can be formed between the continuously connected channel sections. In other words, at least one bend may be a sharp joint having a bend that includes a discontinuity in gradient to induce a change in the direction of fluid flow through the mixing channel. A “sharp” bend refers to the angle between two continuously connected (and substantially straight) sections of the mixing channel, and the angle is less than 120 degrees. It should be noted that a “sharp” bend does not need to include a vertex between two adjacent straight segments (although this is the configuration in some embodiments). Rather, adjacent segments can be connected using a curved bend or smooth joint with a small radius of curvature. In some examples, a bend with a radius of curvature approximately equal to the width of the mixed channel may be appropriate.

[0108] In some embodiments, substantially half of the continuously connected channel portions may be oriented in a first direction. Each of the continuously connected channel portions may extend for 1 millimeter or less, 500 μm or less, 200 μm or less, 100 μm or less, 75 μm or less, or 50 μm or less. Similarly, in some embodiments, substantially half of the continuously connected channel portions may be oriented in a second direction perpendicular to the first direction and / or extend for 1 millimeter or less, 500 μm or less, 200 μm or less, 100 μm or less, 75 μm or less, or 50 μm or less. Any of the continuously connected channel portions may extend for 50 μm or more, 75 μm or more, or 100 μm or more. In some embodiments, substantially half of the continuously connected channel portions oriented in the first direction extend over a shorter distance than substantially half of the continuously connected channel portions oriented in the second direction. Shorter channel sections may also have a reduced cross-sectional area than longer channel sections, introducing multiple constrictions into the fluid flow path and further improving mixing.

[0109] The mixing channel may include at least two bends, more preferably four or more bends, or most preferably ten or more bends. The mixing channel may include 100 or fewer bends, preferably 70 or fewer bends, or most preferably 40 or fewer bends. The exact number of bends in the mixing channel can be selected to achieve the desired mixing, and this depends on the geometry of the bends and the mixing channel as a whole. Thus, in some embodiments described herein, more than two bends, more than four bends, or preferably more than ten bends, and / or fewer than 120 bends, fewer than 80 bends, or preferably fewer than 40 bends provide the desired mixing, and therefore the mixing channel may be configured in this manner.

[0110] In some embodiments, the adapter comprises multiple mixing channels. Each of these mixing channels is configured to provide fluid communication between a first through channel, a second through channel, and a third port. In other words, the mixing channel may comprise multiple branches, each branch configured to provide a meandering path for mixing fluids from a first and second container volume. Alternatively, the adapter may comprise only one mixing channel.

[0111] In some embodiments, further first through channels and further second through channels may be provided. The further first and second through channels can be in fluid communication with a third port via one or more mixing channels, and thus provide additional fluid paths through which fluids from the first and second container volumes can be mixed as they move through the adapter.

[0112] In some embodiments, the second end of the first through channel, the second end of the second through channel, and the second end of the mixing channel merge at a confluence point. Alternatively, in some embodiments, the second end of the first through channel intersects with the second end of the mixing channel, and the second end of the second through channel intersects with the mixing channel at a point offset from the second end of the mixing channel. Such offsets allow for resistance to reduce fluid entry into the first vessel, or allow for the installation of a one-way valve between the offsets. Such offsets may further offer the adapter the advantage of being simpler in structure and therefore more efficiently and cost-effectively manufactured.

[0113] A system is provided according to a second aspect of this disclosure. This system comprises an adapter described in accordance with the first aspect, a first container connected to a first port, and a second container connected to a second port. The first and second containers are fixed-volume containers.

[0114] If necessary, the first container may hold an organic compound in at least 25% alcohol, preferably at least 25% ethanol. The organic compound may be a lipid, if necessary. If further necessary, the second container may hold an anhydrous pharmaceutical, preferably a lyophilized pharmaceutical, more preferably lyophilized RNA. Alternatively, the second container may contain RNA in a solution such as an aqueous solution.

[0115] Lipids in at least 25% alcohol and RNA in a lyophilized state or as a solution can be stored and transported at conventional temperatures, such as room temperature. Therefore, the adapters and systems disclosed herein may enable the mitigation of obstacles associated with storing and transporting RNA-LNP complexes at very low temperatures. Rather, each component of the RNA-LNP complex can be stored and transported at room temperature, and then the RNA-LNP can be formed via one of the adapters disclosed herein at the time of use.

[0116] In some embodiments, the first and second containers are detachably connected to the first and second ports, respectively. Alternatively, the first and second containers can be permanently connected to the first and second ports, respectively. The adapter may be configured to enter into a locking connection with one or more containers to prevent reuse of the adapter.

[0117] If necessary, a syringe can be connected to a third port. The syringe may hold a buffer, preferably an aqueous buffer. In these embodiments, a one-way valve may be provided at the second port of the adapter. Alternatively, if a one-way valve is not provided, the lipids may be provided in an alcohol solution of greater than 25%, preferably greater than 40%, and preferably greater than 60%. In some cases, the alcohol solution may be an ethanol solution. Providing the lipids in such increased concentrations of alcohol may allow the lipids in the alcohol solution to withstand dilution with the reconstituter without affecting the quality of the resulting mRNA-LNP complex drug.

[0118] The adapter may be provided as part of a kit along with at least one of a syringe and a container.

[0119] A third aspect of the present disclosure provides a method for mixing two components of a compound drug via an adapter. The adapter comprises a first port connected to a first container holding a first component, a second port connected to a second container holding a second component, a third port configured to provide a connection to a syringe, a mixing channel extending from a first end to a second end that is in fluid communication with the third port, a first through channel extending from a first end to a second end that is in fluid communication with the mixing channel, and a second through channel extending from a first end to a second end that is in fluid communication with the second port. The mixing channel includes a meandering path along at least a portion of its length. The method includes the steps of connecting a syringe equipped with a plunger to the third port and pulling the plunger. By pulling the plunger, the first component is drawn from the first container into the first passage channel, and the second component is drawn from the second container into the second passage channel. When the plunger is pulled further, the first and second components are drawn into the syringe through the mixing channel.

[0120] Once the first and second components are drawn into the syringe via the mixing channel, the combined drug can be stored in the syringe.

[0121] If necessary, the first component is an organic compound in at least a 25% alcohol solution, and the second component is an anhydrous pharmaceutical product. The organic compound may be a lipid if necessary. The adapter may further be provided with a one-way valve at the second port or between the second port and the mixing channel. Alternatively, if a one-way valve is not provided, the lipid may be provided in an alcohol solution of more than 25%, preferably more than 40%, and preferably more than 60%. In some cases, the alcohol solution may be an ethanol solution.

[0122] In some cases, the syringe may initially hold the aqueous buffer solution. Here, the method may further include the step of pushing the plunger in before pulling it out. Here, pushing the plunger in may transfer at least a portion of the aqueous buffer solution into the second container.

[0123] In some embodiments, the method for mixing the two components may further include the steps of connecting the first container to the first port and connecting the second container to the second port of the adapter, before connecting the syringe to the third port of the adapter.

[0124] In some embodiments, the mixing method further includes the steps of cutting the syringe from the third port and transferring the compound drug from the syringe for analysis or dilution. Alternatively, the method may further include cutting the syringe from the third port and using the compound drug directly.

[0125] A fourth aspect of the present disclosure provides a method for manufacturing an adapter for connecting two or more containers to a syringe. The method includes the steps of forming a first recess in a first polymer component such that the first recess provides at least a portion of a mixing channel extending from a first end to a second end, and fusing the first polymer component to a second polymer component. The mixing channel includes a meandering path along at least a portion of its length.

[0126] In some embodiments, the first depression includes a discontinuous depression. In other words, the first depression may include a series of depressions separated from each other by space, thereby forming a discontinuity. The manufacturing method may further include the step of forming a second discontinuous depression in a second polymer component. Herein, using at least two polymer components involves offsetting the first and second discontinuous depressions from each other such that the second depression provides at least a portion of a mixing channel, and if necessary, the at least two polymer components are offset by 20 to 200 μm.

[0127] If necessary, the first and second recesses can be formed by injection molding or compression molding. Alternatively, the first and second recesses may include a laser-cut polymer film bonded to the injection-molded part.

[0128] The first recess and / or the second recess may provide a first through channel extending from a first end that is in fluid communication with a first port to a second end that is in fluid communication with a mixing channel, and a second through channel extending from a first end that is in fluid communication with a second port to a second end that is in fluid communication with a mixing channel.

[0129] It should be understood that certain terms are used in the above explanation for convenience and are not limiting. Unless otherwise specified, the terms "a," "an," and "the" should be read as meaning "at least one." The term "comprising" should be understood as meaning "comprising but not limiting," so that a system or method that includes certain features or steps may include features or steps not listed, but not limited to those listed. Similarly, terms such as "over," "under," "front," "back," "right," "left," "top," "bottom," and "side" are used for convenience in interpreting the drawings and should not be interpreted as limiting.

[0130] Furthermore, those skilled in the art will understand that modifications can be made to the exemplary embodiments described herein without departing from the present invention. Structural features of the systems and apparatus described herein can be replaced by functionally equivalent parts. Moreover, it will be understood that features from the embodiments can be combined with each other without departing from the present disclosure.

Claims

1. A first port configured to connect to a first container, A second port configured to connect to a second container, A third port configured to connect to a third container, A body that partitions a mixing channel extending from a first end that is in fluid communication with the third port to a second end that is in fluid communication with the first port and the second port. An adapter equipped with, The aforementioned mixing channel, A single cylindrical path, The aforementioned path is surrounded by a plurality of dimples, each of which protrudes into the portion of the main body located radially outward from the path. Includes, The plurality of dimples are divided into two or more sets that are alternately arranged along the longitudinal direction of the path, and each set contains at least two circumferential rows, and the angles of the circumferential rows around the longitudinal axis of the path are shifted for each set, so that the fluid flowing through the path follows a meandering path that extends along the longitudinal direction of the path, entering and exiting the path and the plurality of dimples. An adapter characterized by the following features.

2. The adapter according to claim 1, wherein the mixing channel is a microfluidic channel.

3. The adapter according to claim 1, wherein the mixing channel has an internal dimension of 200 μm to 800 μm.

4. The mixing channel includes a constricted portion, The constricted portion is a part of the mixing channel having an internal dimension smaller than at least one of the preceding and succeeding portions of the mixing channel. The adapter according to claim 1.

5. The adapter according to claim 1, further comprising a one-way valve connected to the second port.

6. The adapter according to claim 1, wherein the third port is configured to communicate with the third container in both directions.

7. The third port is, A rubber diaphragm designed to be punctured by a needle, A fitting configured to attach the third container to the third port. It has at least one of the following: The adapter according to claim 1.

8. The mixing channel comprises at least one bend between the continuously connected channel portions, The angle between the continuously connected, substantially straight channel segments is less than 120 degrees. The adapter according to claim 1.

9. The at least one curved portion is The square-shaped joint between the continuously connected channel portions, The triangular joint between the continuously connected channel portions, sawtooth joint between the continuously connected channel portions It has one of the following: The adapter according to claim 8.

10. A first through channel connecting the first port and the mixed channel, A second through channel connecting the second port and the mixed channel, The adapter according to claim 1, further comprising the following:

11. The adapter includes one or more mixing channels in addition to the mixing channel, Each mixed channel connects the first pass channel and the second pass channel to the third port. The adapter according to claim 10.

12. The first pass channel and the second pass channel are connected to the third port via the mixed channel. The adapter according to claim 10.

13. An adapter according to any one of claims 1 to 12, The first container connected to the first port, The second container connected to the second port and A system equipped with, The first container and the second container are containers of a fixed volume. A system characterized by the following features.

14. The second container contains a lipid component dissolved in an alcohol solution. The system according to claim 13.

15. The first container holds the freeze-dried RNA. The system according to claim 14.

16. The third container further comprises, The third container is a syringe connected to the third port, The syringe holds the buffer solution. The system according to claim 13.

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