Method and adapter for mixing pharmaceutical compositions

Abstract

Embodiments of an adapter (100), a system including the adapter, and a method of using the adapter may be used to mix a first substance and a second substance. The adapter (100) can comprise a main body (101), the body has a first port (102) configured to be connected with a first container to receive a first substance, a second port (104) configured to be connected with a second container to receive a second substance, a third port (130) configured to be connected with a receiving container to output a mixture of the first substance and the second substance, and a mixing chamber, the mixing chamber has a first portion in communication with the first port and the second port and a second portion in communication with the third port. The adapter may also include a mixing pin (160) inserted into the mixing chamber. In some embodiments, the mixing pin at least partially defines at least one microfluidic path for mixing the first substance and the second substance. In some embodiments, at least one of the first channel and the second channel is oriented offset from a central plane of the body.

Description

[0001] Cross - reference to related applications

[0002] This patent application claims the benefit of U.S. Provisional Patent Application No. 63 / 378,230, filed on October 3, 2022, the disclosure of which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates to adapters, systems, and methods of use for mixing at least two substances to produce pharmaceutical complexes. Background Art

[0004] Recent developments in immunology include newly approved messenger RNA - encapsulated lipid nanoparticle (mRNA - LNP) vaccines. The advantage of messenger RNA (mRNA) technology is the ability to rapidly adapt to new antigen designs by altering the mRNA sequence without a complete overhaul of the chemistry and manufacturing controls (CMC) of vaccine production. However, mRNA provided alone is not readily absorbed or delivered efficiently to human immune cells and has unstable chemical and physical properties, and thus cannot be effectively used as a vaccine. Recent developments have shown that if mRNA is encapsulated in a lipid nanoparticle (LNP) carrier, its absorption and stability can be increased to effective levels.

[0005] The preparation of mRNA - LNP vaccines is achieved by mixing ethanol - dissolved lipids with RNA in a buffer under strictly controlled conditions. This mixing is typically carried out in a laboratory using equipment that is generally not suitable for large - scale distribution due to low durability, high cost, high complexity, low batch - to - batch consistency, and / or large batch - to - batch variability. Summary of the Invention

[0006] The inventors have recognized that the shelf - life of mRNA - LNP at room temperature is limited. To extend the shelf - life, mRNA - LNP vaccines must be stored at extremely low temperatures (typically - 20 degrees Celsius to - 80 degrees Celsius). This is a problem because low - temperature distribution is costly and logistically complex. Additionally, there is a risk of waste of mRNA - LNP vaccines if the low - temperature environment fails at any stage of the distribution chain, for example.

[0007] Non-messenger RNA drugs such as RNAi, siRNA, and other oligonucleotides can also be formed into lipid nanoparticle compositions (RNA-LNPs). The RNA-LNP drugs can be chemically modified to improve their stability and shelf life at room temperature (such chemical modification is not possible for mRNA-LNP technology that requires interaction with cellular proteins to function properly). Chemical modification of RNA-LNPs can be difficult and costly to implement, but chemical modification is generally preferred to avoid the high distribution costs associated with unmodified RNA-LNP drugs (which also must be stored at very low temperatures), as well as the difficulty associated with managing drug efficacy over time due to the limited molecular half-life.

[0008] In summary, the cryogenic requirements pose a major challenge to distribution and development. Other issues associated with known systems for producing nanoparticle compositions include limited scalability, availability, and / or reliability. The various embodiments disclosed herein meet one or more of the foregoing needs.

[0009] A first aspect of the present disclosure relates to an adapter having: a body having a first port configured to connect with a first container to receive a first substance, a second port configured to connect with a second container to receive a second substance, a third port configured to connect with a receiving container to output a mixture of the first substance and the second substance, and a mixing chamber having a first portion in communication with the first port and the second port and a second portion in communication with the third port; and a mixing pin inserted into the mixing chamber, wherein the mixing pin at least partially defines at least one microfluidic path for mixing the first substance and the second substance.

[0010] The adapter may have one or more of the following features. The body may also have an opening in a first portion of the mixing chamber, the opening being configured to receive a mixing pin. The mixing pin may be removable from the mixing chamber. The mixing pin may have a flange, and the body may have a recess configured to receive the flange. The mixing pin may have a sealing portion configured to seal the first portion of the mixing chamber. The first port and / or the second port may be substantially parallel to the mixing chamber. The body may further include a first branch channel in communication with the first port and extending at a first angle relative to the mixing chamber, and a second branch channel in communication with the second port and extending at a second angle relative to the mixing chamber. The first angle and / or the second angle may be greater than 90 degrees. The first angle and / or the second angle may be from about 120 degrees to about 160 degrees. The adapter may further include a first plug inserted into an end of the first branch channel and a second plug inserted into an end of the second branch channel. The first branch channel may be configured to direct a first substance toward the mixing pin, and the second branch channel may be configured to direct a second substance toward the mixing pin. The mixing pin defines a first edge surface formed by a first surface and a second surface and a second edge formed by a third surface and a fourth surface, the first edge being configured to separate the first substance, and the second edge being configured to separate the second substance. The first port may be a female Luer connector, the second port may be a female Luer connector, and the third port is a male Luer connector. At least one microfluidic path may be tortuous. At least the microfluidic path may be formed by at least one channel. At least one channel may have a size of about 200 μm to about 1000 μm. At least one channel may have a size of about 400 μm to about 600 μm. At least one channel may include at least one spiral channel. At least one spiral channel may include a first spiral channel and a second spiral channel, wherein the first spiral channel and the second spiral channel intersect at a plurality of intersection points along the longitudinal length of the mixing pin. At least one channel may extend through the mixing pin. The mixing pin may include a plurality of protrusions that extend at least partially around the circumference of the mixing pin and define at least a portion of at least one channel. The plurality of protrusions may extend uniformly around the circumference of the mixing pin and form at least one radial gap relative to the inner surface of the body, the at least one radial gap forming at least a portion of at least one channel. Each of the plurality of protrusions may have at least one first surface and at least one second surface, the at least one first surface being configured to create a seal against the inner surface of the body, and the at least one second surface forming at least one radial gap relative to the inner surface of the body, the at least one radial gap forming at least a portion of at least one channel.

[0011] The second aspect of the present disclosure relates to a system having: an aqueous solution; a lipid solution; a first container configured to receive the aqueous solution; a second container configured to receive the lipid solution; a receiving container; an adapter including: a body having: a first port configured to connect to the first container and receive the aqueous solution, a second port configured to connect to the second container and receive the lipid solution, a third port configured to connect to the receiving container to output a mixture of the aqueous solution and the lipid solution, and a mixing chamber extending between a first portion in communication with the first port and the second port and a second portion in communication with the third port; and a mixing pin configured to be inserted into the mixing chamber, wherein the mixing pin at least partially defines at least one microfluidic path for mixing the aqueous solution and the lipid solution.

[0012] The system may have one or more of the following features. The system may include a second pin configured to be inserted into the mixing chamber, wherein the second mixing pin has a geometry different from that of the mixing pin. The system may include a first storage container containing the aqueous solution and a second storage container containing the lipid solution.

[0013] The third aspect of the present disclosure relates to a method including: introducing a first substance into a first port of an adapter; introducing a second substance into a second port of the adapter; mixing the first substance and the second substance in at least a microfluidic path through, along, and / or around a mixing pin in the adapter; and producing a pharmaceutical complex having the first substance and the second substance.

[0014] The method may have one or more of the following features. The first substance may be an aqueous solution, the second substance may be a lipid solution, and the pharmaceutical complex may include lipid nanoparticles.

[0015] The fourth aspect of the present disclosure relates to an adapter including: a body having: a first port configured to connect to a first container to receive a first substance, a first channel in communication with the first port, a second port configured to connect to a second container to receive a second substance, a second channel in communication with the second port, a third port configured to connect to a receiving container to output a mixture of the first substance and the second substance, and a mixing chamber having a first portion in communication with the first port and the second port and a second portion in communication with the third port; and a mixing pin inserted into the mixing chamber, wherein at least one of the first channel and the second channel is oriented off a central plane of the body.

[0016] The adapter may have one or more of the following features. The body may include an opening in a first portion of the mixing chamber, the opening being configured to receive a mixing pin. The mixing pin may be removable from the mixing chamber. The mixing pin may have an end cap, and the body may have an edge configured to engage the end cap. The adapter may include a sealing member configured to seal the first portion of the mixing chamber. The first port and / or the second port may be substantially parallel to the mixing chamber. The first channel may extend at a first angle relative to the mixing chamber, and the second channel may extend at a second angle relative to the mixing chamber. The first angle and / or the second angle may be greater than 90 degrees. The first angle and / or the second angle may be about 120 degrees to about 160 degrees. The adapter may include a first plug at an end of the first channel and a second plug at an end of the second channel. The first channel and the second channel may be offset from a central plane of the mixing pin. The first channel and the second channel may be on the same side of a transverse axis of the adapter body. The first channel and the second channel may be on opposite sides of a transverse axis of the adapter body. The first channel and the second channel may be connected to the body at different longitudinal positions. The first port may be a female Luer connector, the second port may be a female Luer connector, and the third port may be a male Luer connector. The mixing pin may be formed by at least one channel. The at least one channel may have a size of about 200 μm to about 1000 μm. The at least one channel may have a size of about 400 μm to about 600 μm. The at least one channel may include at least one helical channel.

[0017] A fifth aspect of the present disclosure relates to a system, the system comprising: an aqueous solution; a lipid solution; a first container configured to receive the aqueous solution; a second container configured to receive the lipid solution; a receiving container; an adapter comprising: a body having a first port configured to connect to the first container and receive the aqueous solution, a second port configured to connect to the second container and receive the lipid solution, a third port configured to connect to the receiving container to output a mixture of the aqueous solution and the lipid solution, and a mixing chamber extending between a first portion in communication with the first port and the second port and a second portion in communication with the third port; and a mixing pin configured to be inserted into the mixing chamber, wherein at least one of the first channel and the second channel is oriented offset from a central plane of the body.

[0018] The system may have one or more of the following features. The system may include a second pin configured to be inserted into the mixing chamber, wherein the second mixing pin has a geometry different from that of the mixing pin. The system may include a first storage container containing the aqueous solution and a second storage container containing the lipid solution.

[0019] The sixth aspect of the present disclosure relates to a method having: introducing a first substance into a first port of an adapter body and through a first channel of the adapter body; introducing a second substance into a second port of the adapter body and through a second channel of the adapter body; mixing the first substance and the second substance around a mixing pin in the adapter body, wherein at least one of the first channel and the second channel is oriented off a central plane of the adapter body; and producing a drug complex having the first substance and the second substance.

[0020] The method may have one or more of the following features. The first substance may be an aqueous solution, the second substance may be a lipid solution, and the drug complex may include lipid nanoparticles. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] In the following detailed description, specific embodiments of the present disclosure are described only by way of example and with reference to the drawings, in which:

[0022] Figure 1 A side view of an exemplary system according to the present disclosure is shown.

[0023] Figure 2 Shows Figure 1 An exploded view of a first embodiment of an adapter of the system of.

[0024] Figure 3 Shows Figure 1 And Figure 2 A first cross-sectional view of the adapter of.

[0025] Figure 4 Shows Figures 1 to 3 A second cross-sectional view of the adapter of.

[0026] Figure 5 Shows Figures 1 to 4 A first side view of a mixing pin of the adapter of.

[0027] Figure 6 Shows Figures 1 to 5 A second side view of a mixing pin of the adapter of.

[0028] Figure 7 Shows Figures 1 to 6 A third side view of a mixing pin of the adapter of.

[0029] Figure 8 Shows Figures 1 to 4 A cross-sectional view of a second embodiment of a mixing pin in an adapter of the system of.

[0030] Figure 9 Shows Figure 8 A cross-sectional view of the adapter of.

[0031] Figure 10Shows Figures 1 to 4 An isometric view of a third embodiment of a hybrid pin of the system of

[0032] Figure 11 Shows Figures 1 to 4 In the adapter of Figure 10 A cross-sectional view of a third embodiment of a hybrid pin of

[0033] Figure 12 Shows Figure 11 A liquid volume cross-section of the adapter of

[0034] Figure 13 Shows Figures 1 to 4 An isometric view of a fourth embodiment of a hybrid pin of the system of

[0035] Figure 14 Shows Figures 1 to 4 A partially transparent view of a second embodiment of an adapter of the system of

[0036] Figure 15 Shows Figures 1 to 4 A partially transparent view of a third embodiment of an adapter of the system of

[0037] Figure 16 Shows Figure 15 A longitudinal view of the adapter of

[0038] Figure 17 Shows Figure 15 And Figure 16 A cross-sectional view of the adapter of

[0039] Figure 18 Shows Figures 15 to 17 An isometric view of the adapter of

[0040] Figure 19 Shows Figures 15 to 18 An exploded view of the adapter of

[0041] Figure 20 Shows Figures 15 to 19 An isometric view of the adapter of

[0042] Figure 21 Shows Figures 15 to 17 And Figure 19 A first isometric view of a hybrid pin of

[0043] Figure 22 Shows Figures 15 to 17 And Figure 19 A second isometric view of a hybrid pin of

[0044] Figure 23 Shows Figures 15 to 19 An isometric view of a first plug of the adapter of

[0045] Figure 24 Shows Figures 15 to 19 an isometric view of a second plug of the adapter of

[0046] Figure 25 Shows Figures 1 to 4 an isometric view of a fourth embodiment of an adapter of the system of

[0047] Figure 26 Shows Figure 25 a longitudinal view of the adapter of

[0048] Figure 27 Shows Figures 25 to 26 a first cross-sectional view of the adapter of

[0049] Figure 28 Shows Figures 25 to 26 a second cross-sectional view of the adapter of

[0050] Figure 29 Shows a method of mixing a first substance and a second substance using one or more of the embodiments of Figures 1 to 28 to produce a pharmaceutical complex.

[0051] The same reference numerals are used in the drawings and the following detailed description to refer to the same or similar components. Detailed Description

[0052] Provided is an adapter for connecting one or more fluid containers for microfluidically mixing a first substance and a second substance to produce a pharmaceutical complex. The adapter may include a first port or connector member configured to connect to a first container, a second port or connector member configured to connect to a second container, and a third port or connector member configured to connect to a receiving container. The adapter further includes a mixing chamber that extends from a first portion in fluid communication with the first and second ports to a second portion in communication with the third port. Mixing pins may be received in the mixing chamber and at least partially define at least one microfluidic path through, longitudinally along, and / or circumferentially around the mixing pins. At least one path may cause turbulence as fluid flows through the mixing chamber to mix the fluid components as the fluid components flow through the adapter to the receiving container.

[0053] In some embodiments, at least one path can be tortuous and configured to cause a local change in the flow direction of the components flowing through the mixing chamber. In some embodiments, at least one path can include multiple paths. In some embodiments, the multiple paths can have multiple intersection points configured to cause a local change in the flow direction of the liquid passing through the mixing chamber. In some embodiments, at least one path can have a variable width or diameter configured to cause repeated acceleration and deceleration, thereby causing turbulence. In some embodiments, at least one path can generate vortices to produce mixing with high turbulence.

[0054] The adapter of the present disclosure can provide an improvement over planar microfluidic chips by generating a three-dimensional microfluidic template for mixing. The three-dimensional microfluidic template as discussed herein allows for improved mixing by increasing the volume and flow rate while reducing the hydraulic pressure of the channels. For example, the adapter can have a microfluidic channel or flow path that is larger than the microfluidic chip (e.g., from about 400 μm to about 1000 μm) and / or provide multiple flow paths that can converge along the length of the adapter to increase mixing. Thus, the adapter can have larger features that are easier and / or less expensive to fabricate, for example, by injection molding or 3D printing. The adapter can fill a significant gap in the field of LNP synthesis. The various embodiments of at least one path can provide an easy-to-use, consistent, safe, and / or convenient method for mixing components at the point of care. The adapter can be used as a manual device (e.g., with a syringe) in a small-scale setting or in an automated configuration for a wide customer base working in the early preclinical stage to potentially scale up manufacturing.

[0055] Figure 1 and Figure 2System 10 is shown including a first container 20, a second container 40, a receiving container 60, an adapter 100, and a mixing pin 160. In some embodiments, system 10 may further include a first storage container 80 containing a first substance or component and a second storage container 82 containing a second substance or component. The first container 20 may be configured to transfer the first substance from the first storage container 80 to the adapter 100. The second container 40 may be configured to transfer the second substance from the second storage container 82 to the adapter 100. The adapter 100 may include at least one path configured to mix the first substance and the second substance and transfer the pharmaceutical complex to the receiving container 60. System 10 may be configured as a kit of at least one or all of the first container 20, the second container 40, the receiving container 60, the adapter 100, the mixing pin 160, the first storage container 80, and / or the second storage container 82. System 10 and / or the kit may further include one or more vial adapters 70 for transferring fluid to and / or from one or more of the receiving container 60, the first storage container 80, and / or the second storage container 82. The components of the kit may include packaging for transport to an end user. Although shown with adapter 100 and mixing pin 160, system 10 and / or the kit may include any one or more of adapters 100, 500, 600, 700 and / or mixing pins 160, 260, 360, 460, 660, 760. In some embodiments, system 10 and / or the kit may include a single adapter and multiple mixing pins 160, 260, 360, 460, 660, 760 having the same or different geometries. For example, multiple different types of mixing pins 160, 260, 360, 460, 660, 760 may be included in system 10 and / or the kit such that the end user may select or interchange the mixing pins 160, 260, 360, 460, 660, 760 based on the intended purpose and / or components.

[0056] The first container 20 can be a variable-volume container, such as a first syringe configured to at least temporarily store a first substance and / or transfer the first substance from a first storage container 80 to an adapter 100. The second container 40 can be a variable-volume container, such as a second syringe configured to store a second substance and transfer the second substance from a storage container 82 to the adapter 100. The first syringe 20 can include a first syringe body 22 and a first plunger rod 24, and the second syringe 40 can include a second syringe body 42 and a second plunger rod 44. Each syringe body 22, 42 can have a syringe barrel extending from a proximal end to a distal end along a longitudinal direction. Each syringe body 22, 42 can have a syringe tip at the distal end and a flange at the proximal end. The syringe barrel can be tubular, having an inner surface extending along the longitudinal direction to define a chamber. The chamber can be configured to receive, store, and / or mix substances for dispensing through a distal opening of the syringe tip. The first plunger rod 24 can have a first flange 25 at the proximal end, and the second plunger rod 44 can have a second flange 45 at the proximal end. The syringe tip of the first syringe body 22 can include a first connector 26 for engaging with an external device such as a syringe needle, a container, and / or the adapter 100. The syringe tip of the second syringe body 42 can include a second connector 46 for engaging with the same or a different external device such as a syringe needle, a container, and / or the adapter 100. Each connector 26, 46 can also include a male Luer connector, which includes a syringe tip and a threaded sleeve surrounding the tip. The syringe tip can be tapered to direct fluid flow into the external device (e.g., the adapter 100), and the sleeve can have internal threads configured to secure the syringes 20, 40 to the respective external devices (e.g., the adapter 100). The containers 20, 40 can be any conventional type of syringe and / or reciprocating pump suitable for use in a pharmaceutical environment.

[0057] The flanges 25, 45 can be actuated by being pulled to create a negative pressure to draw a substance into the chamber and / or being pushed to create a positive pressure to expel the substance from the chamber. At least portions of the first syringe 20 and the second syringe 40 can be connected integrally or releasably to enable combined manipulation and / or actuation of the first syringe 20 and the second syringe 40. For example, the system 10 can also have a barrel holder (not shown) having a first inner cavity configured to receive the first syringe body 22 and a second inner cavity configured to receive the second syringe body 42 such that the first syringe 20 and the second syringe 40 can be manipulated together. Each of the first inner cavity and the second inner cavity can be closed or formed by a C-shaped wall configured to snap around the respective syringe bodies 22, 42. The barrel holder can fix the syringe bodies 22, 42 in a substantially parallel arrangement. The system can also include a plunger clamp configured to translate the plunger rods 24, 44 together through the syringe bodies 22, 42 to push and / or pull the material with the same longitudinal translation. For example, the plunger clamp can be configured to attach to the flanges 25, 26, such as having grooves configured to releasably receive the flanges 25, 45. Embodiments of the barrel holder and / or the plunger clamp are further discussed in U.S. Patent Nos. 5,104,375, 6,840,921, and 8,240,511, the entire disclosures of which are expressly incorporated herein by reference.

[0058] The receiving container 60 can be a fixed - volume container, such as a vial that can be attached to the adapter 100 via a vial adapter 70. The vial 60 can include a glass vial 62 that encloses a chamber and has a crown and a neck. The chamber can be sealed by a vial seal at the crown, which is circumferentially attached by an aluminum strip. The vial adapter 70 can have a transverse top wall 72, a connector 74 extending upward from the top wall 72, and a skirt 76 extending downward from the top wall 72. The connector 74 can be a female Luer connector that includes external threads for threaded engagement with a male Luer - lock connector, such as the male Luer - lock connector of the adapter 100. The skirt 76 can be used to telescopically mount on the crown and / or neck of the vial 60. The skirt 76 can surround a cannula (not shown) extending downward from the top wall 72 and is configured to pierce the vial stopper. The cannula can have an inner lumen that is in fluid communication with the chamber of the glass vial 62 when piercing the vial stopper. The vial adapter 70 can be vented to draw air into the container 60 and facilitate the inhalation of fluid through the system. Further discussion of embodiments of the container 60 and / or the vial adapter 70 is provided in U.S. Patent Nos. 8,753,325 and 9,943,463, the entire disclosures of which are expressly incorporated herein by reference. The receiving container 60 can initially contain a buffer solution and is configured to receive materials injected from the first container 20 and the second container 40 and mixed in the adapter 100. Once the first and second components are introduced into the adapter 100, the resulting drug complex can be stored within the receiving container 60.

[0059] However, in some embodiments, the receiving container 60 can be a variable - volume container, such as a syringe, and one or both of the first container 20 and the second container 40 can be fixed - volume containers, such as vials. Further discussion of such embodiments is provided in U.S. Patent Publication 2023 / 0105059, the entire disclosure of which is expressly incorporated herein by reference. It is also contemplated that the first container 20 and the second container 40 can be embodied as the first container 20 and the second container 40 connected to a pump. Flow sensors can be connected to the first container 20 and the second container 40 to control the flow rates of the first and second substances.

[0060] The first storage container 80 and / or the second storage container 82 can have a structure similar to that of the receiving container 60, the discussion of which is all expressly incorporated herein. For example, each of the first storage container 80 and the second storage container 82 can be a fixed - volume container, such as one that encloses a chamber and has a crown 84 and a neck 85. The chamber can be sealed by a vial seal 86 at the crown 84, which is circumferentially attached by an aluminum strip. Each of the first storage container 80 and the second storage container 82 can be attached to the vial adapter 70 as discussed with reference to the receiving container 60.

[0061] The first substance in the first storage container 80 can be an aqueous solution. The aqueous solution can be any aqueous buffer that can be used to dissolve nucleic acids. For example, in some embodiments, the aqueous solution can be a solution of 20 mM citrate and 300 mM NaCl and have a pH in the range of 3 to 6. In some embodiments, the aqueous solution can be a 20 mM phosphate buffered solution (PBS) with a pH of 7. In some embodiments, the aqueous solution can be a solution of 5 mM to 25 mM sodium acetate buffer with a pH in the range of 4 to 6.

[0062] The second substance in the second storage container 82 can be a lipid solution, the composition of which wholly or partly comprises an organic solvent having lipids or a lipid mixture. The lipid solution can include clinical grade lipids dissolved in an organic alcohol solution (e.g., ethanol). In some embodiments, the lipid solution can be an alcohol solution of at least 25%. In some embodiments, the lipid solution can be an alcohol solution of at least 40%. In some embodiments, the lipid solution can be an alcohol solution of at least 60%. The alcohol solution is preferably an ethanol solution. Providing lipids in an increasing concentration of alcohol (e.g., an alcohol solution greater than 40%) allows the lipids in the alcohol solution to be diluted by the reconstructing agent without affecting the quality of the resulting drug complex. The lipid composition in the ethanol solution can be composed of ionizable lipids or cationic lipids or synthetic lipids, structural lipids, PEG-lipids or their derivatives and cholesterol or its derivatives. However, the second substance can include other nanoparticle-forming solutions.

[0063] The therapeutic agent can be carried in at least one of the first substance and / or the second substance. In a preferred embodiment, the therapeutic agent is carried in the first substance. The therapeutic agent can include nucleic acids, drugs, proteins, oligonucleotides, etc. that contain gene editing complexes. The nucleic acids can include RNA and / or DNA. The RNA can be in the form of oligonucleotide RNA, tRNA (transfer RNA), snRNA (small nuclear RNA), rRNA (ribosomal RNA), mRNA (messenger RNA), antisense RNA, siRNA (small interfering RNA), shRNA (short hairpin RNA), ncRNA (non-coding RNA), aptamers, ribozymes, chimeric sequences or derivatives of these groups. The gene editing complex can include gRNA (guide RNA), cas 9 protein, mRNA or DNA encoding the cas 9 protein or the CRISPR-cas9 gRNA complex. The DNA can be in the form of antisense, plasmid DNA, a part of plasmid DNA, pre-condensed DNA, polymerase chain reaction (PCR) products, vectors (P1, PAC, BAC, YAC, artificial chromosomes), expression cassettes, chimeric sequences, chromosomal DNA or derivatives of these groups.

[0064] In some embodiments, the therapeutic agent can be stored in a dehydrated and / or lyophilized state and reconstituted in an aqueous solution to form a first substance prior to introduction into the adapter 100. In such cases, the first storage container 80 can contain the dehydrated therapeutic agent, and the first container 20 can contain the aqueous solution. The aqueous solution can then be introduced from the first container 20 into the first storage container 80 to reconstitute the therapeutic agent. The first solution comprising the therapeutic agent can then be introduced into the first container 20 for introduction into the adapter.

[0065] The first substance (where the therapeutic agent is in a lyophilized state or as a solution) and the second substance can be adapted for transport and mid- or long-term storage at room temperature. Thus, the system 10 and adapter 100 disclosed herein may be able to mitigate the obstacles associated with storing and transporting RNA-LNP complexes at overly low temperatures. Additionally, the adapter 100 can be readily used at the point of care.

[0066] The first substance and the second substance can be mixed using an adapter as described herein. Mixing can result in a liposome formation that entraps the therapeutic agent while forming liposomes. Electrostatic interactions between the negatively charged therapeutic agent (e.g., nucleic acid or mRNA) and the positively charged cationic lipid can form an LNP encapsulating the therapeutic agent. When mRNA is included in the mixture, the LNP can encapsulate the mRNA to form an mRNA-LNP. The drug complex can be a monodisperse LNP. Thus, the system 10 and adapter 100 can be used to form an RNA-LNP (e.g., mRNA-LNP) complex ready for injection by mixing the components of an aqueous solution comprising RNA and a lipid solution. Considering a specific example of forming an mRNA-LNP drug complex, the complex can be formed by mixing a first substance comprising mRNA (or RNA) from the first container 20 and a second substance of a lipid solution from the second container 40 via any of the adapters disclosed herein.

[0067] Based on the expected mixture, the first storage container 80 and the second storage container 82 can have the same or different dimensions. Thus, any reference herein to two storage containers 80, 82 should be interpreted to include three or more storage containers 80, 82. It should be understood that if more than two components are to be mixed, more than two containers can be provided, where each container can contain at least one component. Additionally, any number of components can be provided in an unmixed state within a single container. In some embodiments, the first container 20 and the second container 40 can be pre-filled with the respective substances, such as embodied as pre-filled syringes, such that the first storage container 80 and the second storage container 82 can be omitted.

[0068] As Figures 2 to 4Further shown, the adapter 100 may include a body 101 having a first port 102 configured to connect to the syringe connector 26 of the first container 20 and a second port or connector member 104 configured to attach to the syringe connector 46 of the second container 40.

[0069] The first port 102 may be configured to be received by the first syringe connector 26 and have an external thread 106 configured to threadedly engage the internal thread of the first connector 26. Similarly, the second port 104 may be configured to be received by the second connector 46 and have an external thread 108 around the second tubular member 104 configured to threadedly engage the internal thread of the second syringe connector 46. For example, the ports 102, 104 may be female Luer connectors, and the connectors 26, 46 of the containers 20, 40 may be male Luer connectors. However, additionally or alternatively, the ports 102, 104 may be connected to the containers 20, 40 using other types of connections such as snap-fit, friction fit, and / or press-fit. The adapter 100 may be configured to connect to any number of first containers 20 and second containers 40, and the adapter 100 may have an equal number of ports 102, 104 for connecting to each of the containers 20, 40 accordingly. Additionally, one or more of the ports 102, 104 may include a one-way valve (not shown) to allow fluid to flow from the containers 20, 40 into the adapter 100 and restrict or substantially prevent fluid from flowing out of the adapter 100 back into the respective containers 20, 40.

[0070] The first port 102 may define a first connector channel or port 110, and the second connector member 104 may define a second connector channel 112. In some embodiments, the first connector channel 110 may be configured to receive the tip of the first syringe 20 to place the chamber of the first syringe body 22 in fluid communication with the first connector channel 110, and the second connector channel 112 may be configured to receive the tip of the second syringe 40 to place the chamber of the second syringe body 42 in fluid communication with the second connector channel 112. The first tubular member 102 and the second tubular member 104 may extend substantially parallel to each other to facilitate the combined actuation of the syringes 20, 40, as discussed herein. In some embodiments, as Figures 1 to 4 shown, the first tubular member 102 and the second tubular member 104 may extend substantially parallel to the longitudinal axis of the adapter body 101.

[0071] The adapter body 101 may further include a first branch member 114, a second branch member 116, and a mixing member 118. The first port 102 may extend from the first branch member 114, and the first branch member 114 may connect the first port 102 to the mixing member 118. The second port 104 may extend from the second branch member 116, and the second branch member 116 may connect the second port 104 to the mixing member 118. The first branch member 114 may have a first branch channel 120 configured to receive a fluid flow from the first container 20 through the first connector channel 110, and the second branch member 116 may have a second branch channel 122 configured to receive a fluid flow from the second container 40 through the second connector channel 112. The first and second branch channels 120 and 122 may communicate with a first or upper portion of the mixing chamber 124. The first branch channel 120 and the second branch channel 122 may be angled relative to the longitudinal axis of the mixing member 118, the adapter body 101, and / or the mixing pin 160 to converge the fluid flows from the first syringe 20 and the second syringe 40 into the mixing member 118. The angle of at least one of the first branch channel 120 and the second branch channel 122 relative to the mixing member 118, the adapter body 101, and / or the mixing pin 160 may be at least 90 degrees. As further shown, the angle of at least one of the first branch channel 120 and the second branch channel 122 relative to the mixing member 118, the adapter body 101, and / or the mixing pin 160 may be about 120 degrees to 160 degrees. The first branch channel 120 and the second branch channel 122 may form a Y shape with the mixing member 118. This configuration of the branch channels 120, 122 and the ports 102, 104 may be advantageous for manual mixing such that the syringes can be syringes 22, 42 that are sufficiently spaced apart to be able to be assembled on the adapter body 101 while allowing for the combined actuation of the syringes 22, 42. However, other configurations may be applied in other applications. For example, the ports 102, 104 may be closer together when configured to attach to microtubing of a pump.

[0072] The first branch channel 120 and the second branch channel 122 may be aligned with the central plane of the adapter body 101, and the first branch channel 120 and the second branch channel 122 may direct the first substance and the second substance to opposite faces of the mixing pin 160 and / or create a confluence between the two fluids for initial mixing. In some embodiments, for applications in which the first substance and the second substance require the same flow rate, the first branch channel 120 and the second branch channel 122 may have the same or substantially the same width or diameter (as Figure 3 and Figure 8 shown). In some embodiments (as Figure 11 and Figure 12As shown, for applications where the first and second substances require different flow rates, the first branch channel 120 and the second branch channel 122 may have different widths or diameters. For example (as Figure 11 and Figure 12 further shown), the first branch channel 120 may have a greater width or diameter than the second branch channel 122. In some embodiments (such as Figure 2 , Figure 3 and Figure 8 shown), at least one or both of the first branch channel 120 and the second branch channel 122 may be formed with an open outer end, and the adapter 100 may include a plug 140 inserted into one or both of the branch members 114, 116 to seal the outer ends of the corresponding branch channels 120, 122. In some embodiments (such as Figure 11 shown), at least one or both of the first branch channel 120 and the second branch channel 122 may have a closed outer end formed by the adapter body 101.

[0073] The plug 140 may be removable, replaceable, interchangeable, and / or adjustable. The plug 140 may facilitate the manufacture of the adapter body 101 by allowing the formation of the branch channels 120, 122 in the adapter body 101 by inserting a straight pin (not shown) through injection molding. The pin may be removed from the syringe body 101 through an opening after formation, and the plug 140 may be inserted to seal the openings in the branch channels 120, 122. In some embodiments, the plug 140 may further extend through the branch channels 120, 122 to reduce the negative space in the branch channels 120, 122. For example, as Figure 23 and Figure 24As shown, the plug 140 may include pins 642 that occupy space in the branch channels 120, 122 to reduce the negative space. In this way, the inventors have found that the volume of the branch channels 120, 122 can be reduced or optimized without creating manufacturing complexities during injection molding and / or 3D printing of the small parts in the adapter 101. Additionally, replacing and / or adjusting the plug 140 can change the inlet volume of one or both of the first connector channel 110 and / or the second connector channel 112. For example, the plug 140 can be replaced with a similar plug 140 having different lengths and / or geometries to at least partially occlude one or both of the first connector channel 110 and / or the second connector channel 112. In some embodiments, the plug 140 can be adjusted by being pushed or translated into the branch channels 120, 122 to at least partially occlude one or both of the first connector channel 110 and / or the second connector channel 112. In some embodiments, the plug 140 can have an adjustable length, such as being telescopic to at least partially occlude one or both of the first connector channel 110 and / or the second connector channel 112. Changing the inlet volume using the plug 140 can adjust the fluid mixing ratio and / or reduce the dead volume of the fluid remaining inside the adapter body 101.

[0074] The mixing member 118 may have a mixing chamber 124 configured to receive a mixing pin 160. The mixing pin 160 may be removably inserted into the mixing chamber 124, for example to allow interchange of the mixing pins 160, 260, 360, 460, 660, 760 depending on the intended application and / or substances. More specifically, the geometry of the mixing pins 160, 260, 360, 460, 660, 760 may affect the properties of the drug complex such that the adapter 100 is configured to produce different types of LNPs based on the intended application. The adapter body 101 may have an opening 126 that is longitudinally aligned with and in communication with the mixing chamber 124. The mixing pin 160 may be inserted into the mixing chamber 124 through the opening 126. The opening 126 may be on an upper portion of the body 101, between the first port 102 and the second port 104, and in communication with an upper portion of the mixing chamber 124. As further shown, the mixing pin 160 may include a flange 162, and the body 101 may include a countersunk recess 128 configured to receive the flange 162 when the mixing pin 160 is inserted into the mixing chamber 124. The opening 126 and / or the recess 128 may have a non-circular and / or axially asymmetric cross-section, and the flange 162 may have a non-circular and / or axially asymmetric cross-section corresponding to the opening 126 and / or the recess 128 to ensure that the mixing pin 160 is inserted into the mixing chamber 124 in a specific orientation. For example, the recess 128 and the flange 162 may each be non-circular but bilaterally symmetric, such as a substantially D-shaped cross-section, to ensure proper alignment of the mixing pin 160 relative to the branch channels 120, 122. The cross-sections of the recess 128 and the flange 162 may similarly be rectangular and / or elliptical. In some embodiments (as Figures 2 to 4 shown), the recess 128 may be in a tubular member 129 that extends upward between the branch members 114, 116 from the mixing member 118. As Figure 4 shown, the tubular member 129 may have a width or diameter greater than the width of the mixing member 118 to receive the flange 162. In some embodiments (as Figure 8 shown), the tubular member 129 may be omitted. The mixing pin 160 may be releasably fixed in the mixing chamber 124 by a press fit of the flange 162 within the recess 128. However, additionally or alternatively, the mixing pin 160 may be releasably fixed in the mixing chamber 124 by a snap fit, a clip, a threaded connection, and / or a bayonet connection. The mixing chamber 124 may have a substantially uniform cross-section below the branch channels 120, 122, which at least partially defines at least one microfluidic flow path and / or microfluidic channel for the flow of the first substance and the second substance.

[0075] The mixing pin 160 may have a sealing portion 164 that extends below the flange 162. The sealing portion 164 may have a width or diameter that is less than the width or diameter of the flange 162 and is received in the upper portion of the mixing chamber 124 below the flange 162. The sealing portion 164 may have a shape configured to seal the upper portion of the mixing chamber 124. The sealing portion 164 may be cylindrical.

[0076] At least one flow path may be defined at least partially around the mixing pin 160 for turbulently mixing a first flow of a first material and a second flow of a second material. The mixing pin 160 may include side surfaces on opposite sides, each side surface pointing to one of the branch channels 120, 122. Each of the side surfaces may be configured to divide the flow from one of the branch channels 120, 122 into two separate flow streams. For example, the side surface of the mixing pin 160 pointing to the first branch channel 120 may have a first surface and a second surface 166 that join at a first edge 168. The side surface of the mixing pin 160 pointing to the second branch channel 122 may have a first surface and a second surface 170 that join at a second edge 172. The mixing pin 160 may be inserted into the body 101 such that the first edge 168 and the second edge 172 are aligned with the transverse axis of the adapter body 101. The first edge 168 may be aligned with the first branch channel 120, and the second edge 172 may be aligned with the second branch channel 122 such that the edges 168, 172 may direct or divert the fluid flow from the branch channels 120, 122 around the mixing pin 160. The first edge 168 may divide the fluid flow from the first branch channel 120 into a first fluid path along the first surface of the surfaces 166 and a second fluid path along the second surface of the surfaces 166. Similarly, the second edge 172 may divide the fluid flow from the second branch channel 122 into a first fluid path along the first surface of the surfaces 170 and a second fluid path along the second surface of the surfaces 170. Each of the surfaces 166, 170 may be substantially flat, and the edges 168, 172 may be substantially sharp, blunt, or slightly rounded to reduce interference with the pre-mixed flow from the branch channels 120, 122. The mixing pin 160 may have one or more side surfaces 174 on each side of the mixing pin 160. Each of the side surfaces 174 may extend between a pair of surfaces 166, 170. As Figure 4 shown, the side surface 174 may define a radial width that is less than the radial width of the sealing portion 164 to define a space inside the mixing chamber 124 for the flow for initially mixing the first material and the second material. The side surface 174 may also allow longitudinal movement of the fluid flow.

[0077] The at least one flow path may be tortuous. For example, the at least one flow path may be at least partially defined by at least one helical channel 176, 178. The at least one helical channel 176, 178 may include a first helical channel 176 and a second helical channel 178. The first helical channel 176 and the second helical channel 178 may have different orientations and / or extend in opposite helical directions. At least one side surface 174 may extend below the surface / edge 166 - 172 and fluidly communicate with at least one of the helical channels 176, 178. As shown, the mixing pin 160 may include a pair of side surfaces 174, each side surface being in fluid communication with at least one of the first helical channel 176 and the second helical channel 178. However, in some embodiments, the mixing pin 160 may have a single side surface that is in fluid communication with both the first helical channel 176 and the second helical channel 178. The first helical channel 176 and the second helical channel 178 may intersect at a plurality of intersection points 180 on opposite lateral sides of the mixing pin 160 along the longitudinal length of the mixing pin 160 to create turbulence and mix the first material and the second material. The first helical channel 176 and the second helical channel 178 may form a double helix. When the components pass through the mixing chamber 124 together, turbulence is caused by the tortuous path around the mixing pin 160, so that the components transition from an unmixed state to a mixed state. When the fluid passes through the intersection point 180, a local change is caused in the fluid flow direction. Therefore, when the fluid passes through the intersection point 180, the degree of turbulence (i.e., the Reynolds number) of the fluid flow increases. When the degree of turbulence increases, the parallelism of the components of the fluid flow decreases, so that the degree of mixing can increase. Therefore, increasing the turbulence of the fluid in the mixing chamber can promote the mixing of the components of the fluid. A drug complex may thus be formed from a first component and a second component that pass through the mixing chamber 124 together. The drug complex may exit the first helical channel 176 and the second helical channel 178 of the mixing pin 160 to pass through the bottom portion of the adapter body 101 and then exit the adapter 100 through the tip channel 125 into the receiving container 60.

[0078] Thus, for any given application of the adapter 100, the geometry of the first helical channel 176 and the second helical channel 178 can be selected depending on the degree of turbulence required to achieve the desired amount of mixing. For example, the pitch of the first helical channel 176 and the second helical channel 178 can be designed for the desired turbulence. For applications where a higher degree of turbulence is required to achieve the desired mixing (such as where lipid nanostructures are to be formed), the first helical channel 176 and the second helical channel 178 can have a reduced pitch and a greater number of intersections 180. However, as the number of intersections 180 increases, the resistance of the fluid flowing through the mixing chamber 124 also increases. On the other hand, for applications where a low degree of turbulence is required to achieve the desired mixing or where a lower flow volatility is required to maintain certain physical properties of the components during mixing, the first helical channel 176 and the second helical channel 178 can have a steeper pitch and a smaller number of intersections 180. Thus, the pitch of the first helical channel 176 and the second helical channel 178 can be selected to provide the desired degree of mixing while avoiding impractically high resistance when used with a manually driven syringe. With this in mind, in one particular embodiment, the inventors have found that an arrangement of 8 - 40 intersections 180 (such as 8 - 12 intersections 180) is particularly useful for producing mRNA-LNP or RNA-LNP compositions. However, as the reader will appreciate, different numbers of bends can be used in different contexts.

[0079] The first helical channel 176 and the second helical channel 178 may be formed by grooves or indentations in the outer surface of the mixing pin 160. The first helical channel 176 and the second helical channel 178 may be microfluidic paths to reduce the effect of volume forces on the fluid flow. The first helical channel 176 and the second helical channel 178 may have a width in the range of about 100 μm to about 1000 μm and / or a depth of about 100 μm to about 1000 μm. However, the width and / or depth is preferably about 400 μm to about 1000 μm for ease of manufacture. In a preferred embodiment, the inventors have found that when the width and / or depth of the first helical channel 176 and the second helical channel 178 is about 400 μm to about 600 μm, a drug complex (e.g., mRNA-LNP) can be formed consistently and rapidly. Smaller channels may be used to increase the velocity of the fluid flowing through the mixing chamber 124, which may further improve mixing. At these scales, the effect of the tortuous path on fluid turbulence may be amplified compared to fluid paths with larger channels, and mixing is increased. The higher the velocity of the fluid passing through the mixing chamber 124, the higher the amount of turbulence induced, and thus the higher the degree of turbulence across the mixing chamber 124. However, smaller channels increase pressure and resistance. The disclosed three-dimensional flow path or channels allow for optimal formation of the drug complex by increasing the total flow volume through the adapter 100 and reducing the necessary pressure imposed by the containers 20, 40.

[0080] The adapter body 101 may have a third port or connector member 130 at the bottom portion of the mixing member 118. The third connector member 130 may be a male Luer connector that includes a tip 132 and a sleeve 134 that is configured to be attached to the receiving container 60 via the vial adapter 70. The tip 132 may have a tip channel 125 that communicates with the second or bottom portion of the mixing chamber 124. The tip 132 may be received in the connector 74 of the vial adapter 70, and the sleeve 134 may be threadedly connected to the outer surface of the connector 74 in a Luer connection. The third connector member 130 may be a male Luer connector that is configured to connect to the female Luer connector of the vial adapter 70. However, additionally or alternatively, the connector member 130 may be connected to the receiving container 60 with other types of connections such as snap-fit and / or press-fit. The tip channel 125 may provide a passage for the mixed composition from the mixing chamber 124 to the receiving container 60.

[0081] The adapter body 101 can be formed of a polymer, metal, and / or glass. In a preferred embodiment, the adapter body 101 can be formed as a single integral piece (e.g., by injection molding or 3D printing) including a first port 102, a second port 104, a mixing member 118, a tubular member 129, and / or a connector member 130. Alternatively, the adapter body 101 can be formed of two pieces (e.g., two halves) that are fixed or fused together, each piece being metal, polymer, or glass. To increase the ease with which the fluids to be mixed flow through the adapter 100, a low surface energy material can be used for at least a portion of the adapter body 101. For example, the adapter body 101 and / or the mixing pins 160 can be formed of or coated with a low surface energy material such as ethylene tetrafluoroethylene (ETFE). Other low surface energy materials can also be used, such as fluoropolymer materials other than ETFE. Alternatively, at least one path can be treated to reduce the surface energy. The sides of the channels forming the low surface energy material can reduce the loss of components across the mixing chamber 124 during use, and thus can enable the adapter 100 to operate more effectively. Although the low surface energy material can provide additional advantages in some embodiments, it is an optional feature of the present disclosure.

[0082] Figure 8 and Figure 9 shows Figures 1 to 4A second embodiment of the mixing pin 260 in the adapter 100. Unless otherwise stated, the disclosure of the mixing pin 160 is expressly incorporated herein. As further discussed herein, the mixing pin 260 can be inserted into the mixing chamber 124 of the adapter 100, where the flange 262 is received in the recess 128, and the sealing portion 264 seals the upper portion of the mixing chamber 124. A first substance can be introduced into the first port 102, and a second substance can be introduced into the second port 104. The first substance can pass through the first connector channel 110 and the first branch channel 120 and enter the mixing chamber 124. The second substance can pass through the second connector channel 114 and the second branch channel 122 and enter the mixing chamber 124. The mixing pin 260 can include a plurality of radial protrusions 282 that longitudinally define a first channel 284 therebetween and are radially positioned between the mixing pin 260 and the inner wall of the adapter body 101. The protrusions 282 can extend at least partially around the circumference of the mixing pin 260 and create at least one microfluidic flow path. For example, the protrusions 282 can extend uniformly around the entire circumference of the mixing pin 260 to create a constriction in the mixing chamber 124. In some embodiments, the protrusions 282 can have a substantially uniform outer dimension (e.g., circumference) that is slightly smaller than the inner dimension (e.g., circumference) of the inner wall of the adapter body 101. A second channel 286 can be defined by the gap between the outer dimension of the protrusions 282 and the inner wall of the adapter body 101 to cause turbulence to advantageously mix the materials. The second channel 286 can be smaller than the first channel 284, thereby creating a constriction. In some embodiments, the mixing pin 260 can create a microfluidic path having at least two alternating dimensions including the first channel 284 and the second channel 286 such that the cross-sectional area of the path varies along its length. By including at least two alternating inner dimensions, the fluid flowing through the mixing chamber 124 can experience repeated acceleration and deceleration, thus causing further turbulence in the mixing chamber 124. In a preferred embodiment, the first channel 284 can have a diameter or width of about 250 μm to about 1000 μm, and the second channel 286 can have a width or diameter of about 50 μm to about 200 μm.

[0083] Figures 10 to 12 shows Figures 1 to 4A third embodiment of the hybrid pin 360 of the system 10. Unless otherwise stated, the disclosure of the hybrid pins 160 and / or 260 is expressly incorporated herein. As further discussed herein, the hybrid pin 360 may be inserted into the mixing chamber 124 of the adapter 100, where the flange 362 is received in the recess 128, and the sealing portion 364 seals the upper portion of the mixing chamber 124. A first substance may be introduced into the first port 102, and a second substance may be introduced into the second port 104. The first substance may pass through the first connector channel 110 and the first branch channel 120 and enter the mixing chamber 124. The second substance may pass through the second connector channel 114 and the second branch channel 122 and enter the mixing chamber 124.

[0084] The at least one microfluidic flow path may be tortuous. The at least one flow path may pass through, longitudinally along, and / or circumferentially around the hybrid pin 360. As further shown, the hybrid pin 360 may include at least one first protrusion 382 and at least one second protrusion 383 disposed along the longitudinal length of the hybrid pin 360. The at least one first protrusion 382 and the at least one second protrusion 383 may be longitudinally spaced apart by a first channel 384 defined by a portion of reduced width or diameter of the hybrid pin 360. Each of the at least one first protrusion 382 and the at least one second protrusion 383 may have lateral symmetry. For example, each of the protrusions 382, 383 may include at least one first surface 388 and at least one second surface 389, the at least one first surface being configured to form a seal against the inner surface of the adapter body 101 when inserted into the mixing chamber 124, the at least one second surface forming a second channel 386 formed by a radial clearance relative to the inner surface of the mixing member 118 and being configured to allow flow to pass longitudinally through the mixing chamber 124 and create mixing between opposing circumferential flows around the first channel 384 of the hybrid pin 360. The at least one first surface 388 may be curved to approximate the inner wall of the adapter body 101, and the at least one second surface 389 may be flat to form the second channel 386 relative to the inner wall of the adapter body 101. For example, the protrusions 382, 383 may have a substantially rectangular geometry having a first width defining a pair of first circular side surfaces 388 and a second width defining a pair of second straight side surfaces 389, where the first width is greater than the second width. However, it is also contemplated that one or both or all of the protrusions 382, 383 may define only a single second surface 389 and thus only a single second channel 386, with the remaining circumference being defined by the curved first surface 388. Thus, the second channel 386 may be smaller than the first channel 384. For example, the second channel 386 may be from about 250 μm to about 1000 μm, and the groove 384 may be from about 50 μm to 200 μm.

[0085] The first passage 384 and the second passage 386 may jointly define at least one passage along the longitudinal length of the mixing pin 360 to provide at least one flow path. As Figure 10 and Figure 11 Further shown, the first protrusion 382 and the second protrusion 383 may be radially offset such that the second passage 386 is not longitudinally aligned along the mixing chamber. The first protrusion 382 and the second protrusion 383 may alternate. For example, in a preferred embodiment (as Figure 10 shown), the longitudinally adjacent first protrusion 382 and second protrusion 383 may be offset by 90 degrees and may be longitudinally arranged in the following order: one first protrusion 382, followed by one second protrusion 383, followed by another first protrusion 382, followed by another second protrusion 383, and so on. The misalignment of the second passage 386 may enhance the mixing of the material by requiring the material to travel circumferentially around the mixing pin 360 in order to pass through at least one first surface 388, and the opposing fluid flows will converge at the second passage 386 along the mixing pin 360. However, it is contemplated that additional protrusions with other arrangements may be provided.

[0086] As further shown, the mixing pin 360 may define a closed passage or lumen 390 through an upper portion below the sealing portion 364, the closed passage or lumen being configured to receive a fluid flow, perform an initial mixing, and / or introduce the fluid flow into at least one path of the mixing pin 360 and the mixing chamber 124. The lumen 390 may have a pair of inlet openings 391, each inlet opening communicating with one of the branch channels 120, 122. The lumen 390 may have a first section 390a extending transversely to the longitudinal axis of the mixing pin 360, where opposing fluid flows from the branch channels 120, 122 converge for initial mixing. The lumen 390 may be a second section 390b extending along the longitudinal axis of the mixing pin. The fluid may travel through the second section 390b, and through a second transverse section (not shown), and exit through one or more outlet openings 392 into at least one path defined by the first protrusion 382 and the second protrusion 383. The lumen 390 may have a pair of outlet openings 392, each outlet opening longitudinally aligned with one of the first side surfaces 388 such that the circumferential fluid flow must pass through one of the first passages 384. The inlet openings 391 may each extend through an edge 368 formed by the adjacent surfaces 366. The first edge 368 may be aligned with the first branch channel 120, and the second edge (not shown) may be aligned with the second branch channel 122. The surface 366 may extend to the outer diameter of the mixing pin 360 that contacts the inner surface of the mixing chamber 124. The second sealing portion 365 may be below the surface 366 and have a shape configured to seal around the mixing pin 360 so as to force through the inlet openings 391. The second sealing portion 365 may be cylindrical.

[0087] Figure 13Shows Figures 1 to 4 A fourth embodiment of the mixing pin 460 of the system 10. Unless otherwise stated, the disclosure of the mixing pins 160, 260, and / or 360 is expressly incorporated herein. As further discussed herein, the mixing pin 460 can be inserted into the mixing chamber 124 of the adapter 100, where the flange 462 is received in the recess 128, and the sealing portion 464 seals the upper portion of the mixing chamber 124. A first substance can be introduced into the first port 102, and a second substance can be introduced into the second port 104. The first substance can pass through the first connector channel 110 and the first branch channel 120 and enter the mixing chamber 124. The second substance can pass through the second connector channel 114 and the second branch channel 122 and enter the mixing chamber 124.

[0088] At least one path can be defined at least partially around the mixing pin 460 for turbulently mixing a first stream of the first substance and a second stream of the second substance. The mixing pin 460 can include a side portion facing one of the branch channels 120, 122, the side portion configured to divide the flow from at least one of the branch channels 120, 122 into two separate flow streams. For example, the side portion of the mixing pin 460 facing the first branch channel 120 can have a first surface and a second surface 466 that meet at a first edge 468. Additionally or alternatively, the side portion of the mixing pin 460 facing the second branch channel 122 can have a first surface and a second surface 470 that meet at a second edge (not shown). The first edge 468 and the second edge can be aligned with the transverse axis of the mixing pin 460 and / or the transverse axis of the body 101. The first edge 468 can be aligned with the first branch channel 120, and the second edge 172 can be aligned with the second branch channel 122 such that the edge 468 can direct or divert the fluid flow from the branch channels 120, 122 around the mixing pin 460. The first edge 468 can divide the fluid flow from the first branch channel 120 into a first fluid path along the first surface of the surfaces 466 and a second fluid path along the second surface of the surfaces 466. Similarly, the second edge can divide the fluid flow from the second branch channel 122 into a first fluid path along the first surface of the surfaces 470 and a second fluid path along the second surface of the surfaces 470. Each of the surfaces 166, 170 can be substantially flat, and the edge 468 can be substantially sharp, blunt, or slightly rounded to reduce interference with the flow from the branch channels 120, 122. The mixing pin 460 can have one or more side surfaces 474 on each side of the mixing pin 460. Each of the side surfaces 474 can extend between a pair of surfaces 466, 470. As shown, the side surface 474 can define a radial width less than that of the sealing portion 464 to define a space for the flow for initially mixing the first material and the second material inside the mixing chamber 124.

[0089] The at least one path of the mixing pin 460 may include a first path along a first side of the mixing pin 460 and a second path along a second side of the mixing pin 460. A first side surface of the side surfaces 474 may extend downward and define an inner surface of the first path, and a second side surface of the side surfaces 474 may extend downward and define an inner surface of the second path. The side surfaces 474 may be on opposite sides of the mixing pin 460 and separated by a first convex sealing surface and a second convex sealing surface 465. The sealing surfaces 465 may abut an inner surface of the mixing chamber 124 to prevent fluid from passing between the first path and the second path. The sealing surfaces 465 may extend from an edge 468 at an upper portion of the mixing chamber 124 to a lower portion of the mixing chamber 124 to divide the first fluid path and the second fluid path into two distinct fluid paths. The first fluid path may include a plurality of first protrusions 482 that extend laterally or project from the first side surface 474. The plurality of first protrusions 482 may form an obstruction and flow constriction to the fluid path to create turbulence to effect mixing in the first fluid path. Similarly, the second fluid path may include a plurality of second protrusions 484 that extend laterally or project from the second side surface 474. The plurality of second protrusions 484 may form an obstruction and flow constriction to the fluid path to create turbulence to effect mixing in the second fluid path. For example, the protrusions 482, 484 may divide each of the fluid paths and / or form narrow gaps therebetween to restrict fluid flow, thereby causing local accelerations, intersections, and / or vortices in the fluid flow. Each of the protrusions 482, 484 may have an angled or V-shaped proximal portion that divides the fluid flow. One of the divided fluid streams may follow a path formed between a circular distal portion of the protrusions 482, 484 and a concave portion of the protrusions 482, 484 adjacent distally thereto and collide with the other divided fluid stream to create vortices and turbulence. The protrusions 482, 484 of each of the lateral sides 474 may form an improved Tesla valve to provide turbulence with improved mixing. The first path and the second path may converge at a lower end of the mixing chamber 124 and / or in the tip passage 125 to enter the receiving container 60.

[0090] Figure 14 is shown Figures 1 to 4Second embodiment of the adapter 500 of the system 10. The adapter 500 may include a body 501 having a first port 502 configured to attach to the syringe connector 26 of the first container 20 and a second port 504 configured to attach to the syringe connector 46 of the second container 40. The adapter body 501 may further include a first branch member 514, a second branch member 516, and a mixing member 518. The first port 502 may extend from the first branch member 514, and the first branch member 514 may connect the first port 502 to the mixing member 518. The second port 504 may extend from the second branch member 516, and the second branch member 516 may connect the second port 504 to the mixing member 518. The first branch member 514 may have a first branch channel 520 configured to receive a fluid flow from the first syringe 20 through the first port 502, and the second branch member 516 may have a second branch channel 522 configured to receive a fluid flow from the second syringe 40 through the second port 504. The first branch channel 520 and the second branch channel 522 may be angled relative to the longitudinal axis of the adapter body 501 and / or the mixing pin 160 to converge the fluid flows from the first syringe 20 and the second syringe 40 into the mixing member 518. The angle of at least one of the first branch channel 520 and the second branch channel 522 relative to the mixing chamber 524, the adapter body 501, and / or the mixing pin 160 may be greater than 90 degrees. As further shown, the angle of at least one of the first branch channel 520 and the second branch channel 522 relative to the mixing chamber 524, the adapter body 501, and / or the mixing pin 160 may be from about 120 degrees to 160 degrees. However, other configurations may be applied in other applications, as discussed herein. The first branch channel 520 and the second branch channel 522 may be aligned with the central plane of the adapter body 501 such that the first branch channel 520 and the second branch channel 522 direct the first substance and the second substance to opposite faces of the mixing pin 160. The first branch channel 520 and the second branch channel 522 may form a Y shape with the mixing member 518. Unless otherwise stated, the disclosure of the adapter 100 is hereby expressly incorporated herein. Although shown with the mixing pin 160, the adapter 500 may include any other disclosed mixing pin.

[0091] As further shown, the adapter body 501 may be formed separately from at least one or all of the ports 102, 104, 130. For example, the adapter body 501 may be formed by injection molding or 3D printing, and the ports 102, 104, 130 may be formed separately and coupled to the adapter body 501 by press fit, threaded fit, and / or snap fit. The adapter 500 may further include a retainer 594 configured to be applied to the adapter body 501 to secure the mixing pin 160 in the mixing chamber 124. As shown, the retainer 594 may include a plate secured to the adapter body 501 with one or more threaded fasteners 195. However, additionally or alternatively, the retainer 594 may include other structures, such as clips, sliding doors, or pivot doors. The adapter 500 may further include a seal member 595 configured to seal the proximal end of the mixing chamber 524. The seal member 595 may be a component separate from the mixing pin 160. For example, the seal member 595 may be an elastomeric O-ring disposed around the proximal portion of the mixing pin 160, such as at the seal portion 164. The adapter 500 may include a plug 540 inserted into one or both of the branch members 514, 516 to seal the outer ends of the respective branch channels 520, 522. The plug 540 may have an interface to receive the distal end actuator of a tool for adjustment and / or removal. For example, as shown, the plug 540 may include one or more slots that may mate with a flat head, Phillips head, Torx head, and / or hex head actuator of a tool or screwdriver.

[0092] Figures 15 to 24 Shows Figures 1 to 4 A third embodiment of an adapter 600 of the system 10. As shown, the adapter 600 may include a body 601 having a first port or connector member 602 configured to attach to a syringe connector 26 of a first container 20 and a second port or connector member 604 configured to attach to a syringe connector 46 of a second container 40. The adapter 600 may include a mixing member 618 that receives a mixing pin 660. Unless otherwise stated, the disclosures of the adapters 100, 500 and / or the mixing pins 160, 260, 360, 460 are all expressly incorporated herein.

[0093] The first port 602 can be configured to be received by the first syringe connector 26 and have an external thread 606 that is configured to threadedly engage an internal thread of the first syringe connector 26. The second connector 604 can be configured to be received by the second connector 46 and have an external thread 608 around the second tubular member 608 that is configured to threadedly engage an internal thread of the second syringe connector 46. For example, the first port 602 can be a female Luer connector, and the connector 26 of the first syringe 20 can be a male Luer connector. However, additionally or alternatively, the ports 602, 604 can be connected to the containers 20, 40 using other types of connections such as snap-fit, friction-fit, and / or press-fit connections. The adapter 600 can be configured to connect to any number of first containers 20 and second containers 40, and the adapter 100 can have an equal number of ports 602, 604 for connecting to each of the containers 20, 40 accordingly. Additionally, one or more of the ports 602, 604 can include a one-way valve (not shown) to allow fluid to flow from the containers 20, 40 into the adapter 600 and restrict or substantially prevent fluid from flowing out of the adapter 600 back into the respective containers 20, 40.

[0094] The first port 602 can define a first connector channel 610, and the second connector member 604 can define a second connector channel 612. The first connector channel 610 can be configured to receive the tip of the first syringe 20 to place the chamber of the first syringe body 22 in fluid communication with the first connector channel 610, and the second connector channel 612 can be configured to receive the tip of the second syringe 40 to place the chamber of the second syringe body 42 in fluid communication with the second connector channel 612. The first port 602 and the second port 604 can extend substantially parallel to each other to facilitate the combined actuation of the syringes 20, 40. In some embodiments, as Figure 15 shown, the first port 602 and the second port 604 can extend substantially parallel to the longitudinal axis of the adapter body 601.

[0095] The adapter body 601 may further include a first branch member 614 and a second branch member 616. The first port 602 may extend from the first branch member 614, and the first branch member 614 may connect the first port 602 to the mixing member 618. The second port 604 may extend from the second branch member 616, and the second branch member 616 may connect the second port 604 to the mixing member 618. The first branch member 614 may have a first branch channel 620 configured to receive a fluid flow from the first syringe 20 through the first connector channel 610, and the second branch member 616 may have a second branch channel 622 configured to receive a fluid flow from the second syringe 40 through the second connector channel 612. The first and second branch channels 620 and 622 may communicate with an upper portion of the mixing member 618. The first branch channel 620 and the second branch channel 622 may be angled relative to the longitudinal axis of the adapter body 601 and / or the mixing pin 660 to converge the fluid flows from the first syringe 20 and the second syringe 40 into the mixing member 618. The angle of at least one of the first branch channel 620 and the second branch channel 622 relative to the mixing member 618, the adapter body 601, and / or the mixing pin 160 may be greater than 90 degrees. As further shown, the angle of at least one of the first branch channel 620 and the second branch channel 622 relative to the mixing member 618, the adapter body 601, and / or the mixing pin 160 may be about 120 degrees to 160 degrees. However, other configurations may be applied in other applications, as discussed herein. The first branch channel 620 and the second branch channel 622 may be oriented to deviate from or not align with the central plane of the adapter body 601 (as indicated by the central axis A shown in Figure 16 ). In some embodiments, for applications where the first and second substances require the same flow rate, the first branch channel 620 and the second branch channel 622 may have the same or substantially the same width or diameter (as shown in Figure 15 ). In some embodiments (as shown in Figure 11 and Figure 12 ), for applications where the first and second substances require different flow rates, the first branch channel 620 and the second branch channel 622 may have different widths or diameters. For example (as further shown in Figure 11 and Figure 12 ), the first branch channel 620 may have a greater width or diameter than the second branch channel 622. In some embodiments (as shown in Figure 2 , Figure 3 and Figure 8As shown, at least one or both of the first branch channel 620 and the second branch channel 622 may be formed with an open outer end, and the adapter 600 may include plugs 640 inserted into one or both of the branch members 614, 616 to seal the outer ends of the corresponding branch channels 620, 622. In some embodiments (as Figure 11 shown), at least one or both of the first branch channel 620 and the second branch channel 622 may have a closed outer end formed by the adapter body 601.

[0096] The plugs 640a, 640b may be removable, replaceable, interchangeable, and / or adjustable. The plugs 640a, 640b may facilitate the manufacture of the adapter body 601 by allowing the formation of the branch channels 620, 622 in the adapter body 601 by inserting a straight pin (not shown) through injection molding. The pin may be removed from the syringe body 601 through an opening after formation and a plug 640 may be inserted to seal the opening in the branch channels 620, 622, as discussed above with reference to plug 140 which is expressly incorporated herein. Replacing and / or adjusting plug 640a may change the inlet volume of one or both of the first connector channel 610 and / or the second connector channel 612. For example, the plugs 640a, 640b may be replaced with similar plugs 640a, 640b having different lengths and / or geometries to at least partially occlude one or both of the first connector channel 610 and / or the second connector channel 612. In some embodiments, the plug 640 may be adjusted by being pushed or translated into the branch channels 620, 622 to at least partially occlude one or both of the first connector channel 610 and / or the second connector channel 612. In some embodiments, the plug 640 may have an adjustable length, such as being telescopic to at least partially occlude one or both of the first connector channel 610 and / or the second connector channel 612. Changing the inlet volume using plugs 640a, 640b may adjust the fluid mixing ratio and / or reduce the dead volume of the fluid remaining inside the adapter body 601. As Figures 23 to 24As shown, the plugs 640a, 640b may include end caps 641 and pins 642. The end caps 641 may be configured to attach to the branch channels 620, 622 to secure the plugs 640a, 640b. The pins 642 may be configured to extend into at least one of the branch channels 620, 622. As further discussed with respect to plug 140 (the discussion of which is expressly incorporated herein), the pins 642 may be configured to occupy space in the branch channels 620, 622 to reduce negative space. The plugs 640a, 640b may also include grooves 643 configured to receive a sealing member (not shown). The plugs 640a, 640b may be the same or different for each of the branch channels 620, 622. For example, the plugs 640a, 640b for one of the branch channels 620, 622 may include the pins 642, and the plugs 640a, 640b for the other of the branch channels 620, 622 may not include the pins 642.

[0097] The mixing member 618 may have a mixing chamber 624 configured to receive a mixing pin 660. The mixing pin 660 may be removably inserted into the mixing chamber 624, for example to allow for interchange of the mixing pin depending on the intended application and / or substances. The body 601 may have an opening 626 that is longitudinally aligned with and in communication with the mixing chamber 624. The mixing pin 660 may be inserted into the mixing chamber 624 through the opening 626. The opening 626 may be on an upper portion of the body 601, between the first port 602 and the second port 604, and in communication with an upper portion of the mixing chamber 624. As further shown, the mixing pin 660 may include an end cap 662, and the body 601 may include a rim 628 configured to engage the end cap 662 when the mixing pin 660 is inserted into the mixing chamber 624. The rim 628 may be on a tubular member 629 that extends upward from the mixing member 618 between the branch members 614, 616. The end cap 662 may have a sleeve portion 663 that extends downward and is configured to receive or surround the rim 628 of the body 601. The sleeve portion 663 may include one or more flexible protrusions 665 configured to bend radially outward and releasably engage the rim 628 when the rim 628 is received in the sleeve portion 663 to fix the mixing pin 660 in the mixing chamber 624 in a press fit and / or snap fit manner. The one or more flexible protrusions 665 may be cantilevered to an upper portion of the end cap 662. However, additionally or alternatively, the mixing pin 660 may be removably fixed in the mixing chamber 624 by other types of snap fits, press fits, threaded connections, and / or bayonet connections.

[0098] The mixing pin 660 may have a relatively large diameter, such as greater than 8 mm. The diameter of the mixing pin 660 may provide design flexibility for the configuration of the first branch channel 620 and / or the second branch channel 620. As discussed above, when inserted into the mixing chamber 624, the first branch channel 620 and / or the second branch channel 622 may be positioned or oriented off the lateral axis A (representing the central plane) of the adapter body 601 and / or the mixing pin 660 or not aligned with the lateral axis. The off-nature of the first branch channel 620 and / or the second branch channel 622 may create angular momentum and potential vortices of the fluid flow around the mixing pin 660. In some embodiments (as Figures 15 to 20 shown), the first branch channel 620 and the second branch channel 622 may be positioned on the same side of the lateral axis A such that the first and second substances are introduced into the mixing chamber 624 in opposite directions and immediately collide. In some embodiments (as Figures 25 to 26 shown), the first branch channel 620 and the second branch channel 622 may be positioned on opposite sides of the lateral axis A of the body 601 such that the first and second substances may flow in the same circumferential direction when introduced into the mixing chamber 624. In some embodiments (not shown), one of the branch channels 620, 622 may be oriented to align with the lateral axis A and the other of the branch channels 620, 622 may be oriented off the lateral axis A or not aligned with the lateral axis. In some embodiments (not shown), the branch channels 620, 622 may be connected to the adapter body 601 at different longitudinal positions. For example, the first branch channel 620 may be connected to the adapter body 601 at a position above or below the second branch channel 622.

[0099] At least one path may be defined at least partially around the mixing pin 660 for turbulently mixing the first flow of the first substance and the second flow of the second substance. The mixing pin 660 may have a sealing portion 664 that extends below the end cap 662. The sealing portion 664 may have a shape configured to seal the upper portion of the mixing chamber 624. The sealing portion 664 may have a width or diameter less than the width or diameter of the end cap 662 and is received in the upper portion of the mixing chamber 624 below the end cap 662. The sealing portion 664 may be cylindrical. The mixing pin 660 may have a channel portion 667 that is below the sealing portion 664 and has a width or diameter less than the sealing portion 664. Additionally or alternatively, the channel 667 may receive a sealing member 695 that is a separate component, such as an elastomeric O-ring. The mixing pin 660 may further include a threaded outer portion 675 that defines at least one helical channel 676. The threaded outer portion 675 may have a width or diameter greater than the channel 667, and the threaded outer portion 675 may extend for a majority of the length of the mixing pin 660 (e.g., greater than half the length and / or greater than two-thirds of the length).

[0100] Thus, for any given application of the adapter 600, the geometry of the at least one helical channel 676 can be selected depending on the degree of turbulence required to achieve the desired amount of mixing. For example, the pitch of the at least one helical channel 676 can be designed for the desired turbulence. For applications where a higher degree of turbulence is required to achieve the desired mixing (such as where lipid nanostructures are to be formed), the at least one helical channel 676 can have a reduced pitch. On the other hand, for applications where a low degree of turbulence is required to achieve the desired mixing or where a lower flow volatility is required to maintain certain physical properties of the components during mixing, the at least one helical channel 676 can have a steeper pitch. Thus, the pitch of the at least one helical channel 676 can be selected to provide the desired degree of mixing while avoiding impractically high resistance when used with a manually driven syringe. In some embodiments, the at least one helical channel 676 can include a double helix, as discussed and shown with respect to the embodiments of Figures 5 to 7 as incorporated herein by reference expressly. The at least one helical channel 676 has a width of from about 200 μm to about 1000 μm. In a preferred embodiment, the at least one helical channel 676 can have a width of from about 400 μm to about 600 μm to facilitate manufacturing and optimize mixing and hydraulics. Additionally, the bottom of the at least one helical channel 676 can be spaced from the inner surface of the adapter body 601 by from about 200 μm to about 1000 μm. In a preferred embodiment, the bottom of the at least one helical channel 676 can be spaced from the inner surface of the adapter body 601 by from about 400 μm to about 600 μm.

[0101] The body 601 can have a third port or connector member 630 at the bottom portion of the mixing member 618. The third port 630 can be a male Luer connector that includes a tip 632 and a sleeve 634 that is configured to be attached to the receiving container 60 via the vial adapter 70. The tip 632 can have a tip channel 625 that communicates with the second or bottom portion of the mixing chamber 624. The tip 632 can be received in the connector 74 of the vial adapter 70, and the sleeve 634 can be threadedly connected to the outer surface of the connector 74 in a Luer connection. The third port 630 can be a male Luer connector that is configured to connect to the female Luer connector of the vial adapter 70. However, additionally or alternatively, the third port 630 can be connected to the receiving container 60 with other types of connections such as snap-fit and / or press-fit connections. The tip lumen 625 can provide a pathway for the mixed composition from the mixing chamber 624 to the receiving container 60.

[0102] Figures 25 to 28 is shown Figures 1 to 4A fourth embodiment of the adapter 700 of the system 10. As shown, the adapter 700 may include a body 701 having a first port or connector member 702 configured to attach to the syringe connector 26 of the first container 20 and a second port or connector member 704 configured to attach to the syringe connector 46 of the second container 40. Unless otherwise stated, the disclosures of adapters 100, 500, 600 and / or mixing pins 160, 260, 360, 460, 660 are all expressly incorporated herein.

[0103] As shown, the adapter body 701 may further include a first branch member 714, a second branch member 716, and a mixing member 718. The first port 702 may extend from the first branch member 714, and the first branch member 714 may connect the first port 702 to the mixing member 718. The second port 704 may extend from the second branch member 716, and the second branch member 716 may connect the second port 704 to the mixing member 718. The first branch member 714 may have a first branch channel 720 configured to receive a fluid flow from the first syringe 20 through the first connector channel 710, and the second branch member 716 may have a second branch channel 722 configured to receive a fluid flow from the second syringe 40 through the second connector channel 712. The first and second branch channels 720 and 722 may communicate with an upper portion of the mixing member 718. The first branch channel 720 and the second branch channel 722 may be angled relative to the longitudinal axis of the adapter body 701 and / or the mixing pin 760 to converge the fluid flows from the first syringe 20 and the second syringe 40 into the mixing member 718. As discussed above with reference to adapter 600, the first branch channel 720 and the second branch channel 722 may be oriented to deviate from or not align with the central plane of the adapter body 701 (as shown by axis A in Figure 26 . In some embodiments, for applications where the first and second substances require the same flow rate, the first branch channel 720 and the second branch channel 722 may have the same or substantially the same width or diameter (as shown in Figure 15 . In some embodiments (as shown in Figure 11 and Figure 12 ), for applications where the first and second substances require different flow rates, the first branch channel 720 and the second branch channel 722 may have different widths or diameters. For example (as further shown in Figure 11 and Figure 12 ), the first branch channel 720 may have a greater width or diameter than the second branch channel 722. In some embodiments (as shown in Figure 2 , Figure 3 and Figure 8As shown, at least one or both of the first branch channel 720 and the second branch channel 722 may form an open outer end, and the adapter 700 may include a plug 740 inserted into one or both of the branch members 714, 716 to seal the outer ends of the corresponding branch channels 720, 722. In some embodiments (as Figure 11 shown), at least one or both of the first branch channel 720 and the second branch channel 722 may have a closed outer end formed by the adapter body 601.

[0104] The plugs 740a, 740b may be removable, replaceable, interchangeable, and / or adjustable. Replacing and / or adjusting the plug 740a may change the inlet volume of one or both of the first connector channel 710 and / or the second connector channel 712. For example, the plugs 740a, 740b may be replaced with similar plugs 740a, 740b having different lengths and / or geometries to at least partially occlude one or both of the first connector channel 710 and / or the second connector channel 712. In some embodiments, the plug 740 may be adjusted by being pushed or translated into the branch channels 720, 722 to at least partially occlude the first connector channel 710 and / or the second connector channel 712. In some embodiments, the plug 740 may have an adjustable length, such as being telescopic to at least partially occlude the first connector channel 710 and / or the second connector channel 712. Changing the inlet volume using the plugs 740a, 740b may adjust the fluid mixing ratio and / or reduce the dead volume of the fluid remaining inside the adapter body 701. The discussion of the plugs 140, 640a, 640b is hereby expressly incorporated by reference.

[0105] As further discussed and shown with respect to the adapter 600, the mixing member 718 may have a mixing chamber 724 configured to receive a mixing pin 760. The mixing pin 760 may be removably inserted into the mixing chamber 724, for example to allow for interchange of the mixing pin depending on the intended application and / or substances. The body 701 may have an opening longitudinally aligned with and in communication with the mixing chamber 724. The mixing pin 760 may be inserted into the mixing chamber 724 through the opening 726. The opening may be on an upper portion of the body 701, between the first port 702 and the second port 704, and in communication with an upper portion of the mixing chamber 724. As further shown, the mixing pin 760 may include a flange cap 762, and the body 701 may include an edge configured to engage the flange cap 762 when the mixing pin 760 is inserted into the mixing chamber 724.

[0106] As discussed above, when inserted into the mixing chamber 624, the first branch channel 720 and / or the second branch channel 722 may be oriented to deviate from the lateral axis A (representing the central plane) of the adapter body 701 and / or the mixing pin 760. The deviating nature of the first branch channel 720 and / or the second branch channel 722 may create angular momentum and potential vortices of the fluid flow around the mixing pin 760. As Figure 25 and Figure 26 shown, the first branch channel 720 and the second branch channel 722 may be positioned on opposite sides of the lateral axis A of the body 701 such that the first and second substances may flow in the same circumferential direction when introduced into the mixing chamber 724. At least one path may be defined at least partially around the mixing pin 760 for turbulently mixing the first flow of the first substance and the second flow of the second substance. As Figure 25 shown, the mixing pin 760 may have an outer surface that can be smooth. The space between the outer surface of the mixing pin 760 and the inner surface of the adapter body 701 may be 200 μm or less.

[0107] As Figure 29 shown, the present disclosure also includes a method 1000 of mixing at least two substances via any one of the adapters 100, 500, 600, 700 and / or the mixing pins 160, 260, 360, 460, 660, 760 disclosed herein to produce a pharmaceutical complex.

[0108] As indicated in steps 1002, 1004, the method may include transferring a first substance from a first storage container 80 to a first container 20 and transferring a second substance from a second storage container 82 to a second container 40. However, in some embodiments, the first container 20 and / or the second container 40 may be packaged as pre-filled containers, such as pre-filled syringes, thereby omitting the storage containers 80, 82 from the system or kit. As shown in steps 1006, 1008, the method may include attaching the first container 20 to the first ports 102, 502, 602, 702 of the adapters 100, 500, 600, 700 and attaching the second container 40 to the second ports 104, 504, 604, 704 of the adapters 100, 500, 600, 700. The method may also include attaching a receiving container 60 to the ports 102, 502, 602, 702 of the adapter 100. For example, as shown, one or both of the first container 20 and the second container 40 may be variable volume containers, such as syringes. The receiving container 60 may be a fixed volume container, such as a vial attached to the adapter 100 via a vial adapter 70.

[0109] As indicated in step 1010, the method may further include introducing the first and second substances into the adapters 100, 500, 600, 700 by depressing the plunger rods 24, 44 of each of the first container 20 and the second container 40. The first substance may enter the mixing chambers 124, 524, 624, 724 through the first branch channels 120, 520, 620, 720, and the second substance may enter the mixing chambers 124, 524, 624, 724 through the second branch chambers 122, 522, 622, 722. In some embodiments, the first branch channels 120, 520, 620, 720 and / or the second branch channels 122, 522, 622, 722 may be aligned with the transverse axis of the adapter bodies 101, 501, 601, 701. In some embodiments, at least one of the first branch channels 620, 720 and / or the second branch channels 622, 722 is oriented offset from the transverse axis of the adapter bodies 601, 701. In some embodiments, the first branch channels 620, 720 and the second branch channels 622, 722 are oriented offset from the transverse axis of the adapter bodies 601, 701. In some embodiments, the first branch channels 620, 720 and the second branch channels 622, 722 are on the same side of the transverse axis of the adapter bodies 601, 701. In some embodiments, the first branch channels 620, 720 and the second branch channels 622, 722 are on opposite sides of the transverse axis of the adapter bodies 601, 701.

[0110] Thus, initially, at the upper portion of the mixing chambers 124, 524, 624, 724, the first and second substances are in an unmixed state with respect to each other. Then, as indicated in step 1012, the first and second substances may pass through, longitudinally along, and / or circumferentially around the mixing pins 160, 260, 360, 460, 660, 760 via, for example, one or more microfluidic channels, and the first and second substances may gradually transition from the unmixed state to an increasingly mixed state. The turbulence induced in the fluid flow by the mixing chambers 124, 524, 624, 724 of the adapter causes the components to be mixed as needed when reaching the lower portion of the mixing chambers 124, 524, 624, 724. In step 1014, mixing the first and second substances may produce a drug complex having the first and second substances. In some embodiments, the first substance may be an aqueous solution, the second substance may be a lipid solution, and the drug complex may include an LNP. For example, the aqueous solution may include mRNA, and the drug complex may include mRNA-LNP. In step 1016, the drug complex may be received in the receiving container 60.

[0111] In some embodiments, the method further includes disconnecting the receiving container 60 from the connector member 130 and transferring the drug complex from the receiving container 60 for dilution and / or further analysis. Alternatively, the method may further include disconnecting the receiving container 60 from the connector member 130 and directly using the drug complex. In some embodiments, the first and second containers may be removably connected to the first and second ports, respectively, and the adapter may be reusable. Alternatively, the first and second containers may be permanently connected to the first and second ports, respectively. The adapters 100, 500, 600, 700 may be configured to engage in a locking connection with one or more of the containers 20, 40 to prevent reuse of the adapters 100, 500, 600, 700. In some embodiments, the mixing pins 160, 260, 360, 460, 660, 760 may be removable from the adapter bodies 101, 601, 701. In some embodiments, the mixing pins 160, 260, 360, 460, 660, 760 may be fixed to the adapter bodies 101, 601, 701.

[0112] The mixing chambers 124, 524, 624, 724 may have a circular cross-section formed by the cylindrical inner surface of the adapter bodies 101, 601, 701. However, it is also contemplated that the mixing chambers 124, 524, 624, 724 may have other cross-sections, such as oval, square, and / or rectangular. The outer surface of the mixing pins 160, 260, 360, 460, 660, 760 may have an outer surface corresponding to the inner surface of the mixing chambers 124, 524, 624, 724 to form the microfluidic channels or flow paths as discussed herein. The mixing pins 160, 260, 360, 460, 660, 760 may be solid for ease of manufacture, but alternatively may be hollow with a longitudinal lumen therethrough.

[0113] It should be understood that certain terms used in the foregoing description are for convenience and not for limitation. Unless otherwise specified, the terms "a", "an", and "the" shall be understood to mean "at least one". The term "comprising" shall be understood to mean "comprising but not limited to", such that a system or method that includes a particular feature or step is not limited solely to the listed features or steps, but may also include unlisted features or steps. Similarly, terms such as "above", "below", "front", "rear", "right", "left", "top", "bottom", "side", etc. are used for ease of interpreting the drawings and should not be construed as limiting.

[0114] Those skilled in the art should also understand that the exemplary embodiments described herein can be modified without departing from the present invention. The structural features of the systems and devices described herein can be replaced with functionally equivalent parts or completely omitted. In addition, it should be understood that the features from the embodiments can be combined with each other without departing from the present disclosure.

Claims

1. An adapter, comprising: A body, the body comprising: A first port configured to connect with a first container to receive a first substance, A second port configured to connect with a second container to receive a second substance, A third port configured to connect with a receiving container to output a mixture of the first substance and the second substance, and A mixing chamber having a first portion in communication with the first port and the second port and a second portion in communication with the third port; and A mixing pin inserted into the mixing chamber, wherein the mixing pin at least partially defines at least one microfluidic path for mixing the first substance and the second substance.

2. The adapter according to claim 1, wherein the body further comprises an opening in the first portion of the mixing chamber, the opening being configured to receive the mixing pin.

3. The adapter according to claim 1, wherein the mixing pin is removable from the mixing chamber.

4. The adapter according to claim 1, wherein the mixing pin has a flange, and the body has a recess configured to receive the flange.

5. The adapter according to claim 1, wherein the mixing pin includes a sealing portion configured to seal the first portion of the mixing chamber.

6. The adapter according to claim 1, wherein the first port and / or the second port is substantially parallel to the mixing chamber.

7. The adapter according to claim 1, wherein the body further comprises: A first branch channel in communication with the first port and extending at a first angle relative to the mixing chamber, and A second branch channel in communication with the second port and extending at a second angle relative to the mixing chamber.

8. The adapter according to claim 7, wherein the first angle and / or the second angle is greater than 90 degrees.

9. The adapter according to claim 8, wherein the first angle and / or the second angle is from about 120 degrees to about 160 degrees.

10. The adapter according to claim 7, further comprising a first plug inserted into an end of the first branch channel and a second plug inserted into an end of the second branch channel.

11. The adapter according to claim 7, wherein the first branch channel is configured to direct the first substance toward the mixing pin, and the second branch channel is configured to direct the second substance toward the mixing pin.

12. The adapter according to claim 1, wherein the mixing pin defines a first edge surface formed by a first surface and a second surface and a second edge formed by a third surface and a fourth surface, the first edge being configured to separate the first substance, and the second edge being configured to separate the second substance.

13. The adapter according to claim 1, wherein the first port is a female Luer connector, the second port is a female Luer connector, and the third port is a male Luer connector.

14. The adapter according to claim 1, wherein the at least one microfluidic path is tortuous.

15. The adapter according to claim 1, wherein the at least one microfluidic path is formed by at least one channel.

16. The adapter according to claim 15, wherein the at least one channel has a size of from about 200 μm to about 1000 μm.

17. The adapter according to claim 16, wherein the at least one channel has a size of from about 400 μm to about 600 μm.

18. The adapter according to claim 15, wherein the at least one channel comprises at least one helical channel.

19. The adapter according to claim 18, wherein the at least one helical channel comprises a first helical channel and a second helical channel, and wherein the first helical channel and the second helical channel intersect at a plurality of intersection points along the longitudinal length of the mixing pin.

20. The adapter according to claim 15, wherein the at least one channel extends through the mixing pin.

21. The adapter according to claim 15, wherein the mixing pin comprises a plurality of protrusions that extend at least partially around the circumference of the mixing pin and define at least a portion of the at least one channel.

22. The adapter according to claim 21, wherein the plurality of protrusions extend uniformly around the circumference of the mixing pin and form at least one radial gap relative to the inner surface of the body, and the at least one radial gap forms at least a portion of the at least one channel.

23. The adapter according to claim 21, wherein each of the plurality of protrusions has at least one first surface and at least one second surface, the at least one first surface being configured to create a seal against the inner surface of the body, and the at least one second surface forming at least one radial gap relative to the inner surface of the body, and the at least one radial gap forms at least a portion of the at least one channel.

24. A system, comprising: an aqueous solution; a lipid solution; a first container configured to receive the aqueous solution; a second container configured to receive the lipid solution; a receiving container; an adapter, the adapter comprising: a body having: a first port configured to be connected to the first container and receive the aqueous solution, a second port configured to be connected to the second container and receive the lipid solution, a third port configured to be connected to the receiving container to output a mixture of the aqueous solution and the lipid solution, a mixing chamber that extends between a first portion in communication with the first port and the second port and a second portion in communication with the third port; and a mixing pin configured to be inserted into the mixing chamber, wherein the mixing pin at least partially defines at least one microfluidic path for mixing the aqueous solution and the lipid solution.

25. The system according to claim 24, further comprising a second pin configured to be inserted into the mixing chamber, wherein the second mixing pin has a geometry different from that of the mixing pin.

26. The system according to claim 24 further includes a first storage container containing the aqueous solution and a second storage container containing the lipid solution.

27. A method includes: introducing a first substance into a first port of an adapter; introducing a second substance into a second port of the adapter; mixing the first substance and the second substance in at least a microfluidic path through, along, and / or around a mixing pin in the adapter; and generating a drug complex having the first substance and the second substance.

28. The method according to claim 27, wherein the first substance is an aqueous solution, the second substance is a lipid solution, and the drug complex includes lipid nanoparticles.

29. An adapter includes: a body, the body including: a first port configured to connect with a first container to receive a first substance, a first channel in communication with the first port, a second port configured to connect with a second container to receive a second substance, a second channel in communication with the second port, a third port configured to connect with a receiving container to output a mixture of the first substance and the second substance, a mixing chamber having a first portion in communication with the first port and the second port and a second portion in communication with the third port; and a mixing pin inserted into the mixing chamber, wherein at least one of the first channel and the second channel is oriented off a central plane of the body.

30. The adapter according to claim 29, wherein the body further includes an opening in the first portion of the mixing chamber configured to receive the mixing pin.

31. The adapter according to claim 29, wherein the mixing pin is removable from the mixing chamber.

32. The adapter according to claim 29, wherein the mixing pin has an end cap and the body has an edge configured to engage the end cap.

33. The adapter according to claim 29 further includes a sealing member configured to seal the first portion of the mixing chamber.

34. The adapter according to claim 29, wherein the first port and / or the second port is substantially parallel to the mixing chamber.

35. The adapter according to claim 29, wherein the first channel extends at a first angle relative to the mixing chamber and the second channel extends at a second angle relative to the mixing chamber.

36. The adapter according to claim 35, wherein the first angle and / or the second angle is greater than 90 degrees.

37. The adapter according to claim 36, wherein the first angle and / or the second angle is about 120 degrees to about 160 degrees.

38. The adapter according to claim 35 further includes a first plug in an end of the first channel and a second plug in an end of the second channel.

39. The adapter according to claim 35, wherein the first channel and the second channel are offset from a central plane of the mixing pin.

40. The adapter according to claim 39, wherein the first channel and the second channel are on the same side of the transverse axis of the adapter body.

41. The adapter according to claim 39, wherein the first channel and the second channel are on opposite sides of the transverse axis of the adapter body.

42. The adapter according to claim 29, wherein the first channel and the second channel are connected to the body at different longitudinal positions.

43. The adapter according to claim 29, wherein the first port is a female Luer connector, the second port is a female Luer connector, and the third port is a male Luer connector.

44. The adapter according to claim 29, wherein the mixing pin is formed by at least one channel.

45. The adapter according to claim 44, wherein the at least one channel has a size of about 200 μm to about 1000 μm.

46. The adapter according to claim 45, wherein the at least one channel has a size of about 400 μm to about 600 μm.

47. The adapter according to claim 44, wherein the at least one channel includes at least one helical channel.

48. A system, comprising: an aqueous solution; a lipid solution; a first container configured to receive the aqueous solution; a second container configured to receive the lipid solution; a receiving container; an adapter, the adapter comprising: a body having: a first port configured to connect to the first container and receive the aqueous solution, a second port configured to connect to the second container and receive the lipid solution, a third port configured to connect to the receiving container to output a mixture of the aqueous solution and the lipid solution, a mixing chamber extending between a first portion in communication with the first port and the second port and a second portion in communication with the third port; and a mixing pin configured to be inserted into the mixing chamber, wherein at least one of the first channel and the second channel is oriented to deviate from the central plane of the body.

49. The system according to claim 48, further comprising a second pin configured to be inserted into the mixing chamber, wherein the second mixing pin has a geometry different from that of the mixing pin.

50. The system according to claim 48, further comprising a first storage container containing the aqueous solution and a second storage container containing the lipid solution.

51. A method, comprising: introducing a first substance into a first port of an adapter body and through a first channel of the adapter body; introducing a second substance into a second port of the adapter body and through a second channel of the adapter body; mixing the first substance and the second substance around a mixing pin in the adapter body, wherein at least one of the first channel and the second channel is oriented to deviate from the central plane of the adapter body; and producing a pharmaceutical complex having the first substance and the second substance.

52. The method according to claim 51, wherein the first substance is an aqueous solution, the second substance is a lipid solution, and the pharmaceutical complex comprises lipid nanoparticles.

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