Apparatus and method for delivering high viscosity fluids

Abstract

One example of a device can deliver fluids having high viscosity, including fluids having a viscosity of 1,000 cP or more, through a channel. The device can be or include a syringe or a syringe. A barrel, a hub, a needle, or a combination thereof can define at least a portion of the channel. Methods of flowing fluids having such high viscosity are also disclosed herein. In certain embodiments, a method includes flowing a first fluid of relatively high viscosity and a lubricant of relatively low viscosity through a channel simultaneously, for example by using the lubricant to separate the first fluid from an inner surface of the channel, as is the case with a core annular flow. By sizing and shaping the channel as disclosed herein, particularly at a constriction, a stable core annular flow can be achieved, which makes it easier to flow a high viscosity fluid at a useful flow rate by manually applying force.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 581,610, filed September 8, 2023, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] This disclosure generally relates to allowing a high-viscosity fluid to flow through a channel. In some embodiments, the channel is contained within a syringe, and the fluid is a pharmaceutical composition. Background Technology

[0003] Biologics, including monoclonal antibodies (mAbs), enzymes, peptides, and recombinant therapeutic proteins, have demonstrated significant value in treating a wide range of complex and intractable diseases. Over the past decade, the shift from intravenous to subcutaneous injection has shown promise in reducing injection time from hours to minutes, lowering administration costs, and improving the patient experience.

[0004] The available volume in subcutaneous tissue limits the maximum injection volume to a few milliliters. To deliver the target dose, biologics must be highly concentrated, and thus become extremely viscous. Injecting such high-viscosity drug products using conventional hypodermic syringes and needles is impractical due to the excessive force required. Several methods have been proposed to achieve these injections: manual injection using large needles and extended time intervals; multiple injections to achieve the desired dosage; the use of autoinjectors that utilize gas or spring actuation to increase injection force; needle-free methods, such as jet injectors; encapsulation of the drug product to reduce effective viscosity; and co-injection of hyaluronidase to increase the available volume in subcutaneous tissue.

[0005] However, these methods have many drawbacks, including poor patient experience, complex equipment, and applicability to a wide variety of formulations. Slow, manual injection using large-bore needles (up to 22 gauge) can cause pain and patient discomfort, impacting the patient experience. Other methods, such as jet injectors and autoinjectors, are mechanically complex, expensive, and must be customized for each drug product, potentially requiring additional regulatory approvals. In some cases, reusing equipment also carries a potential risk of contamination. Encapsulation, excipient, and hyaluronidase methods can alter or interact with the drug product itself, introducing incompatibility risks. Therefore, each individual drug product requires costly reformulation, development, validation, and / or regulatory approval. Furthermore, encapsulation methods can encounter needle clogging and suspension stability issues, complicating delivery and dosing accuracy.

[0006] Therefore, there remains a need for methods and devices suitable for delivering high-viscosity fluids, especially for drug delivery. Summary of the Invention

[0007] Core-ring flow can be used to facilitate the delivery of high-viscosity drug products through a needle, thereby making injection easier. A relatively low-viscosity fluid can be used as a lubricant to allow a relatively high-viscosity fluid to flow through the channel. The lubricant separates the higher-viscosity fluid from the inner surface of the channel. These fluids may flow coaxially but at different speeds. Therefore, the force required to flow a viscous fluid is largely independent of the fluid's exact viscosity. Such channels may exist, for example, in the needle and needle hub of a syringe or syringe. However, using such a lubricant alone may only allow fluids up to a specific viscosity to flow, for example, under manually applied force.

[0008] This document discloses, in particular, methods for flowing very high-viscosity fluids and devices through which fluids of varying viscosities (including very high viscosities) can flow. For example, the methods and devices disclosed herein can flow fluids having viscosities in the range of 5 cP to 10,000 cP at any location. Such fluids can flow under manually applied forces (e.g., forces applied when squeezing a syringe). This disclosure encompasses the understanding that the size and shape of channels, particularly the size and shape of any constrictions within the channels, enable the delivery of high-viscosity fluids through the channels (e.g., through syringes). The devices and channels disclosed herein can be used with high efficiencies, for example, greater than 20%, greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%. This allows fluids [e.g., high viscosity (e.g., at least 10 cP)] to flow at a rate of at least 1 mL / min. Such high efficiency can be achieved for channels and / or devices using core-ring flow, even when the lubricant is miscible and / or the channel and / or device orientation is not perpendicular. Therefore, the pressure required to achieve fluid flow using the devices and / or channels disclosed herein can approach the theoretical limits of laminar flow, ideal flow, fully expanded flow, and fully concentric core-ring flow (an improvement on existing devices). Thus, in some embodiments, relatively high viscosity fluids can flow with relatively low applied forces.

[0009] In some aspects, the present invention relates to a fluid delivery device comprising a channel extending from an inlet to an outlet (e.g., in a needle hub, optionally also in a needle tip). In some embodiments, the channel is sized and shaped such that a first fluid having a viscosity of at least 10 cP (e.g., at least 15 cP, greater than 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP) can flow from the inlet (e.g., a first end of the channel and / or an initial position within the channel) through the channel to the outlet and flow through the outlet. In some embodiments, the channel has a curvature such that a first fluid having a viscosity of at least 10 cP (e.g., at least 15 cP, at least 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP) can flow from the inlet (e.g., a first end of the channel and / or an initial position within the channel) through the channel to the outlet and flow through the outlet. In some embodiments, the channel is sized and shaped such that a first fluid can flow through the channel from an inlet (e.g., a first end of the channel and / or an initial position within the channel) to an outlet and through the outlet in a core-ring flow (e.g., coaxial lubrication) [e.g., where the lubricant coats the inner surface of the channel (e.g., and is concentric and coaxial with the (more viscous) first fluid flowing through the channel), and where the first fluid does not contact the inner surface of the channel, e.g., where the lubricant has a viscosity of less than 10 cP (e.g., in the range of 0.5 cP to 10 cP, e.g., 0.5 cP to 5 cP or 0.5 cP to 2 cP)]. In some embodiments, the longitudinal axis (e.g., the main axis) of the channel is located within 45 degrees (e.g., within 10, 20, 30, or 40 degrees) of a line perpendicular to gravity.In some embodiments, the first fluid has a viscosity of at least 10 cP (e.g., at least 15 cP, greater than 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP).

[0010] In some embodiments, the core-annular flow has an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 80%, or greater than 90% when the first fluid and lubricant are immiscible and / or the channel orientation is perpendicular). In some embodiments, the channel is sized and shaped such that the first fluid can flow at this efficiency when the channel's longitudinal axis (e.g., the main axis) is within 45 degrees (e.g., within 10, 20, 30, or 40 degrees) of a line perpendicular to gravity. In some embodiments, the channel is sized and shaped such that the first fluid can flow at this efficiency only when (e.g., only if) the first fluid exhibiting a core-ring flow and the lubricant are miscible.

[0011] In some implementations, the channel is sized and shaped such that a first fluid can be delivered through the channel by manually applying force at the inlet (e.g., with a plunger).

[0012] In some implementations, a force not exceeding 40 N (e.g., not exceeding 30 N, not exceeding 25 N, not exceeding 20 N, not exceeding 15 N, not exceeding 12.5 N, or not exceeding 10 N) can cause fluid to flow through the channel and through the outlet.

[0013] In certain embodiments, the size and shape of the channel are designed such that a first fluid having a viscosity of at least 10 cP (e.g., at least 15 cP, at least 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP or at least 5,000 cP) can flow through the channel from an inlet (e.g., the first end of the channel and / or an initial position within the channel) to an outlet and through the outlet in core-annular flow (e.g., coaxial lubrication) (e.g., steady core-annular flow) [e.g., where a lubricant coats the inner surface of the channel (e.g., and is concentric and coaxial with the (more viscous) first fluid flowing through the channel), and where the first fluid does not contact the inner surface of the channel, e.g., where the lubricant has a viscosity of less than 10 cP (e.g., a viscosity in the range of 0.5 cP to 10 cP, e.g., 0.5 cP to 5 cP or 0.5 cP to 2 cP)].

[0014] In some embodiments, the device includes a constriction portion (e.g., in a needle hub) disposed in the channel between the inlet and the outlet, the constriction portion having an internal shape that includes a convex portion relative to the interior of the channel (e.g., where, according to the coordinate system defined as in Figure 3 A, the second derivative of the internal profile of the constriction portion is positive (>0) at at least some point along the internal profile).

[0015] In certain embodiments, the constriction portion has an internal shape that is fully convex relative to the interior of the channel [e.g., having a shape defined by where R is the radius, z is the position along the channel, and -1 < n < -0.1 (e.g., n = -1 / 3)].

[0016] In certain embodiments, the constriction portion tapers more sharply with position at the larger diameter end of the constriction portion and less sharply with position at the smaller diameter end.

[0017] In certain embodiments, the second derivative of the internal profile of the constriction portion is positive (>0) at every point along the internal profile.

[0018] In some embodiments, the channel includes an inner surface, and the device contains a first fluid and a lubricant, each disposed in the channel, wherein the lubricant separates the first fluid from the inner surface (e.g., wherein the inner surface is textured), and the lubricant has a lower viscosity than the first fluid.

[0019] In some embodiments, the first fluid has a shear stress not exceeding 1000 times the shear stress of the lubricant (e.g., not exceeding 100 times, 10 times, 5 times, or 2 times the shear stress of the lubricant).

[0020] In some implementations, the first fluid and lubricant are coaxially disposed in at least a portion of the channel.

[0021] In some implementations, the channel, the first fluid, and the lubricant are configured such that, when flowing, the flow of the first fluid is characterized by an eccentricity (E) of E < 1.

[0022] In some implementations, E < 0.05 (e.g., E < 0.02 or E = 0).

[0023] In some embodiments, the channel includes a second inlet, (ii) which is an inlet for a first fluid, and (iii) which is an inlet for a lubricant (e.g., where the needle hub including at least a portion of the channel includes the first inlet and the second inlet) (e.g., where the first inlet and the second inlet are spatially separated, e.g., at the needle hub).

[0024] In some embodiments, the ratio of the area of ​​the first entrance to the area of ​​the second entrance is between 0.02 and 5 (e.g., 0.02 to 2, 0.02 to 4, 0.02 to 3, e.g., 0.04 to 2, 0.04 to 4, 0.04 to 3, 0.05 to 2, 0.06 to 2, 0.07 to 2, 0.02 to 4, 0.02 to 3, 0.02 to 1.8, 0.02 to 1.6, 0.02 to 1.4, 0.04 to 4, 0.04 to 3, 0.04 to 1.8, 0.04 to 1.6, 0.04 to 1.4, 0.06 to 4, 0.06 to 3, 0.06 to 2, 0.06 to 1.8, 0.06 to 1.6, 0.06 to 5). The range is 1.4, 0.07 to 4, 0.07 to 3, 0.07 to 2, 0.07 to 1.8, 0.07 to 1.6, 0.07 to 1.4, 0.1 to 4, 0.1 to 3, 0.1 to 2, 0.1 to 1.8, 0.1 to 1.6, 0.1 to 1.4, 0.2 to 4, 0.2 to 3, 0.2 to 2, 0.3 to 4, 0.3 to 3, 0.3 to 2, 0.4 to 4, 0.4 to 3, 0.4 to 2, 0.5 to 4, 0.5 to 3, 0.5 to 2, 0.5 to 1.8, 0.5 to 1.6, or 0.5 to 1.4).

[0025] In some implementations, the lubricant is water-based.

[0026] In some implementations, the lubricant is non-aqueous.

[0027] In some implementations, the lubricant contains a buffer solution.

[0028] In some implementations, the first fluid contains the same buffer solution as that contained in the lubricant.

[0029] In some embodiments, the first fluid has a concentration of 5 cP to 10,000 cP (e.g., 5 cP to 5,000 cP, 5 cP to 4,000 cP, 5 cP to 3,000 cP, 5 cP to 2,500 cP, 5 cP to 2,000 cP, 20 cP to 10,000 cP, 20 cP to 5,000 cP, 20 cP to 4,000 cP, 20 cP to 3,000 cP, 20 cP to 2,500 cP, 20 cP to 2,000 cP, 50 cP to 10,000 cP, 50 cP to 5,000 cP, 50 cP to 4,000 cP, 50 cP to 3,000 cP, 50 cP to 2,500 cP, 50 cP to 2,000 cP, 75 cP). 75 cP to 10,000 cP, 75 cP to 5,000 cP, 75 cP to 4,000 cP, 75 cP to 3,000 cP, 75 cP to 2,500 cP, 75 cP to 2,000 cP, 100 cP to 10,000 cP, 100 cP to 5,000 cP, 100 cP to 4,000 cP, 100 cP to 3,000 cP, 100 cP to 2,500 cP, 100 cP to 2,000 cP, 250 cP to 10,000 cP, 250 cP to 5,000 cP, 250 cP to 4,000 cP, 250 cP to 3,000 cP, 250 cP to 2,500 cP, 250 cP to 2,000 cP, 50 ... Viscosities in the range of cP to 10,000, 500 cP to 5,000 cP, 500 cP to 4,000 cP, 500 cP to 3,000 cP, 500 cP to 2,500 cP, 500 cP to 2,000 cP, 1,000 cP to 10,000, 1,000 cP to 5,000 cP, 1,000 cP to 4,000 cP, 1,000 cP to 3,000 cP, 1,000 cP to 2,500 cP, or 1,000 cP to 2,000 cP.

[0030] In some embodiments, the lubricant has a viscosity in the range of 0.5 cP to 10 cP (e.g., 0.5 cP to 5 cP or 0.5 cP to 2 cP).

[0031] In some embodiments, the lubricant is no more than 50% of the total volume of the material in the channel (e.g., no more than 40%, no more than 30%, no more than 25%, no more than 20%, no more than 15%, no more than 10%, or no more than 5%).

[0032] In some embodiments, the volume ratio of the first fluid to the lubricant is not less than 1:1 (e.g., not less than 2:1, not less than 3:1, not less than 4:1, not less than 5:1, not less than 6:1, not less than 7:1, not less than 8:1 or not less than 9:1).

[0033] In some embodiments, the volume ratio of the first fluid to the lubricant does not exceed 200:1 (e.g., not exceeding 100:1).

[0034] In some embodiments, the first fluid is a pharmaceutical composition (e.g., a formulation) (e.g., containing small molecules and / or biological products) [e.g., containing small molecules and / or biological products (e.g., monoclonal antibodies (mAbs), polyclonal antibodies (pAbs), enzymes, peptides, recombinant therapeutic protein formulations, or combinations thereof)].

[0035] In some embodiments, the size and shape of the channel are designed such that a fluid having a viscosity at any location within the range of at least 5 cP to 10,000 cP (e.g., from 5 cP to 5,000 cP, from 5 cP to 4,000 cP, from 5 cP to 3,000 cP, from 5 cP to 2,500 cP, from 5 cP to 2,000 cP, from 5 cP to 1,500 cP, or from 5 cP to 1,200 cP) can flow from the inlet through the channel to the outlet and flow through the outlet.

[0036] In some embodiments, the delivery device includes a syringe [e.g., operable by manually applying force (e.g., force applied to one or more plungers)].

[0037] In some embodiments, the syringe includes a barrel and a needle hub (e.g., a needle hub including a constricted portion) (e.g., a 3D-printed needle hub) in fluid communication with the barrel (e.g., through a tube), the barrel (e.g., the tip of the barrel) and the needle hub each defining a portion of the channel.

[0038] In some implementations, the needle hub includes the inlet.

[0039] In some embodiments, the syringe includes a needle with an outlet, and the body of the needle defines a portion of the channel (e.g., there are no obvious right angles in the fluid path through the needle hub and / or the needle).

[0040] In some embodiments, a portion of the needle is disposed within the end of the needle hub, the portion of the needle hub including a needle inlet, and the needle inlet including a gently tapering portion relative to the inner diameter of the needle.

[0041] In some implementations, the outlet of the needle hub is located inside the needle.

[0042] In some implementations, the needle is smaller than 22 (e.g., 25 or 27).

[0043] In some implementations, the diameter of the channel does not exceed 5 cm (e.g., not exceeding 4 cm, 3 cm, 2 cm, 1 cm or 0.5 cm).

[0044] In some implementations, the size and shape of the channel are designed to eliminate viscous displacement during the flow of fluid (e.g., a first fluid) through the channel.

[0045] In some aspects, the present invention relates to a method for delivering a first fluid through a channel (e.g., in a needle hub, optionally also in a needle tip), the first fluid having a viscosity of at least 10 cP (e.g., at least 15 cP, greater than 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP), the method comprising simultaneously flowing a lubricant and the first fluid through the channel and out of an outlet of the channel (e.g., into or out of the needle tip), wherein the lubricant has a lower viscosity than the first fluid.

[0046] In some embodiments, the first fluid has a concentration of 50 cP to 10,000 cP (e.g., 50 cP to 5,000 cP, 50 cP to 4,000 cP, 50 cP to 3,000 cP, 50 cP to 2,500 cP, 50 cP to 2,000 cP, 75 cP to 10,000 cP, 75 cP to 5,000 cP, 75 cP to 4,000 cP, 75 cP to 3,000 cP, 75 cP to 2,500 cP, 75 cP to 2,000 cP, 100 cP to 10,000 cP, 100 cP to 5,000 cP, 100 cP to 4,000 cP, 100 cP to 3,000 cP, 100 cP to 2,500 cP, 100 cP to 2,000 cP). 250 cP to 10,000, 250 cP to 5,000 cP, 250 cP to 4,000 cP, 250 cP to 3,000 cP, 250 cP to 2,500 cP, 250 cP to 2,000 cP, 500 cP to 10,000, 500 cP to 5,000 cP, 500 cP to 4,000 cP, 500 cP to 3,000 cP, 500 cP to 2,500 cP, 500 cP to 2,000 cP, 1,000 cP to 10,000, 1,000 cP to 5,000 cP, 1,000 cP to 4,000 cP, 1,000 cP to 3,000 cP, 1,000 cP to 2,500 cP Viscosity in the range of cP (or 1,000 cP to 2,000 cP).

[0047] In some embodiments, the lubricant has a viscosity of less than 10 cP (e.g., a viscosity in the range of 0.5 cP to 10 cP, such as 0.5 cP to 5 cP or 0.5 cP to 2 cP).

[0048] In some implementations, the method includes manually applying force to a first fluid (e.g., a lubricant) to cause the first fluid to flow through a channel.

[0049] In some implementations, the force is applied at the entrance to the passage by manually applying force (e.g., with a plunger).

[0050] In some implementations, the force does not exceed 40 N (e.g., not exceeding 30 N, not exceeding 25 N, not exceeding 20 N, not exceeding 15 N, not exceeding 12.5 N, or not exceeding 10 N).

[0051] In some embodiments, the lubricant and the first fluid exhibit core-annular flow (e.g., coaxial lubrication) (e.g., steady core-annular flow) when flowing simultaneously through the channel.

[0052] In some embodiments, the first fluid and the lubricant are miscible.

[0053] In certain embodiments, the core-annular flow has an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., in the case where the first fluid and the lubricant are immiscible and / or the channel orientation is vertical, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 80%, or greater than 90%) ). In some embodiments, the first fluid flows at this efficiency when the longitudinal axis (e.g., the major axis) of the channel is within 45 degrees (e.g., within 10 degrees, 20 degrees, 30 degrees, or 40 degrees) of a line perpendicular to gravity. In some embodiments, the first fluid flows at this efficiency when (e.g., only when) the first fluid and the lubricant are miscible.

[0054] In certain embodiments, the method includes flowing the lubricant and the first fluid through a constriction (e.g., a needle seat) in the channel, the constriction having an internal shape that includes a convex portion relative to the interior of the channel (e.g., where Figure 3 in the coordinate system defined as in A, the second derivative of the internal profile of the constriction is positive (>0) at at least some point along the internal profile).

[0055] In certain embodiments, the constriction has an internal shape that is completely convex relative to the interior of the channel [e.g., having a shape defined by where R is the radius, z is the position along the channel, and -1 < n < -0.1 (e.g., n = -1 / 3)].

[0056] In certain embodiments, the constriction tapers more sharply with position at the larger diameter end of the constriction and less sharply with position at the smaller diameter end.

[0057] In certain embodiments, the second derivative of the internal profile of the constriction is positive (>0) at every point along the internal profile.

[0058] In certain embodiments, during flow, the shear stress of the first fluid does not exceed 1000 times (e.g., does not exceed 100 times, does not exceed 10 times, does not exceed 5 times, or does not exceed 2 times) the shear stress of the lubricant.

[0059] In some embodiments, the lubricant separates the first fluid from the inner surface of the channel (e.g., the first fluid and the lubricant are coaxially disposed in at least a portion of the channel).

[0060] In some implementations, the flow of the first fluid is characterized by an eccentricity (E) of E < 1.

[0061] In some implementations, E < 0.05 (e.g., E < 0.02 or E = 0).

[0062] In some implementations, the method includes (e.g., simultaneously) supplying a first fluid to the channel through a first inlet and a lubricant to the channel through a second inlet.

[0063] In some embodiments, the lubricant is aqueous. In some embodiments, the lubricant is non-aqueous. In some embodiments, the lubricant contains a buffer solution. In some embodiments, the first fluid contains the same buffer solution as that contained in the lubricant.

[0064] In some embodiments, the lubricant is no more than 50% of the total volume of the material in the channel (e.g., no more than 40%, no more than 30%, no more than 25%, no more than 20%, no more than 15%, no more than 10%, or no more than 5%).

[0065] In some embodiments, the volume ratio of the first fluid to the lubricant is not less than 1:1 (e.g., not less than 2:1, not less than 3:1, not less than 4:1, not less than 5:1, not less than 6:1, not less than 7:1, not less than 8:1 or not less than 9:1).

[0066] In some embodiments, the volume ratio of the first fluid to the lubricant does not exceed 200:1 (e.g., not exceeding 100:1).

[0067] In some embodiments, the first fluid is a pharmaceutical composition (e.g., a formulation) [e.g., containing small molecules and / or biological products (e.g., monoclonal antibodies (mAbs), polyclonal antibodies (pAbs), enzymes, peptides, recombinant therapeutic protein formulations, or combinations thereof)] (e.g., and the method includes subcutaneous administration of the pharmaceutical composition via a channel).

[0068] In some implementations, the syringe [e.g., operable by manually applying force (e.g., applying force to one or more plungers)] includes a channel.

[0069] In some embodiments, the syringe includes a barrel and a needle hub (e.g., a needle hub including a constricted portion) (e.g., a 3D-printed needle hub) in fluid communication with the barrel (e.g., through a tube), the barrel (e.g., the tip of the barrel) and the needle hub each defining a portion of the channel.

[0070] In some embodiments, the cylinder includes an inlet for a first fluid (e.g., and a separate inlet for a lubricant).

[0071] In some embodiments, the syringe includes a needle with an outlet, and the body of the needle defines a portion of a channel.

[0072] In some embodiments, a portion of the needle is disposed within the end of the needle hub, the portion of the needle hub including a needle inlet, and the needle inlet including a gently tapering portion relative to the inner diameter of the needle.

[0073] In some implementations, the outlet of the needle hub is located inside the needle.

[0074] In some implementations, the needle is smaller than 22 (e.g., 25 or 27).

[0075] In some implementations, the diameter of the channel does not exceed 5 cm (e.g., not exceeding 4 cm, 3 cm, 2 cm, 1 cm or 0.5 cm).

[0076] In some implementations, the first fluid is allowed to flow through the channel so that viscous displacement does not occur.

[0077] In some implementations, the flow of the first fluid occurs at a flow rate of at least twice (e.g., at least three times or at least four times) that of the lubricant.

[0078] In some implementations, the flow of the first fluid occurs at a flow rate not exceeding five times the flow rate of the lubricant.

[0079] In some embodiments, the flow of the first fluid occurs at a flow rate of at least 1 mL / min (e.g., at least 2 mL / min, at least 3 mL / min, at least 4 mL / min, at least 5 mL / min, at least 6 mL / min, at least 7 mL / min, at least 8 mL / min, at least 9 mL / min, or at least 10 mL / min).

[0080] In some implementations, the flow of the first fluid occurs at a flow rate not exceeding 20 mL / min.

[0081] In certain embodiments, the flow of the lubricant occurs at a flow rate of at least 0.5 mL / min (e.g., at least 1 mL / min, at least 1.5 mL / min, at least 2 mL / min, or at least 2.5 mL / min).

[0082] In certain embodiments, the flow of the lubricant occurs at a flow rate not exceeding 3 mL / min.

[0083] In some aspects, the present invention relates to a fluid delivery needle hub (e.g., a plastic needle hub) (e.g., a 3D printed needle hub) that includes a channel extending from an inlet of the needle hub to an outlet of the needle hub, the channel including a constriction portion having an internal shape including a convex portion relative to the interior of the channel (e.g., where, according to the coordinate system defined as in Figure 3 A, the second derivative of the internal profile of the constriction portion is positive (>0) at at least some point along the internal profile).

[0084] In certain embodiments, the size and shape of the channel are designed such that a first fluid having a viscosity greater than 10 cP (e.g., at least 15 cP, at least 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP) can flow from the inlet (e.g., the first end of the channel and / or an initial position within the channel) through the channel to the outlet and flow through the outlet.

[0085] In certain embodiments, the size and shape of the channel are designed such that a fluid having a viscosity at any position within at least the range from 5 cP to 10,000 cP can flow from the inlet through the channel to the outlet and flow through the outlet.

[0086] In certain embodiments, the constriction portion has an internal shape that is completely convex relative to the interior of the channel [e.g., having a shape defined by where R is the radius, z is the position along the channel, and -1 < n < -0.1 (e.g., n = -1 / 3)].

[0087] In certain embodiments, the constriction portion tapers more sharply with position at the larger diameter end of the constriction portion and less sharply with position at the smaller diameter end.

[0088] In some implementations, the second derivative of the contour of the contracted portion is positive (>0) at every point along the contour.

[0089] In some aspects, the present invention relates to an apparatus comprising a needle hub and a needle attached to the needle hub, wherein the lumen of the needle is in fluid communication with the channel.

[0090] In some implementations, the access point to the needle is located within the channel.

[0091] In some implementations, the needle inlet includes a gently constricted portion relative to the inner diameter of the lumen.

[0092] In some implementations, the outlet of the needle hub is located within the lumen.

[0093] In some implementations, the needle is smaller than 22 (e.g., 25 or 27).

[0094] In some aspects, the present invention relates to a fluid delivery device comprising a channel extending from an inlet to an outlet, wherein the size and shape of the channel are designed such that it has a capacity of at least 5 cP to 10,000 cP (e.g., from 5 cP to 5,000 cP, from 5 cP to 4,000 cP, from 5 cP to 3,000 cP, from 5 cP to 2,500 cP, from 5 cP to 10,000 cP, from 10 cP to 5,000 cP, from 10 cP to 4,000 cP, from 10 cP to 3,000 cP, from 10 cP to 2,500 cP, from 25 cP to 5,000 cP, from 25 cP to 4,000 cP, from 25 cP to 3,000 cP, from 25 cP to 2,500 cP, from 25 cP to 2,000 cP, from 50 cP to 2,000 cP, from 50 cP to 2,000 cP, from 25 ... CP to 10,000 cP, from 50 cP to 5,000 cP, from 50 cP to 4,000 cP, from 50 cP to 3,000 cP, from 50 cP to 2,500 cP, from 50 cP to 2,000 cP, from 75 cP to 10,000 cP, from 75 cP to 5,000 cP, from 75 cP to 4,000 cP, from 75 cP to 3,000 cP, from 75 cP to 2,500 cP, from 75 cP to 2,000 cP, from 100 cP to 10,000 cP, from 100 cP to 5,000 cP, from 100 cP to 4,000 cP, from 100 cP to 3,000 cP, from 100 cP to 2,5 ... CP to 2,000 cP, from 250 cP to 10,000, from 250 cP to 5,000 cP, from 250 cP to 4,000 cP, from 250 cP to 3,000 cP, from 250 cP to 2,500 cP, from 250 cP to 2,000 cP, from 500 cP to 10,000 cP, from 500 cP to 5,000 cP, from 500 cP to 4,000 cP, from 500 cP to 3,000 cP, from 500 cP to 2,500 cP, from 500 cP to 2,000 cP, from 1,000 cP to 10,000 cP, from 1,000 cP to 5,000 cP, from 1,000 cP to 4,000 cP, from 1,000 cP to 2,500 cP, from 500 cP to 2,000 cP, from 1,000 cP to 10,000 cP, from 1,000 cP to 5,000 cP, from 1,000 cP to 4,000 cP, from 1,000 cP to 2,000 cP. A fluid with a viscosity at any location within the range of 1,000 cP to 3,000 cP, 1,000 cP to 2,500 cP, or 1,000 cP to 2,000 cP can flow from the inlet (e.g., the first end of the channel and / or the initial position within the channel) through the channel to the outlet.

[0095] In some aspects, the present invention relates to a device for delivering fluids (e.g., a syringe comprising a body, a needle hub, and optionally a needle), wherein the device is shaped to deliver fluids (e.g., with a viscosity of at least 5 cP, such as at least 10 cP, such as at least 20 cP, such as at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP). When the fluid (cP) flows through the device, a core-ring flow (e.g., coaxial lubrication) is established for delivering the fluid (e.g., delivering the fluid to the subject) through the outlet from the device's cylinder (e.g., and through the device's needle hub and / or needle) (e.g., through the operation of the plunger, for example, through the mechanical operation of the plunger by the user, for example, by manual force).

[0096] In some embodiments, the flow of the fluid is characterized by an eccentricity (E) of E<1 (e.g., E<0.05, E<0.02, E=0).

[0097] In some embodiments, the fluid is a viscous pharmaceutical formulation, and the device is shaped to create a stable core-ring flow for delivering the fluid to the subject as the fluid flows through the device.

[0098] In some embodiments, the flow of the fluid is characterized by an eccentricity (E) of E<1 (e.g., E<0.05, E<0.02, E=0).

[0099] In some aspects, the present invention relates to an apparatus (e.g., an syringe comprising a barrel, a needle hub, and optionally a needle) for delivering viscous pharmaceutical formulations, wherein the apparatus is shaped to deliver the viscous pharmaceutical formulation (e.g., with a viscosity of at least 5 cP, such as at least 10 cP, such as at least 20 cP, such as at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP). When the viscous pharmaceutical formulation (cP) flows through the device, a core-ring flow (e.g., coaxial lubrication) is established to enable the fluid (e.g., delivery of the formulation to a subject) to be delivered through an outlet from the cylinder of the device (e.g., and through the needle hub and / or needle of the device) (e.g., by the operation of a plunger, e.g., by the mechanical operation of the plunger by a user, e.g., by hand) wherein the shear stress of the internal fluid containing the viscous pharmaceutical formulation (e.g., substantially composed of the viscous pharmaceutical formulation, e.g., composed of the viscous pharmaceutical formulation) is not significantly greater than the shear stress of the external lubricating fluid (e.g., not greater than 1000 times, not greater than 100 times, not greater than 10 times, not greater than 10 times, not greater than 5 times, not greater than 3 times, not greater than 2 times, not greater than 1.1 times, or not greater than 1.0 times).

[0100] In some embodiments, the device includes a needle holder with a convex profile (e.g., the opposite of a concave profile).

[0101] In some aspects, the present invention relates to a device for delivering fluids (e.g., a syringe comprising a body, a needle hub, and optionally a needle), wherein the device is shaped to deliver fluids (e.g., with a viscosity of at least 5 cP, such as at least 10 cP, such as at least 20 cP, such as at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP). When the fluid (cP) flows through the device, a core-ring flow is established for delivering the fluid (e.g., delivering the fluid to the subject) through the outlet from the cylinder of the device (e.g., and through the needle hub and / or needle of the device) (e.g., through the operation of the plunger, e.g., through the mechanical operation of the plunger by the user, e.g., by hand), wherein the core-ring flow is not completely eccentric (e.g., the flow of the fluid is characterized by an eccentricity (E) of E < 1, e.g., E < 0.05, e.g., E < 0.02, e.g., E = 0), and wherein the throughput flow (e.g., the flow through the outlet) is greater than the total compliance flow (e.g., the compliance flow throughout all sections of the core-ring flow) (e.g., at least twice, e.g., at least five times, e.g., at least ten times).

[0102] In some aspects, the present invention relates to a device for delivering fluids (e.g., a device of any embodiment described herein), wherein the device is shaped to establish a non-perfectly eccentric core-ring flow and has associated resistance and compliance components designed to stabilize the core-ring flow (e.g., a dynamic system of core-ring flow) as the fluid flows through the device to prevent viscous displacement.

[0103] In some aspects, the present invention relates to a device for delivering fluid (e.g., a device of any embodiment described herein), wherein the device is shaped to establish a non-perfectly eccentric core-ring flow and, as the fluid flows through the device, matches the ratio of the resistance of one or more lubricant fluid passages to the resistance of one or more viscous fluid passages to within 1000% (e.g., where the ratio of the larger to the smaller of the two resistances is 10 or less, e.g., 5 or less, e.g., 3 or less, e.g., 2 or less, e.g., 1.5 or less, e.g., 1.2 or less, e.g., 1.1 or less) or within 10000% (e.g., where the ratio of the larger to the smaller of the two resistances is 100 or less, e.g., 50 or less, e.g., 30 or less, e.g., 20 or less, e.g., 10 or less, e.g., 5 or less, e.g., 2 or less).

[0104] In some aspects, the present invention relates to a device for delivering fluids (e.g., a device of any embodiment described herein), wherein the device is shaped to establish a non-perfectly eccentric core-ring flow, and wherein the device includes one or more fluid dampers to isolate compliant elements, thereby reducing (e.g., preventing) viscous displacement caused by compliant flow as the fluid flows through the device.

[0105] In some aspects, the present invention relates to a device for delivering fluids (e.g., a device according to any embodiment of the embodiments described herein), wherein the device is shaped to establish a non-perfectly eccentric core-ring flow, and wherein the device matches the upstream pressure of a lubricant reservoir and a viscous fluid reservoir as the fluid flows through the device.

[0106] In some aspects, the present invention relates to a device (e.g., an injection cartridge comprising a barrel, a needle hub, and optionally a needle) (e.g., a device of any embodiment described herein), wherein the device is shaped to handle viscous fluids (e.g., with a viscosity of at least 5 cP, such as at least 10 cP, such as at least 20 cP, such as at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP). When the fluid (cP) flows through the device, a core-annular flow (e.g., coaxial lubrication) is established for delivering the fluid (e.g., delivering the preparation to the subject) through the outlet from the cylinder of the device (e.g., and through the needle hub and / or needle of the device) (e.g., through the operation of the plunger, e.g., through the mechanical operation of the plunger by the user, e.g., by hand) and wherein the device includes one or more features designed to perform one or more of the following (i) to (iv): (i) reducing and / or minimizing lubricant compliance ( (ii) to reduce upstream resistance of lubricants and viscous fluids. and (iii) Associate with (e.g., match the upstream resistance of the lubricant and viscous fluid to a coefficient not greater than 10,000, 3,000, 1,000, 100, 10, 5, 3, 2, 1.5, 1.2, or 1.1); and (iii) reduce and / or minimize pressure disturbances. (iv) reduce and / or minimize core annular flow resistance (e.g., maximize through flow and / or minimize compliant flow). ).

[0107] In some embodiments, the device includes components designed to reduce and / or minimize lubricant compliance. One or more characteristics of the lubricant, wherein the lubricant compliance is defined as (Volume change corresponding to a unit change in pressure), where No more than 10 11 [ (For example, no more than 3 × 10) -12 Not greater than 1×10 -12 No more than 3×10 -13 No more than 5×10 -13 or not greater than 1×10 -14 [ ]).

[0108] In some implementations, one or more features designed to reduce or minimize lubricant compliance include mechanisms for eliminating air bubbles in the device (e.g., ventilated surfaces and / or narrow fluid passageways that are unlikely to trap air bubbles).

[0109] In some embodiments, the device includes upstream resistance designed to reduce the resistance of the lubricant and viscous fluid. and One or more characteristics associated with (for example, matching the upstream resistance of the lubricant and the viscous fluid to a coefficient not greater than 10, 5, 3, 2, 1.5, 1.2 or 1.1).

[0110] In some embodiments, the device includes a viscous fluid flow channel and a lubricant flow channel, wherein one or more features include a choke point (e.g., a resistive region in the form of a thin tube and / or a filter, e.g., including densely packed elements with small orifices) located within the lubricant flow channel (e.g., wherein the cross-sectional area of ​​the lubricant flow channel in a particular region is significantly smaller than the cross-sectional area of ​​the viscous fluid flow channel). (See, for example, [reference needed]) Figure 10A For example, where R is defined as follows: and ,in This refers to the pressure drop between the fluid storage tank and the initiation point of the annular flow. R should be set such that, given the relative flow rates of the viscous fluid and lubricant... v and R l Related, so that and The difference is not significant; for example, among them / Not greater than approximately 100,000, for example, not greater than approximately 10,000, for example, not greater than approximately 1,000, for example, not greater than 100, for example, not greater than approximately 50, for example, not greater than approximately 20, for example, not greater than 10, for example, not greater than 5) (for example, where Rv / Rl is approximately 1 within one order of magnitude, for example, within 5 times, for example, within 2 times, for example, within 1.5 times, for example, within 1.1 times).

[0111] In some implementations, the device includes components designed to reduce and / or minimize pressure disturbances. One or more characteristics of ).

[0112] In some embodiments, the device includes a lubricant reservoir and a viscous substance reservoir, and one or more features designed to reduce and / or minimize disturbances include a common (e.g., a single) pressure headspace shared between the lubricant reservoir and the viscous substance reservoir.

[0113] In some implementations, one or more features designed to reduce and / or minimize disturbances include flow channels or other regions with a diameter small enough to induce viscous losses (e.g., flow channels with a diameter of no more than 2 mm, no more than 1 mm, no more than 0.5 mm, no more than 0.2 mm, or about 0.2 mm).

[0114] In some embodiments, the device includes a needle holder that initiates the core annular flow, wherein one or more features designed to reduce and / or minimize disturbances include a damping element disposed between the needle holder and an upstream element of compliance (e.g., the most compliant upstream element) to limit pressure disturbances experienced by the compliant upstream element and reduce the likelihood of viscous displacement.

[0115] In some embodiments, the device includes components designed to reduce and / or minimize core annular flow resistance (e.g., maximize through flow and / or minimize compliant flow). One or more characteristics of ).

[0116] In some embodiments, one or more features designed to reduce and / or minimize core annular flow resistance include a convex needle seat and / or a smooth profile (e.g., a profile with minimal or no discontinuities, e.g., a profile with a continuous (e.g., substantially continuous) derivative).

[0117] In some embodiments, the core-annular flow has an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 80%, or greater than 90% when the first fluid and lubricant are immiscible and / or the channel orientation is perpendicular). In some embodiments, the channel is sized and shaped such that the first fluid can flow at this efficiency when the channel's longitudinal axis (e.g., the main axis) is within 45 degrees (e.g., within 10, 20, 30, or 40 degrees) of a line perpendicular to gravity. In some embodiments, the channel is sized and shaped such that the first fluid can flow at this efficiency only when (e.g., only if) the first fluid exhibiting a core-ring flow and the lubricant are miscible.

[0118] Any two or more features described in this specification (including in the Summary of the Invention section) may be combined to form embodiments of this disclosure, whether or not they are specifically and explicitly described as separate combinations in this specification. Attached Figure Description

[0120] The teachings of the invention described herein will be more fully understood from the following description of various exemplary embodiments when read in conjunction with the accompanying drawings. It should be understood that the figures described below are for illustrative purposes only and are not intended to limit the scope of the teachings of the invention in any way. The foregoing and other objects, aspects, features, and advantages of this disclosure will become more apparent and better understood by referring to the following description taken in conjunction with the accompanying drawings, in which:

[0121] Figure 1A This is an illustration of an injection cartridge according to an exemplary embodiment of the present disclosure (for illustrative purposes, the needle hub and needle assembly are separated from the cartridge body);

[0122] Figure 1B This is a flowchart of a method for delivering fluid according to an exemplary embodiment of the present disclosure;

[0123] Figure 2 The following are schematic diagrams illustrating exemplary embodiments according to this disclosure: a core-annular flow (sub-figure A), a comparison of the injection force required for a conventional syringe (as a function of viscosity) with that required for a syringe as disclosed herein (sub-figure B), an experimentally derived graph of the injection force versus time for a 500 cP first fluid (sub-figure C), and an experimentally derived graph of the injection force versus time for a 1266 cP first fluid (sub-figure D).

[0124] Figure 3 The illustration shows a schematic diagram (sub-figure A) of a needle hub with marked dimensions according to an exemplary embodiment of the present disclosure, and a photograph of a prototype needle hub with a constricted portion (sub-figure B).

[0125] Figure 4 The diagram illustrates concentric annular flow, fully eccentric annular flow, and partially eccentric annular flow according to exemplary embodiments of the present disclosure.

[0126] Figure 5 The illustration shows viscous displacement and core-ring flow according to an exemplary embodiment of the present disclosure, presented as photographs and graphs of pressure gradient versus time;

[0127] Figure 6 The illustration shows a prototype pin holder according to an exemplary embodiment of the present disclosure;

[0128] Figure 7A simplified diagram of an syringe according to an exemplary embodiment of the present disclosure is shown, which uses a lubricant to facilitate the delivery of a viscous fluid by utilizing a core-ring flow having indicated compliance, resistance, and pressure.

[0129] Figure 8 The illustration shows a core-ring flow apparatus according to an embodiment of the present disclosure, the apparatus having separate viscous material reservoirs and lubricant reservoirs and a needle seat for establishing a core-ring flow, wherein the relevant compliance and the expression for estimating the magnitude of physical compliance are illustrated on the left and right sides of the apparatus (left figure) (right figure);

[0130] Figure 9 The illustration shows a qualitative performance comparison of low-compliance and high-compliance tubes for core-ring needle holders according to exemplary embodiments of the present disclosure;

[0131] Figure 10A The illustration shows a method for matching the resistance to the simultaneous flow of viscous fluid and lubricant according to an exemplary embodiment of the present disclosure;

[0132] Figure 10B The illustration shows a comparison of upstream compliance and downstream compliance in an apparatus with two storage tanks according to an exemplary embodiment of the present disclosure;

[0133] Figure 11 The illustration shows simulation results of the contour of the contracted portion (e.g., in the needle hub) according to an exemplary embodiment of the present disclosure;

[0134] Figure 12 The figures illustrate further simulation results for the static pressure (subplot A) and pressure gradient (subplot B) of the needle seat profile with n = -1 / 3 according to an exemplary embodiment of the present disclosure, and for the static pressure (subplot C) and pressure gradient (subplot D) of the needle seat profile with n = 3.

[0135] Figure 13 A comparison was made between a conventional needle-coil interface (sub-Figure A) and an alternative needle-coil interface (sub-Figure BC) according to an exemplary embodiment of this disclosure, which mitigate or eliminate problems caused by the abrupt contraction portion present in the conventional needle-coil interface; and

[0136] Figure 14 The illustration shows photographs (sub-figure AC) of exemplary needle holders with different contours according to an exemplary embodiment of the present disclosure, and three exemplary needle holders according to an exemplary embodiment of the present disclosure before viscous displacement. o / Q i The relationship between viscosity and the viscosity of the first fluid (subplot D).

[0137] Figure 15Various Qs according to exemplary embodiments of this disclosure are illustrated. o / Q i The value represents the ideal pressure reduction factor under fully developed laminar flow conditions.

[0138] Figure 16 The illustration shows pressure values ​​in a core-ring flow device under various conditions according to an exemplary embodiment of the present disclosure.

[0139] The accompanying drawings may not be drawn to scale. Detailed Implementation

[0140] It is conceivable that the systems, apparatus, methods, and processes of this disclosure encompass changes and modifications made using information from the embodiments described herein. Changes and / or modifications to the systems, apparatus, methods, and processes described herein can be performed by those skilled in the art.

[0141] Throughout this specification, where articles, devices, and systems are described as having, including, or containing specific components, or where processes and methods are described as having, including, or containing specific steps, it is conceivable that there may also be articles, devices, and systems according to certain embodiments of this disclosure that are substantially composed of or comprised of the described components, and processes and methods according to certain embodiments of this disclosure that are substantially composed of or comprised of the described processing steps.

[0142] It should be understood that the order of steps or the sequence of certain actions is not important as long as operability is not compromised. Furthermore, two or more steps or actions may be performed simultaneously. As will be understood by those skilled in the art, the terms "over / above / on" and "under / below / beneath" are relative terms and may be used interchangeably with reference to the different orientations of layers, elements, and substrates included in this disclosure. For example, a first layer on a second layer in some embodiments means that the first layer is directly on and in contact with the second layer. In other embodiments, a first layer on a second layer may include another layer located therebetween.

[0143] In this application, unless otherwise apparent from the context or expressly stated otherwise, (i) the term “a” is to be understood as “at least one”; (ii) the term “or” is to be understood as “and / or”; (iii) the terms “comprising” and “including” are to be understood as encompassing the listed components or steps, whether presented alone or together with one or more additional components or steps; (iv) the terms “about” and “approximately” are to be understood as allowing for variations in the standard, as would be understood by one of ordinary skill in the art; and (v) where a range is provided, endpoints are included. In some embodiments, unless otherwise stated or otherwise apparent from the context (except where such figures may exceed 100% of possible values), the terms “about” or “about” refer to a range of values ​​belonging to the stated reference values ​​in any direction (greater or less) of 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less.

[0144] This document discloses, in particular, devices and components of such devices capable of delivering fluids of high viscosity (including fluids with a viscosity of 1,000 cP or higher) through a channel. The channel may be located in a device such as a syringe or syringe. A barrel, needle hub, needle, or a combination thereof may define at least a portion of the channel. This document also discloses methods for flowing fluids of high viscosity (including fluids with a viscosity of 1,000 cP or higher) through a channel. In some embodiments, one method involves simultaneously flowing a relatively high-viscosity first fluid (e.g., containing a pharmaceutical composition) and a relatively low-viscosity lubricant through the channel, achieved, for example, by using the lubricant to separate the first fluid from the inner surface of the channel, as is the case with core-annular flow (e.g., coaxial lubrication). Related discussion of core-annular flow (e.g., coaxial lubrication) can be found in Jayaprakash, V. et al., Enhancing the Injectability of High Concentration Drug Formulations Using Core Annular Flows. Adv Healthcare Mater.The disclosure of this article, found at https: / / doi.org / 10.1002 / adhm.202001022, is hereby incorporated herein by reference in its entirety. By designing the channel size and shape as disclosed herein, particularly at the constricted portion (e.g., in a needle hub where the channel size is reduced from the tip of the barrel to the needle size), a stable core-ring flow can be achieved, which makes it easier to manually apply force to flow high-viscosity fluids (e.g., pharmaceutical compositions) at a useful flow rate (e.g., greater than 1 mL / min). By designing the channel size and shape as disclosed herein, particularly with a certain curvature (e.g., in a needle hub where the channel size is reduced from the tip of the barrel to the needle size), a stable core-ring flow can be achieved, which makes it easier to manually apply force to flow high-viscosity fluids (e.g., pharmaceutical compositions) at a useful flow rate (e.g., greater than 1 mL / min).

[0145] In some embodiments, the fluid delivery device includes a channel extending from an inlet to an outlet (e.g., in a needle hub, optionally also in a needle). In some embodiments, the channel is sized and shaped such that a first fluid having a viscosity of at least 5 cP (e.g., at least 10 cP) can flow from the inlet (e.g., a first end of the channel and / or an initial position within the channel) through the channel to the outlet and flow through the outlet, for example, in a wicking flow. In some embodiments, the channel is sized and shaped such that a first fluid with a viscosity greater than 20 cP can flow from the inlet through the channel to the outlet and flow through the outlet. In some embodiments, the channel is sized and shaped such that a first fluid having a viscosity of at least 15 cP can flow from the inlet through the channel to the outlet and flow through the outlet. In some embodiments, the channel has a certain curvature such that a first fluid having a viscosity of at least 5 cP (e.g., at least 10 cP, at least 15 cP, greater than 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP) can, for example, flow from the inlet (e.g., the first end of the channel and / or the initial position within the channel) through the channel to the outlet and flow through the outlet in a core-annular flow manner.

[0146] Figure 1AAn exemplary syringe 100 is illustrated. The syringe 100 includes a plunger 102, a barrel 104, a needle hub 108, and a needle 110. The barrel 104 includes a tip 106 having an outlet. The needle hub 108 includes an inlet and an outlet leading to the needle 110. The needle 110 includes a body having a lumen extending through the body to an outlet 112. The needle 110 is attached to the needle hub 108. The needle hub 108 may be detachably attached to the tip 106, but is shown separated in the figure for illustrative purposes. The barrel 104 includes a channel. The needle hub 108 includes a channel. The needle 110 includes a channel in fluid communication with a needle hub 18. The barrel 104 is in fluid communication with the needle hub 108 and with the needle 110 via the needle hub 108. The needle hub 108 is in fluid communication with the needle 110. The syringe 100 may be described as including a channel partially defined by one or more of a syringe body 104, a needle hub 108, and a needle tip 110. In some embodiments, the channel is defined only by the needle hub and the needle tip (e.g., needle hub 108 and needle tip 110). In some embodiments, the channel is defined only by the needle hub (e.g., needle hub 108). The needle hub 108 includes a constriction portion having a maximum diameter corresponding to the size of the tip 106 and a minimum diameter corresponding to the size of the lumen of the needle tip 110. The needle hub 108 may be 3D printed. The syringe body 104 may include the constriction portion. The needle tip 110 may include the constriction portion. A first fluid and lubricant may be supplied to the needle hub 108 using the syringe body 104 and subsequently delivered through the needle tip 110 and exited from the outlet 112. In some embodiments, the first fluid and lubricant flow in a wicking annular flow. In some embodiments, the needle hub includes an inlet for the channel. In some embodiments, the syringe or injector includes a needle with an outlet for a channel, and the body of the needle defines a portion of the channel (e.g., there are no obvious right angles in the fluid path through the needle hub and / or the needle).

[0147] Lubricants can wet the inner surfaces of channels in devices such as needle hubs. The inner surfaces of the channels can be textured to promote wetting by low-viscosity fluids such as lubricants.

[0148] In some embodiments, a dual-barrel syringe is used to deliver a fluid. For example, the inner barrel may be used to deliver a first fluid (e.g., containing a pharmaceutical composition), and the outer barrel may be used to deliver a lubricant. The annular flow of such fluid may begin at or before the outlet of the common tip of the dual barrels, or in the needle hub to which the dual barrels are attached.

[0149] In some embodiments, the device (e.g., a syringe) includes a needle hub and two fluid reservoirs, one for a lubricant and one for a viscous fluid. The needle hub may include two inlets, each in fluid communication with one of the fluid reservoirs. These two inlets are spatially separated (e.g., not concentric) on the needle hub (e.g., across the surface of the needle hub). Therefore, fluid from each fluid reservoir can simultaneously flow into the needle hub, for example, using pressure applied to the fluid reservoir by a plunger. A wicking flow can be initiated in the needle hub. The needle hub may define at least a portion of a passage. The needle hub may include a constriction portion to induce a wicking flow. In some embodiments, pressure can be applied to both reservoirs simultaneously and optionally substantially equally (as shown) to allow the viscous fluid and lubricant to flow into and through the needle hub. The needle hub may, for example, have a side of the needle hub opposite the fluid reservoir in fluid communication with the needle tip. If a needle tip is present, fluid flowing from the fluid reservoir into the needle hub may flow into and out of the needle tip. During fluid flow, a core-ring flow may form in the needle hub, at least in part due to the contraction in the needle hub, and this core-ring flow persists until the needle tip. The needle hub may be closed, for example comprising a closed body including two inlets (one for each fluid reservoir) and one outlet (e.g., in fluid communication with the needle tip). Figure 8 The illustration shows an example of a dual-tank syringe with a needle hub, which also includes a needle.

[0150] The syringe or syringe can be operated by manually applying force (e.g., applying force to one or more plungers of the syringe). In some embodiments, a force not exceeding 40 N (e.g., not exceeding 30 N, 25 N, 20 N, 15 N, 12.5 N, or 10 N) can cause fluid to flow through the channel and flow through (e.g., out) the outlet of the channel (e.g., the outlet of a needle). Manual force can be applied to the first fluid to cause it to flow through the channel in any suitable manner, including in some embodiments where the device including the channel is a syringe, by manually pushing a component of the device (e.g., the plunger) (e.g., using a pinching action, for example, utilizing the plunger and one or more tabs disposed at the end of the syringe).

[0151] Figure 1BAn example method 10 for delivering a first fluid through a channel is illustrated. In step 12, a first fluid and a lubricant are provided into the channel (e.g., via one or both inlets). The channel may be located within a needle hub, or the needle hub may define at least a portion of the channel (e.g., optionally combined with a needle). In step 14, manual force is applied to at least the first fluid. This can be achieved, for example, by pushing a plunger in contact with the first fluid (e.g., by pinching). In some embodiments, manual force is also applied (e.g., simultaneously) to the lubricant. In step 16, due to the manual application of at least the first fluid, the first fluid and the lubricant flow simultaneously through the channel. In step 18, the first fluid and the lubricant are simultaneously directed to and flow through the outlet of the channel (such as the needle outlet), thereby delivering the first fluid. Steps 16 and 18 can be performed simultaneously. In the case of using a syringe, the outlet may be the needle outlet, and the delivery produced by method 10 may be a percutaneous and / or subcutaneous delivery of the first fluid. Steps 16 and 18 can occur under annular flow (e.g., coaxial lubrication). Step 16 may include allowing the first fluid and lubricant to flow simultaneously through a constricted portion in the channel (e.g., in the needle hub, such as the needle hub of a syringe needle).

[0152] As discussed throughout the following paragraphs, establishing stable coaxial flow in a channel is not straightforward due to the presence of several flow instabilities. Stable coaxial lubrication can be achieved by adjusting key flow parameters, and injection forces (e.g., for syringes) can be reduced by several orders of magnitude (e.g., to levels achievable manually). The described devices (e.g., syringes and syringes) can maintain stable coaxial lubrication and unlock extremely low injection forces for high-viscosity formulations: solutions with viscosities up to 1200 cP can be dispensed through a ½” 27 gauge needle. Figure 2 The sub-graph BC) can be easily and quickly injected manually with an injection force significantly lower than 30 N.

[0153] Any low-viscosity aqueous or non-aqueous formulation can be used as a lubricant. The buffer solution of the first fluid itself (if present) can be used as a lubricant to ensure that the delivered fluid (e.g., the injected product) remains consistent in quality, thereby eliminating the need for reconstitution. The fraction of the total delivered (e.g., injected) volume (e.g., containing the buffer solution) can be kept as low as 10%, for example, to maximize the total dose of the pharmaceutical composition contained in the delivered first fluid.

[0154] Using a buffer solution of the first fluid as a lubricant to establish a core-loop flow may slightly dilute the final concentration of the delivered first fluid (e.g., a pharmaceutical composition). Using a core-loop flow may produce a significantly greater force reduction (e.g., >5-fold, >10-fold, >15-fold, or >20-fold) compared to dilution of the first fluid. Therefore, the devices disclosed herein (e.g., syringes) may be able to administer substances present in the first fluid at higher possible concentrations than could be achieved through dilution [e.g., higher possible doses of a pharmaceutical composition (e.g., one or more active ingredients therein)].

[0155] In some embodiments, the device includes either a syringe or a syringe (e.g., an autoinjector). In some embodiments, the syringe is manually operable [e.g., it can be used to deliver fluid from the outlet of the syringe (e.g., the outlet of a needle) using manually applied force]. In some embodiments, the syringe is manually operable [e.g., it can be used to deliver fluid from the outlet of the syringe (e.g., the outlet of a needle) using manually applied force]. In some embodiments, the manually applied force for causing fluid flow through the channel (e.g., in a device such as a syringe or syringe) does not exceed 40 N (e.g., not exceeding 35 N, not exceeding 30 N, not exceeding 25 N, not exceeding 20 N, not exceeding 15 N, not exceeding 12 N, or not exceeding 10 N).

[0156] Figure 2Subfigure A illustrates the injection of a viscous pharmaceutical composition (in this case, a biological product) through a core-ring flow channel (e.g., a needle hub and / or needle tip) lubricated by its buffer solution. Subfigure B illustrates that, compared to conventional syringe injection, the force required to induce flow on at least a first fluid (e.g., a viscous pharmaceutical composition) using the syringe disclosed herein is significantly reduced. Even at relatively low first fluid viscosities (e.g., about 10 cP, about 20 cP), the force required to be applied to a conventional syringe (e.g., by squeezing the syringe to push the plunger) exceeds the force achievable manually (the shaded transitions indicate the transition from manually feasible to manually infeasible). In contrast, when using the device disclosed herein (e.g., the syringe), fluids with viscosities several orders of magnitude larger can be easily flowed with manually applied force. The gray dots correspond to the injection forces of fluids with varying viscosities, experimentally measured, ranging from about 50 cP to about 1250 cP. The error bars and signs of the 49 cP, 77 cP, and 1266 cP fluid samples are approximately the same and therefore not shown. The standard injection force at 6 mL / min using a 1 cm diameter syringe plunger with a ½” 27G needle was calculated using the Hagen-Poiseuille equations (Equation 1+2). Injections of 49 cP, 77 cP, and 500 cP fluids were performed at 6 mL / min using a ½” 27G needle with 12% v / v lubricant. Injections of 1266 cP fluid were performed at 7 mL / min using a ½” 27G thin-walled needle with 22% v / v lubricant. Subplot CD illustrates the force versus time curves for 500 cP fluid core annular flow injection (Subplot C) and 1266 cP fluid core annular flow injection (Subplot D). As can be seen from Subplot CD, although the force varies with time, it remains within the limits of manual injection capability. For example, it seems relatively easy for a user (such as a doctor or nurse) to squeeze the syringe firmly enough to produce a flow rate of about 6-7 mL / min.

[0157]

[0158] Given the pressure drop through the needle Injector plunger area Liquid viscosity Needle length Liquid flow rate and needle radius In such cases, equations 1 and 2 can be used to calculate the expected injection force of a conventional syringe and needle.

[0159] The compatibility of the pharmaceutical compositions with the devices disclosed herein (e.g., syringes or syringes, such as auto-injectors) is well-established, as these devices do not fundamentally alter or interact with the pharmaceutical compositions. Furthermore, as discussed later, relatively small amounts of lubricants and / or benign lubricants (e.g., those immiscible with but biocompatible with the pharmaceutical compositions, or the same lubricants used with the solvents and / or buffers in the pharmaceutical compositions) can be used while maintaining operability. This represents a significant advantage over other methods for delivering (e.g., via syringes or syringes) high doses of pharmaceutical compositions, such as encapsulation and hyaluronidase, which require costly validation or reformulation to ensure compatibility.

[0160] Reducing viscous displacement and eccentricity are two important aspects that can promote the injectability of fluids with high viscosity (including viscosities exceeding 1,200 cP).

[0161] Figure 3 The relevant physical channel (e.g., needle hub) design parameters are indicated. The relevant fluid parameters are the flow rates of the internal first fluid and the external lubricant. and ), viscosity ( and ) and density ( and ).

[0162] Figure 3 Subfigure A illustrates a portion of a channel (e.g., in a needle hub) used to initiate the annular flow, and marks important dimensions. This channel includes a constriction section. The contour of the constriction section is drawn as a line, but can be a curve or piecewise function of any range, as discussed further later. Figure 3 Sub-figure B is an image of the fabricated needle hub with a stable core-ring flow (visible through differentially stained viscous first fluid).

[0163] Stable core-annular flow can be maintained by mitigating various fluid instabilities, such as, for example, high eccentricity and / or viscous displacement. Two fluids flow simultaneously through a channel, where one fluid (lubricant) separates the other fluid (first fluid) from the inner surface of the channel; this flow can be characterized by an eccentricity parameter (E). Stable core-annular flow is characterized by a low eccentricity parameter. In some embodiments, 0 ≤ E < 1. Figure 4The illustration shows the characteristics of different eccentricity parameter regions. Further discussion on this eccentricity parameter can be found in Jayaprakash, V. et al., Enhancing the Injectability of High Concentration Drug Formulations Using Core Annular Flows. Adv Healthcare Mater. The disclosure of this publication, found at https: / / doi.org / 10.1002 / adhm.202001022, is hereby incorporated herein by reference in its entirety. The closer E is to 0 (e.g., E < 0.05, E < 0.02, or E = 0), the greater the benefit of the core-annular flow. Nevertheless, significant benefits can still be obtained when E is closer to 1 (e.g., when E < 1). The devices disclosed herein can achieve such values ​​of eccentricity parameter. Preferably, a stable core-annular flow exhibits no instability in terms of the pressure drop or force required to maintain a constant injection rate (e.g., in some embodiments, a stable core-annular flow has at most minimal instability caused by the pressure drop or force required to maintain a constant injection rate). Significant changes in force or pressure drop indicate viscous displacement or other fluid instability. Figure 5 The illustration shows the viscous displacement compared to a stable core-ring flow.

[0164] If the device (e.g., the syringe) is not directly aligned with gravity, the density difference between the internal primary fluid and the external lubricant will cause the internal and external fluids to become misaligned. As mentioned earlier, this will lead to performance degradation.

[0165] To mitigate eccentricity, the time for fluid to travel through any section of the channel should be shorter than the time required for eccentricity to form. Therefore, two timescales can be defined: the convection timescale (…). ) and eccentricity time scale ( )

[0166]

[0167] in L For the length of the equipment section, A c For cross-sectional area, The average flow velocity, s This is the difference between the lubricant radius and the viscous liquid thread radius (i.e., the distance the viscous liquid must travel before contacting the inner wall of the equipment). g It is the gravitational constant, and The angle of inclination relative to the horizontal plane.

[0168] therefore, Standards were proposed for designing devices (e.g., syringes) with core-ring flow that appropriately reduce eccentricity.

[0169] Despite this standard, it has been observed that even when At the same time, a stable core-ring flow may also exist. For example, Figure 6 It shows in The prototype needle hub exhibits a stable core-ring flow. While the (darker) first fluid (which is more viscous than the surrounding lubricant) does fall into the constricted section (e.g., within the needle hub), fluid effects near the constriction stabilize the flow and re-establish the concentricity of the viscous fluid flowing into and within the needle. The flow rate of the first (internal) fluid is approximately twice that of the lubricant (external fluid). While not wanting to be bound by any particular theory, fluid boundary and edge effects are expected to influence the formation of eccentricity. Because the above equations (3-4) do not account for such effects, even when Even at that time, a stable core-ring flow can still be observed.

[0170] like Figure 5 The viscous displacement illustrated herein is an instability that occurs when a viscous fluid intrudes into the passageway of a lubricant. This reduces / eliminates the lubricating effect of the lubricant, resulting in a sharp increase in fluid resistance and effectively blocking / slowing down the flow of both internal and external fluids. During viscous displacement, the internal viscous liquid may displace the lubricant and come into contact with the inner walls of the passage (e.g., the passage included in a needle and / or needle hub). Viscosity displacement is an undesirable instability that can become a limiting factor for the performance of, for example, wicking flows, in high viscosity conditions and with low lubricant volume fractions.

[0171] The law of conservation of mass can be applied to the control volume leading to the needle hub to derive a representative fundamental equation, which at least explains the following: Figure 7 This section describes many aspects of viscous displacement in the design of channels (e.g., needle hubs). (Note that while the following derivations are representative and helpful in understanding viscous displacement phenomena, they do not imply a very precise characterization of fluid properties. That is, there may be some discrepancies between the performance expected from the following equations and the performance achieved experimentally.) Figure 7 The elements considered in this analysis are illustrated. For simplicity, it is assumed that the fluid is incompressible, thus the analysis simplifies to a volume conservation equation: .

[0172] In the above volume conservation equation It is the volumetric flow rate of the fluid flowing into the control volume. It is the volume that controls the volume ( VThe rate of change over time, and It is the flow rate of fluid flowing out of a controlled volume. Typically, flow rate... and Controlled by relative pressure and fluid resistance. For example, for laminar flow through a pipe with a circular cross-section, the Hagen-Poiseuille equation is:

[0173]

[0174] Here, R It is fluid resistance. It is related to the reduction of pressure. D It's the pipe diameter. It is the fluid viscosity, and He is the supervisor.

[0175] refer to Figure 7 The relevant pressure and fluid resistance can be used to deduce the properties of lubricants and viscous fluids. and A representative expression.

[0176]

[0177] The assumed gage pressure is the pressure relative to the outlet of the control volume.

[0178] In order to determine The representative expression for the term takes into account mechanical compliance. This is because pressure fluctuations within the equipment are inevitably non-zero. The volume of the fluid passage will oscillate due to mechanical deformation. With a length of... L And the initial unpressurized radius is R i Taking a cylindrical tube as an example, the volume of the cylindrical tube under a certain steady-state pressure can be written as:

[0179]

[0180] Using Young's law and the formula for circumferential stress, the stress caused by pressure The increase in radius can be written as:

[0181]

[0182] in P(t) For pressure, E Let be the Young's modulus of the material, and Let be the tube thickness. By combining the two equations above and taking the partial derivative with respect to time (since this is a stability analysis), we obtain the following expression:

[0183]

[0184] More generally, the volume change term in response to pressure fluctuations can be written as ,in C It is about controlling the compliance of volume.

[0185] By using the expressions for the volume change of the control volume and the inflow and outflow rates, the following representative equation can be derived:

[0186] General formula:

[0187] Lubricant flow in the channel (e.g., needle hub):

[0188] Viscous flow in channels (e.g., needle hubs):

[0189] The device design strategy for mitigating viscous displacement can be directly derived from the two equations above. It should be noted that, while not intending to be bound by any particular theory, viscous displacement occurs at least in fluid paths where viscous fluid preferentially flows into the lubricant, displacing the lubricant and reducing its flow rate through channels (e.g., needle holders) relative to the viscous fluid. Therefore, balancing the above equations allows for [a solution] when facing destabilization [problems]. Device designs that allow sufficient amounts of lubricant and viscous fluid to flow through channels (e.g., needle hubs) in a good relative ratio during disturbances can (e.g., will) mitigate viscous displacement.

[0190] Two important flows are at play: Flow (hereinafter referred to as "throughput flow") and with The related flow (hereinafter referred to as "compliant flow"). When the through flow in the core-ring flow region exceeds the compliant flow, a stable core-ring flow with inviscid displacement can be achieved. The ratio of the through flow to the compliant flow is calculated to obtain a dimensionless number:

[0191]

[0192] in This indicates the compliance of the control volume under discussion, and the flow is based on the local pressure gradient at the outlet and the resistance per unit length. This is described in terms of the ideal value, which should be maximized above the critical threshold where viscous displacement occurs due to lubricant depletion, in order to promote stable core-ring flow.

[0193] To maximize this value, we need to minimize the perturbation ( Minimize compliance ( ), and minimize the resistance of the core annular flow ( ).

[0194] The first consideration is minimizing compliance. As described in the equation above, the unwanted destabilization of the flow into and out of the channel (e.g., the needle hub) due to disturbances is caused by the non-zero compliance of the device (e.g., the channel and / or other components), which leads to problems when subjected to pressure fluctuations ( The volume changes during this process. Compliance can come from a variety of sources, such as radial deformation of cylindrical channels, axial deformation of compressed elements, and the compressibility of the fluid (liquid or gas).

[0195] Figure 8 A device exhibiting a core-ring flow via a channel is illustrated. The device includes a channel at least partially located within a needle holder. The needle holder connects two fluid reservoirs: one for a viscous fluid and one for a lubricant. The needle holder includes two inlets, each in fluid communication with one of the reservoirs, and a constriction section (not shown separately) for inducing the core-ring flow. Pressure can be applied to both reservoirs simultaneously and optionally substantially equally (as shown) to cause the viscous fluid and lubricant to flow into and through the needle holder, and then into and out of a needle tip in fluid communication with the needle holder on the side of the needle holder opposite the fluid reservoir. During fluid flow, a core-ring flow is formed in the needle holder, at least partially due to the constriction section, and this core-ring flow persists until the needle tip. Various compliance terms that may be considered in device design (e.g., channel or channel constriction section design) are shown, where the compliance contribution C of the viscous fluid is... v (Compliance mechanism) is given on the left and the compliance contribution of the lubricant is C. cv (Compliance mechanisms) are given on the right. On the right, expressions for estimating the physical compliance magnitude of various compliance mechanisms are provided, along with orders-of-magnitude estimates of compliance for the physical parameters of the relevant device (e.g., a syringe).

[0196] When optimizing a system with many compliant components, the most urgent task is to minimize the maximum compliance first, as it has the most significant impact on the system. Figure 8 In the case of the device shown, the compliance of the actuating finger is neglected because its compliance affects both the lubricant and viscous sides, making its effect more complex and potentially offsetting. The next highest compliance is air compliance. It has been experimentally demonstrated that the presence of air bubbles within the lubricant channels significantly exacerbates viscous displacement. Operationally, this can be easily avoided by ensuring that the presence of air bubbles in the lubricant channels is reduced (preferably completely eliminated).

[0197] To more rigorously demonstrate this concept, we tested a core-ring-shaped flow needle holder with adjustable compliance, such as... Figure 9 As shown. During the operation of the transparent needle hub, it was observed that when the tube compliance of the needle hub was low, the needle hub rarely experienced viscous displacement, and only experienced a very small degree of viscous displacement. Figure 9 As shown, viscous displacement is visible here as the viscous internal fluid (colored red) moves upward into the lubricant channel. When running with the same fluid at the same relative flow rate, but using a tube with higher compliance, the needle seat exhibits significantly worse behavior, experiencing more frequent viscous displacement. The effects of viscous displacement are also more severe because the volume of viscous fluid infiltrating the lubricant channel is significantly larger. The high-compliance tube, due to its longer length and lower Young's modulus of its material, has approximately 30 times higher compliance. Stable operation is characterized by a wicking flow, where the lubricant fluid (transparent) surrounds the viscous fluid (red) as it contracts. When viscous displacement occurs, the viscous fluid infiltrates the lubricant channel, as indicated by the black arrow on the left for illustrative purposes.

[0198] Minimizing system compliance reduces compliance flow caused by pressure disturbances, thereby stabilizing equipment operation. When compliance flow ( When the inflow and outflow terms of the governing equations for lubricant flow and viscous flow are smaller than those of the above-mentioned lubricant flow and viscous flow, compliance is sufficiently minimized.

[0199] Various structural features in channels and / or devices can be used to minimize compliance and thus mitigate the likelihood of viscous displacement or viscous displacement. For example, mechanisms for eliminating air bubbles in devices, such as ventilator surface chemicals (e.g., coatings), and the use of narrow fluid channels that do not easily trap air bubbles, can be used. Similarly, methods can be employed to remove dissolved air from the fluid before it flows through the channel (e.g., before it is supplied to a reservoir (e.g., a tank for a syringe or syringe), or after it is so supplied and before one or more fluids flow out of the reservoir), to reduce the likelihood of harmful bubble formation. Compliance, expressed numerically, can be defined as… (The volume change corresponding to a unit change in pressure), therefore its unit is [ The observed compliance was at least... Highly compliant elements exhibit poor performance. Furthermore, it has been observed that compliance with... Even a 0.1 mL air bubble can lead to poor performance. A typical polypropylene syringe is... It has been observed that it exhibits good performance. Therefore, in some embodiments, compliance is preferably <10. -11 More preferably <10 -12 Even better .

[0200] If any lubricant fluid passage upstream of a lubricant reservoir or channel (e.g., needle hub) has significant mechanical compliance, fluctuations in equipment pressure can cause significant changes in the flow rate into and out of the channel (e.g., needle hub). If this pressure increases substantially, the volume of the fluid passage increases, resulting in a reduction in the flow of lubricant into and out of the channel (e.g., needle hub). This will lead to lubricant depletion within the channel (e.g., needle hub), causing viscous fluid expansion within the channel (e.g., needle hub), thereby resulting in a viscous displacement event.

[0201] Next, we will consider the issue of matching upstream resistance. Observation Figure 7 We can assume that, due to the parallelism of streamlines, the lubricant pressure in the channel (e.g., the needle hub) is the same as the viscous fluid pressure in the channel. Therefore, we can estimate the upstream pressure of lubricant storage tanks and viscous substance storage tanks as follows:

[0202]

[0203] in and These are the flow rates of lubricant and viscous fluid, respectively. and These represent the fluid resistances of the lubricant and the viscous fluid, respectively. Ignoring the effect of compliance, we can express the relative flow rates of the lubricant and viscous fluid flowing into the needle hub as:

[0204]

[0205] To promote the stability of the lubricated annular flow, it is important that the relative flow rates of the lubricant and the viscous fluid remain stable to avoid lubricant depletion. In this instability analysis, we assume that the pressure within the needle hub may change rapidly over a timescale where the overall lubricant pressure remains constant; therefore, we assume... and It is constant over time.

[0206] In this expression, if ,but It will be The function. However, if Then the expression becomes only a function of fluid resistance, where This is a very favorable situation for stability because the relative flow rate is independent of time. Essentially, pressure disturbances in the system may affect the absolute flow rates of lubricants and viscous fluids, but not the relative flow rates, since the effects on the flow rates are equal.

[0207] Given the required relative flow rates of lubricant and viscous fluid, these conditions can be engineered by selecting appropriate resistance to minimize the impact of pressure fluctuations on stability.

[0208] Increasing lubricant resistance can also help resist reverse flow that may occur during viscous displacement, limiting the extent to which viscous fluid can reversibly intrude into the lubricant channels and mitigating the harmful effects of viscous displacement.

[0209] We fabricated a prototype device incorporating these resistance-matching concepts, which significantly outperformed a prototype device without these concepts. At a relative flow rate of 0.14 between the lubricant and the viscous fluid, the device with resistance matching exhibited smooth injection of 1266 cP of fluid without significant viscous displacement. For the device without resistance matching, injection of 1266 cP of fluid at a relative flow rate of 0.27 between the lubricant and the viscous fluid inevitably resulted in significant viscous displacement, which disrupted the injection process.

[0210] Pressure fluctuations within a device can alter the amount of each fluid flowing into and out of a channel (e.g., needle hub). If pressure fluctuations change the flow rate of viscous fluids and lubricants in significantly different ways, the flow can become unstable. For example, suppose the pressure within the channel (e.g., needle hub) increases dramatically, and suppose the pressure in the reservoirs of viscous fluids and lubricants is constant. This will reduce the pressure drop between that one or more fluid reservoirs and the channel (e.g., needle hub), thereby reducing the flow rate of lubricant and viscous fluids into the channel (e.g., needle hub). The change in lubricant flow rate will affect the lubricant fluid resistance, Function of upstream pressure Changes in the flow rate of viscous fluids will affect the viscous fluid resistance. Function of upstream pressure If the fluid resistances of the viscous fluid passage and the lubricant fluid passage are not properly correlated, the flow rate variations between the two fluids will be significantly different. This can lead to lubricant depletion in the passage (e.g., needle hub), resulting in viscous displacement. Properly correlating the fluid resistances can minimize the effects of viscous displacement.

[0211] One way to achieve this is by creating small "throttling points" within the lubricant flow channels, as it can be difficult to manufacture devices that match resistance with constant-diameter flow channels. This specific resistive region can take the form of a thin tube or a resistive element [e.g., a filter (e.g., a porous membrane) and / or a densely packed element with small pores]. These two methods can also be used in combination. Figure 10AThe illustration depicts a throttling point (small-diameter flow channel) (in the middle figure) and a resistive element (e.g., a filter). For example, a small-diameter flow channel (throttling point) in a tank for lubricants might have a diameter, for example, not exceeding 50%, 40%, 30%, 20%, or 10% of the larger diameter of the tank. The pore size and pore density of the filter are such that the total cross-sectional area of ​​the pores through which the fluid can flow in the tank (e.g., the average value in the filter thickness direction) does not exceed 50%, 40%, 30%, 20%, or 10% of the diameter of the tank. Tanks of different diameters for viscous fluids and for lubricants can be used to at least partially match the flow resistance of these two fluids (e.g., in combination with small-diameter flow channels and / or resistive elements (e.g., filters)). In these cases, the diameter refers to the inner diameter, as the thickness of the tank or other fluid flow channel may vary, for example, for reasons of compliance minimization.

[0212] Generally, to apply this concept, the resistance of the lubricant must be increased because the viscosity of a lubricant is typically much lower than that of a viscous fluid. Due to manufacturing limitations of small diameters, it is unlikely that a constant diameter flow channel can be used as the lubricant flow channel, at least not at a very high cost. Instead, this resistance is more likely to be provided using a short section of a smaller diameter flow channel or by using a resistive element (e.g., a filter).

[0213] Resistance can be defined as ,in This refers to the pressure drop between the fluid storage tank and the initiation point of the annular flow in the channel (e.g., in a needle holder). (Subscript) l It refers to lubricants. Therefore, similarly, Preferably, given the relative flow rates of the viscous fluid and the lubricant, and Related, so that and The difference won't be too significant. Even when the equipment is not optimized for resistance matching at all, in Suitable performance was also observed at that time. At that time, significantly better performance may be observed. In some implementations, The number of particles in the device is no greater than 100,000, preferably no greater than 10,000, more preferably no greater than 1,000, no greater than 100, no greater than 10, or no greater than 5. In some embodiments, The pressure drop is in the range of 0.5 to 5, for example, 0.5 to 2, or 0.5 to 1.5. This type of pressure drop can be used in twin-cylinder designs, or designs with two fluid reservoirs having an output to a separate inlet that then outputs to a needle holder, such as... Figure 8 As shown.

[0214] Next, we will consider how to minimize disturbances. Reducing the amplitude of disturbances helps stabilize the flow through the equipment. Pressure disturbances can cause instability in the relative flow rates of lubricants and viscous fluids, leading to viscous displacement. Disturbances can originate from a variety of sources, such as non-constant actuating forces / pressures, environmental vibrations, inhomogeneities in fluid properties (density, viscosity, etc.), particulate matter, etc.

[0215] Therefore, it is preferable (and can improve stability) to take precautions for the injection process and fluid such as: reducing fluctuations in the actuation profile; ensuring fluid homogeneity (thorough mixing, uniform temperature, etc.); removing particulate matter that may disturb the core-annular flow profile; reducing external vibrations; or a combination thereof.

[0216] Fluctuations in actuating force / pressure can lead to instability. Using a single pressure headspace shared between the lubricant and viscous fluid storage tanks can mitigate this instability. This ensures that pressure fluctuations have a similar effect on both the lubricant and viscous fluid, thus maintaining similar relative flow rates. The resistance can be designed to ensure that the relative flow rate of the viscous fluid to the lubricant reaches the desired value when pressure is applied from a single pressure headspace. Such equipment has been shown to operate with high stability at a viscous fluid viscosity of 500 cP and a relative flow rate of 0.33 between the lubricant and the viscous fluid.

[0217] Pressure fluctuations can cause particularly significant disruption when combined with highly compliant components, leading to compliant flow. Another strategy to minimize the negative impact of disturbances is to use dampers to isolate sensitive, highly compliant components. This concept is illustrated in... Figure 10B In viscous flow, high-frequency pressure disturbances are inherently damped because the rearrangement of the velocity distribution during flow through the channel consumes energy. Viscous flow does not immediately adjust to changes in the pressure gradient. The frequencies at which disturbances are effectively damped are described by the characteristic timescales of viscous connectivity:

[0218]

[0219] Therefore, given the pipe diameter (D) and fluid density ( ) and fluid viscosity In such cases, dampers can be designed to isolate compliant components from a specific frequency range, thereby mitigating the effects of compliant flow and reducing the severity of viscous displacement.

[0220] It has been observed that designs that use dampers (with high fluid resistance) to isolate the most compliant components from channels (e.g., needle hubs) are significantly better than designs that do not use isolation dampers.

[0221] Given that viscous displacement is a transient instability effect, minimizing disturbances to the equipment will improve its stability. Minimizing pressure fluctuations will minimize the [equation missing] in the above equation. This can lead to a more constant inflow and outflow of lubricant and viscous fluid into and out of channels (such as needle hubs), thereby reducing the effects of lubricant depletion.

[0222] Structural features of devices that can minimize disturbances include: a shared pressure headspace; a shared actuation system (e.g., in cases where viscous fluids and lubricants do not necessarily share a headspace but are driven by the same force); regions with high viscous losses that can be used to dampen pressure disturbances; and flow channels with reduced diameters small enough to induce viscous losses; and the use of dampers.

[0223] The damped frequency is a function of the diameter. ), where R is the radius of the circular cross-section tube. Fluid dampers can be employed in conjunction with... Figure 10A The same design is shown. For example, the fluid damper can be a region with a small diameter, or a resistive element with significant viscous loss (e.g., a filter). It has been experimentally observed that the relative placement of these elements has a significant effect. In some embodiments, the damper is positioned between the needle holder (the starting point of the wicking flow) and an upstream (e.g., the most compliant) element. Such an arrangement can limit pressure disturbances to the compliant element, thereby reducing the likelihood of viscous displacement. This damping effect has been observed for a small channel diameter of 0.2 mm, therefore a channel diameter <2.0 mm (e.g., <1.0 mm, <0.5 mm, or <0.2 mm) is preferred.

[0224] Next, we will consider how to minimize channel resistance. This can be achieved by calculating the resistance throughout the entire process. D h arrive D can The shear force expression within the contraction region is kept constant to perform analytical contour optimization of the contraction region profile. This profile should allow the fluid flow to contract evenly.

[0225]

[0226] The Navier-Stokes equations for the viscous limits in the r and z directions in an axisymmetric cylindrical coordinate system are presented above. Gravity is neglected. By scaling and integrating the individual shear terms, an analytical needle profile that keeps specific shear terms constant can be determined.

[0227] For example, by constantly changing v z Caused zDirectional shearing terms can be integrated as follows: ：

[0228]

[0229] Where R(z) forms the contour of the contracted portion, for example, Figure 3 As shown. Other conditions will produce alternative profiles; for example, specifying a constant... This will produce an exponential profile.

[0230] Among all four shear terms shown in the Navier-Stokes equations, the following possible orders contribute to the analytic profile:

[0231] A simulation model was built in Ansys Fluent software to assist in the optimization of the pin header profile. This model calculated, for example... Figure 11 The diagram shows the laminar flow distribution of the two fluids in the needle hub, constriction section, and needle tip. Sub-figure A illustrates the distribution based on... Figure 3 Subplot B illustrates the simulated core-ring flow of the experimental needle hub geometry. Blue (bottom) indicates the internal viscous first fluid (or inlet), while red (top) indicates the presence of lubricant (or inlet). As can be seen, lubricant can fill sharp corners. Subplot BD illustrates the flow following the parameters where n is -1 / 3, -1, and +3, respectively. The simulated needle seat profile is derived from an analytical equation of the form. In some embodiments, the internal profile of the contraction portion has a shape determined by... The shape is defined such that -1 ≤ n ≤ -0.1 (e.g., n = -1 / 3).

[0232] In some implementations, the geometry that best mitigates viscous displacement should minimize fluid stress in (e.g., any) contracted portions (e.g., within the needle hub). Therefore, the metrics used to compare simulated needle hub profiles are the maximum fluid strain and pressure gradient in the axial and radial directions at various points within the syringe barrel. Selected values ​​are shown in Table 1.

[0233]

[0234] Table 1

[0235] As can be seen from Table 1, the contour of the contracted portion at n = -1 / 3 (illustrated in...) Figure 11In subplot B), the needle seat profile (n = -1, n = +3) minimizes fluid shear forces compared to the other two illustrated profiles. This leads us to recognize that the contraction at smaller diameters may be more important than the contraction at larger diameters: the n = -1 / 3 profile highlights a gentle taper at smaller diameters and a more abrupt taper at larger diameters. Generally, the convex needle seat profile performs better than the concave needle seat profile. Figure 12 As shown, this effect can be observed by comparing the pressure maps along the axis for the n = 3 and n = -1 / 3 contraction portions (e.g., in the needle hub). The n = -1 / 3 needle hub (subplot AB) exhibits a relatively uniform contraction portion, with its pressure gradient remaining approximately constant throughout the process. However, the n = 3 contraction portion (e.g., in the needle hub) (subplot CD) has a small initial pressure gradient at the start of contraction, which develops into a very large pressure gradient at the end of contraction. For this n = 3 contraction portion, the relatively rapid thinning of the profile near the neck leads to an increase in the pressure gradient and fluid shear force at the neck, indicating that the neck is more susceptible to viscous displacement.

[0236] In a general sense, each individual fluid element flowing into a needle holder with a constriction section (e.g., each reservoir flowing into that needle holder) either travels through the constriction section or participates in a “compliant flow” ( This means the fluid doesn't flow through the constriction section but instead flows elsewhere. "Stiffness" can be associated with each of these types of flow, which are respectively related to needle hub fluid resistance and system compliance. If the device's mechanical compliance is low (i.e., the device is stiff) compared to the stiffness of the fluid flow through the constriction section, then the compliant flow will be minimal because the fluid will choose the path of least resistance and flow through the constriction section. This framework leads to the conclusion that the resistance of the constriction section (and consequently, the resistance to the annular flow) should be minimized. This allows lubricant and viscous fluids to preferentially flow into and out of the needle hub, thus maintaining lubrication and preventing viscous displacement.

[0237] Minimizing the core annular flow resistance can also lead to a reduction in pressure drop, thereby reducing the actuation force of the device, which is another preferred option.

[0238] The resistance of the constricted portion in the channel (and consequently the resistance to the core-ring flow) is expressed with a depth far greater than a single number. Due to the transient nature of viscous displacement, it is helpful to consider how the resistance of the constricted portion and / or core-ring flow changes in response to slight disturbances. Consider first the operation of a device initially in steady state and then slightly disturbed. If this disturbance results in a reduction in lubricant flow relative to the viscous flow (whether due to compliance or fluid resistance), the lubricating effect of the core-ring flow will be less effective. This will lead to an increase in the channel pressure (e.g., needle seat) required to drive the flow. This increase in channel pressure can have the effect of further reducing lubricant flow, thus further increasing pressure, leading to a runaway transient effect of lubricant depletion and viscous displacement. In this case, the rate of increase in the resistance of the constricted portion and / or core-ring flow for a given disturbance is a key quality: relatively disturbance-resistant designs (e.g., those experiencing small changes in flow resistance or fluid flow rate upon disturbance) are more likely to remain stable than those experiencing significant changes. In this sense, the stiffness of the contraction section (and / or the fluid undergoing core-annular flow) needs to be considered not only under steady-state operation, but also in response to disturbances.

[0239] These transient considerations can be particularly important during device startup, when, for example, the needle hub initially does not contain viscous fluid. After flow initiation, a significant amount of viscous fluid enters the needle hub and must be contained within the needle tip. This is associated with a sudden, large increase in pressure, which can lead to uncontrolled compliant flow, as described above, which depletes the lubricant and results in viscous displacement. Therefore, preloading the needle hub and / or pausing between needle hub loading and further fluid flow may be a desirable practice to mitigate such detrimental effects.

[0240] The foregoing analysis is not limited to the component used as an example above; such analysis can be performed on any relevant fluid passage or mechanical component of the device disclosed herein, for example, regardless of whether it is related to... Figure 8 The illustrated dual-tank syringes may be similar or dissimilar. In other words, resistance and compliance of any and all fluid paths in the equipment can be considered, and in the analysis of the equipment, it may be desirable to take into account these resistances and compliance, which may contribute to fluid performance.

[0241] In some embodiments, the contraction portion (e.g., in the needle hub) includes a convex portion relative to the interior of the channel (e.g., through the needle hub) (e.g., a portion of the channel is included in the needle hub). For example, in some embodiments, the second derivative of the interior profile of the contraction portion is positive (>0) at at least some portions of the profile (e.g., using...). Figure 3(Coordinate system in subgraph A). In some embodiments, the contraction portion (e.g., in the needle hub) is convex relative to the interior of the channel (e.g., through the needle hub) at at least some portions of the contraction portion. In some such embodiments, the contraction portion (e.g., in the needle hub) is completely convex relative to the interior of the channel (e.g., through the needle hub) (e.g., a portion of the channel is included in the needle hub). For example, in some embodiments, the second derivative of the interior profile of the contraction portion is positive (>0) at every point along the profile. In some embodiments, the contraction portion (e.g., in the needle hub) tapers relatively more sharply with position at the larger diameter end of the contraction portion, and relatively less sharply with position at the smaller diameter end.

[0242] Devices (e.g., syringes or syringes) may include a needle and a needle hub. The needle and needle hub may be in fluid communication with each other. The needle may include an outlet of a channel. The body of the needle may define a portion of the channel (e.g., the lumen of the needle may define that portion). A portion of the channel may be included within the needle. Improved performance can also be achieved at the interface between the needle hub and (e.g., the inserted) needle by using a smoother taper that at least partially mitigates viscous displacement. Since in some embodiments the needle has the smallest inner diameter of the entire device (e.g., the inner diameter of the needle lumen), introducing a wicking flow into the needle is crucial for maintaining performance (e.g., achieving initial fluid flow from the channel outlet, which serves as the needle outlet, or achieving flow at a sufficiently high flow rate). Generally, abrupt contractions at the needle-needle hub interface should be avoided. Figure 13 A comparison was made between a standard needle-to-coggle interface (sub-figure A) and alternative needle-to-coggle interfaces (sub-figure BC), which can mitigate or eliminate problems caused by the sudden contraction portion present in the standard needle-to-coggle interface. Figure 13 The illustration is a cross-sectional view, in which the needle hub with a simple (linear) contraction is shown in light shading, while the needle tip is shown in dark shading.

[0243] In some implementations, a portion of the needle tip is disposed within the needle hub (e.g., within the end of the needle hub), for example, as... Figure 13 As illustrated in sub-figure AB. Unlike the conventional design (Figure A), the first alternative needle-coil interface (sub-figure B) does not include a sharp constriction. The portion of the needle disposed within the needle coil may include a needle inlet comprising a gently constricting portion relative to the inner diameter of the needle, such as... Figure 13As illustrated in sub-figure B. The gently constricting portion can be, for example, a slope in the range of 15-75 degrees, such as 15 to 60 degrees or 15 to 45 degrees. In another alternative needle-coil interface design, the outlet of the needle coil is located within the needle (sub-figure C). Blunt-end needles can be inserted without needle machining, but still avoid the sharp needle-coil interface and associated adhesive displacement problems. In some embodiments, the needle coil includes a second constricting portion (e.g., including a convex portion) to facilitate obtaining a sufficiently small minimum needle coil diameter to be inserted into the needle. Such needles, whether partially located within or partially outside the needle coil outlet (e.g., around the needle coil outlet), can be secured in place by pressure and / or friction and / or by adhesive (e.g., glue). In some embodiments, the needle is smaller than 22 gauge (e.g., 25 or 27 gauge) (e.g., a gauge in the range of 23 to 27). In some implementations, the needle is a 23-gauge, 24-gauge, 25-gauge, 26-gauge, 27-gauge, 30-gauge, or smaller needle.

[0244] Two additional geometry optimization studies have been conducted (and incorporated into the best-performing prototype described in Example 1 below). First, the distance between the channel inlet for the first fluid (e.g., in the needle hub) and the starting point of the contraction portion (e.g., in the needle hub) is... L h Besides being an important parameter for reducing eccentricity, it can also significantly affect viscous displacement behavior. Operating conditions and / or the profile (e.g., shape) of the contracted portion may influence the preferred shape. L h In some implementations, the inlet and the constriction portion are set to be no more than 5 mm apart, for example, no more than 4 mm, no more than 3 mm, no more than 2 mm, no more than 1 mm, no more than 0.8 mm, no more than 0.6 mm, no more than 0.5 mm, or no more than 0.4 mm apart.

[0245] Secondly, the first fluid inlet ( A i ) and lubricant inlet ( A o The relative area ratio between (). A i and A o In this case, it is defined by the following equation.

[0246]

[0247] In some implementation schemes, A i / Ao Preferably within the range of 0.07 to 1.38. Higher values... A i / A o It may produce better performance in reducing viscous displacement, but extremely high A i / A o This becomes difficult to manufacture while maintaining concentricity of subsequent flows. In some implementations, the channel includes two inlets: one for the first fluid and one for the lubricant. For example, a twin-cylinder injection cartridge (e.g., having an inner and outer cylinder) has such inlets. Twin-tank equipment (such as...) Figure 8 The type illustrated in the diagram is another example of such an inlet. In some embodiments, the ratio of the area of ​​the inlet for the first fluid to the area of ​​the second inlet for the lubricant is in the range of 0.02 to 5. For example, this area ratio can be 0.02 to 2, 0.02 to 4, 0.02 to 3, such as 0.04 to 2, 0.04 to 4, 0.04 to 3, 0.05 to 2, 0.06 to 2, 0.07 to 2, 0.02 to 4, 0.02 to 3, 0.02 to 1.8, 0.02 to 1.6, 0.02 to 1.4, 0.04 to 4, 0.04 to 3, 0.04 to 1.8, 0.04 to 1.6, 0.04 to 1.4, 0.06 to 4, 0.06 to 3, 0.06 to 2, 0.06 to 1.8, 0.06 to 1.6, 0 The range is 0.06 to 1.4, 0.07 to 4, 0.07 to 3, 0.07 to 2, 0.07 to 1.8, 0.07 to 1.6, 0.07 to 1.4, 0.1 to 4, 0.1 to 3, 0.1 to 2, 0.1 to 1.8, 0.1 to 1.6, 0.1 to 1.4, 0.2 to 4, 0.2 to 3, 0.2 to 2, 0.3 to 4, 0.3 to 3, 0.3 to 2, 0.4 to 4, 0.4 to 3, 0.4 to 2, 0.5 to 4, 0.5 to 3, 0.5 to 2, 0.5 to 1.8, 0.5 to 1.6, or 0.5 to 1.4.

[0248] In some embodiments, the lubricant comprises water. For example, the lubricant may be or comprise an aqueous solution (e.g., physiological saline). In some embodiments, the lubricant comprises a biocompatible and / or metabolizable oil (e.g., squalene, safflower oil, fluorinated oil (e.g., HFE-7500), mineral oil, and / or triglyceride oil). In some embodiments, the lubricant comprises a buffer (e.g., a pharmaceutically acceptable buffer, such as a buffer suitable for use with biological products). In some embodiments, the lubricant comprises a formulation (e.g., a pharmaceutical formulation, such as a biological product). In some embodiments, the lubricant comprises an immune adjuvant (e.g., MF59, AS02, AS03, and / or AS04). In some embodiments, the lubricant is aqueous. In some embodiments, the lubricant is non-aqueous. In some embodiments, the lubricant comprises a buffer. In some embodiments, the first fluid comprises the same buffer as the buffer contained in the lubricant.

[0249] In some embodiments, the first fluid and the lubricant are independent components. For example, the first fluid may contain a pharmaceutical composition containing an aqueous solvent (e.g., water), while the lubricant is non-aqueous (e.g., containing an organic solvent). In some embodiments, the first fluid (e.g., a pharmaceutical composition) and the lubricant contain one or more of the same components (e.g., solvents and / or buffers). For example, in some embodiments, the lubricant and the first fluid (e.g., a pharmaceutical composition) contain water. In some embodiments, the first fluid and the lubricant contain one or more different components and one or more of the same components. For example, in some embodiments, the first fluid and the lubricant contain the same components, except that the first fluid contains a pharmaceutical composition (e.g., a biological product). For example, in some embodiments, both the first fluid and the lubricant contain water, and the first fluid further contains a pharmaceutical composition (e.g., a biological product), while the lubricant does not contain that pharmaceutical composition (e.g., a biological product). In some embodiments, the first fluid and the lubricant contain exactly the same components (e.g., buffers), except that one of the fluids (e.g., the first fluid) has an additional component (e.g., a pharmaceutical composition). In some embodiments, the first fluid and the lubricant are miscible. In some implementations, the first fluid and the lubricant are immiscible.

[0250] In some embodiments, the lubricant and the first fluid do not substantially mix in at least a portion of the device (e.g., in the needle, needle hub, barrel, or combinations thereof). In some embodiments, the lubricant mixes with the first fluid at a maximum of 50% when present in at least a portion of the device (e.g., in the needle, needle hub, barrel, or combinations thereof). That is, when present in at least a portion of the device (e.g., in the needle, needle hub, barrel, or combinations thereof), up to 50% (e.g., up to 40%, up to 30%, up to 20%, up to 10%, or up to 5%) of the lubricant mixes with the first fluid, while the remainder of the lubricant remains unmixed with the first fluid. In some embodiments, the degree of mixing can be determined by visual inspection and / or measurement of concentration changes.

[0251] In some embodiments, the first fluid and the lubricant contain exactly the same components (e.g., buffer solution and drug), but the concentrations of one or more of these components differ (e.g., drug). For example, in some embodiments, the first fluid and the lubricant contain exactly the same components (e.g., buffer solution and drug composition), but the concentration of one or more of these components (e.g., drug composition) is higher in the first fluid. In some embodiments, the first fluid has a high concentration of biological product, while the lubricant has a low concentration (e.g., none) of biological product, but the first fluid and the lubricant are otherwise identical, and the viscosity and / or density of the first fluid may be higher (e.g., much higher) than that of the lubricant.

[0252] In some embodiments, the molar concentration of a component (e.g., a pharmaceutical composition) in the lubricant is greater than or equal to 5%, greater than or equal to 10%, greater than or equal to 20%, greater than or equal to 30%, greater than or equal to 40%, greater than or equal to 50%, greater than or equal to 60%, greater than or equal to 75%, greater than or equal to 90%, or greater than or equal to 95% of the molar concentration of the component (e.g., a pharmaceutical composition) in the lubricant is less than or equal to 100%, less than or equal to 99%, less than or equal to 95%, less than or equal to 90%, less than or equal to 80%, less than or equal to 70%, less than or equal to 60%, or less than or equal to 50% of the molar concentration of the component in the first fluid. Combinations of these ranges are also possible (e.g., greater than or equal to 5% and less than or equal to 100%, or greater than or equal to 10% and less than or equal to 50%). For example, if the molar concentration of the component is 1 M in the first fluid and 0.1 M in the lubricant, then the molar concentration of the component in the lubricant will be 90% lower than the molar concentration in the first fluid.

[0253] In some embodiments, the lubricant constitutes no more than 50% by volume of the total volume of the material within the channel (e.g., no more than 40%, 30%, 25%, 20%, 15%, 10%, or 5%). In some embodiments, the volume ratio of the first fluid to the lubricant is no less than 1:1 (e.g., no less than 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, or 9:1). In some embodiments, the volume ratio of the first fluid to the lubricant does not exceed 200:1 (e.g., no more than 100:1).

[0254] In some embodiments, the first fluid [e.g., in a channel (e.g., flowing through a channel)] has a viscosity in the range of 5 cP to 10,000 cP. For example, the first fluid may have a viscosity in the range of 5 cP to 5,000 cP, 5 cP to 4,000 cP, 5 cP to 3,000 cP, 5 cP to 2,500 cP, 5 cP to 2,000 cP, 5 cP to 1,750 cP, 5 cP to 1,500 cP, or 5 cP to 1,250 cP. For example, the first fluid may have a viscosity in the range of 10 cP to 10,000, 10 cP to 5,000 cP, 10 cP to 4,000 cP, 10 cP to 3,000 cP, 10 cP to 2,500 cP, 10 cP to 2,000 cP, 10 cP to 1,750 cP, 10 cP to 1,500 cP, or 10 cP to 1,250 cP. For example, the first fluid may have a viscosity in the range of 15 cP to 10,000, 15 cP to 5,000 cP, 15 cP to 4,000 cP, 15 cP to 3,000 cP, 15 cP to 2,500 cP, 15 cP to 2,000 cP, 15 cP to 1,750 cP, 15 cP to 1,500 cP, or 15 cP to 1,250 cP. For example, the first fluid may have a viscosity in the range of 20 cP to 10,000, 20 cP to 5,000 cP, 20 cP to 4,000 cP, 20 cP to 3,000 cP, 20 cP to 2,500 cP, 20 cP to 2,000 cP, 20 cP to 1,750 cP, 20 cP to 1,500 cP, or 20 cP to 1,250 cP. For example, the first fluid may have a viscosity in the range of 50 cP to 10,000, 50 cP to 5,000 cP, 50 cP to 4,000 cP, 50 cP to 3,000 cP, 50 cP to 2,500 cP, 50 cP to 2,000 cP, 50 cP to 1,750 cP, 50 cP to 1,500 cP, or 50 cP to 1,250 cP. For example, the first fluid may have a viscosity in the range of 75 cP to 10,000, 75 cP to 5,000 cP, 75 cP to 4,000 cP, 75 cP to 3,000 cP, 75 cP to 2,500 cP, 75 cP to 2,000 cP, 75 cP to 1,750 cP, 75 cP to 1,500 cP, or 75 cP to 1,250 cP.For example, the first fluid may have a viscosity in the range of 100 cP to 10,000, 100 cP to 5,000 cP, 100 cP to 4,000 cP, 100 cP to 3,000 cP, 100 cP to 2,500 cP, 100 cP to 2,000 cP, 100 cP to 1,750 cP, 100 cP to 1,500 cP, or 100 cP to 1,250 cP. For example, the first fluid may have a viscosity in the range of 250 cP to 10,000, 250 cP to 5,000 cP, 250 cP to 4,000 cP, 250 cP to 3,000 cP, 250 cP to 2,500 cP, 250 cP to 2,000 cP, 250 cP to 1,750 cP, 250 cP to 1,500 cP, or 250 cP to 1,250 cP. For example, the first fluid may have a viscosity in the range of 500 cP to 10,000, 500 cP to 5,000 cP, 500 cP to 4,000 cP, 500 cP to 3,000 cP, 500 cP to 2,500 cP, 500 cP to 2,000 cP, 500 cP to 1,750 cP, 500 cP to 1,500 cP, or 500 cP to 1,250 cP. For example, the first fluid may have a viscosity in the range of 1,000 cP to 10,000, 1,000 cP to 5,000 cP, 1,000 cP to 4,000 cP, 1,000 cP to 3,000 cP, 1,000 cP to 2,500 cP, 1,000 cP to 2,000 cP, 1,000 cP to 1,750 cP, 1,000 cP to 1,500 cP, or 1,000 cP to 1,250 cP. In some embodiments, the first fluid [e.g., in a channel (e.g., flowing through a channel)] has a viscosity of at least 10 cP (e.g., at least 15 cP, greater than 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP).

[0255] In some embodiments, the channel is sized and shaped to allow fluids with viscosities ranging from at least 5 cP to 10,000 cP at any location to flow through the channel (e.g., from inlet to outlet and through the outlet) [e.g., in swivel flow (e.g., coaxial lubrication)]. In some embodiments, the channel is sized and shaped to allow fluids with viscosities ranging from at least 5 cP to 5,000 cP to flow through the channel. In some embodiments, the channel has a curvature to allow fluids with viscosities ranging from at least 5 cP to 10,000 cP to flow through the channel (e.g., from inlet to outlet and through the outlet) [e.g., in swivel flow (e.g., coaxial lubrication)]. In some embodiments, the channel has a curvature to allow fluids with viscosities ranging from at least 5 cP to 5,000 cP to flow through the channel.

[0256] In some embodiments, the lubricant has a viscosity in the range of 0.5 cP to 10 cP. For example, in some embodiments, the lubricant has a viscosity in the range of 0.5 cP to 5 cP or 0.5 cP to 2 cP. In some embodiments, the lubricant has a viscosity of less than 10 cP, such as less than 5 cP, less than 4 cP, less than 3 cP, less than 2 cP, or less than 1.5 cP.

[0257] In some embodiments, the lubricant and the first fluid exhibit a core-ring flow (e.g., coaxial lubrication) (e.g., stable core-ring flow) when flowing simultaneously through the channel. In some embodiments, the lubricant and the first fluid exhibit a core-ring flow (e.g., coaxial lubrication) (e.g., stable core-ring flow) as the first fluid flows through the device. The core-ring flow (e.g., through the channel and / or device) can achieve an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%). This type of core-ring flow can occur when the longitudinal axis of the channel is within 45 degrees of a line perpendicular to gravity. This type of core-ring flow can occur when the first fluid and lubricant are miscible. In some embodiments, the core-ring flow (e.g., through the channel and / or device) achieves an efficiency greater than 40% (e.g., greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) when the first fluid and lubricant are immiscible. This occurs. In some implementations, when the longitudinal axis of the channel... When located within 45 degrees of a line perpendicular to gravity and / or when the first fluid and the lubricant are miscible, the first fluid can flow with an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%).

[0258] In some embodiments, the fluid (e.g., pharmaceutical composition) delivery device includes a channel extending from an inlet to an outlet (e.g., in a needle hub, optionally also in a needle), wherein the device has an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., in a spool-annular flow) for allowing fluid to flow from the inlet to the outlet and through the outlet. In some embodiments, the fluid (e.g., a pharmaceutical composition) delivery device includes a channel extending from an inlet to an outlet (e.g., in a needle hub, optionally also in a needle), wherein the device has an efficiency of greater than 40% (e.g., greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., in a wicking flow) for the fluid to flow from the inlet to the outlet and through the outlet, provided that the first fluid and lubricant are immiscible. In some embodiments, the first fluid has a viscosity of at least 5 cP, at least 10 cP, at least 15 cP, or greater than 20 cP. In some embodiments, the fluid (e.g., a pharmaceutical composition) delivery device includes a channel extending from an inlet to an outlet (e.g., in a needle hub, optionally also in a needle tip), wherein the device has an efficiency of greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., in a spool-annular flow) for allowing fluid to flow through the channel. In some embodiments, the first fluid has a viscosity of at least 5 cP, at least 10 cP, at least 15 cP, or greater than 20 cP. In some embodiments, the fluid (e.g., a pharmaceutical composition) delivery device has an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., in a core-annular flow) for allowing fluid to flow through the outlet of the device. In some embodiments, the first fluid has a viscosity of at least 5 cP, at least 10 cP, at least 15 cP, or greater than 20 cP. In some embodiments, the first fluid may have an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., in core-annular flow). The fluid flows through a channel (e.g., a channel in a device). In some embodiments, the first fluid has a viscosity of at least 5 cP, at least 10 cP, at least 15 cP, or greater than 20 cP.

[0259] In some embodiments, the longitudinal axis of the channel is located within 45 degrees of the line perpendicular to gravity. In some embodiments, the longitudinal axis of the channel is located within 45 degrees of the line perpendicular to gravity. In some embodiments, when the longitudinal axis of the channel... When located within 45 degrees of a line perpendicular to gravity, the first fluid can flow with an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%). In some embodiments, when flowing with a miscible lubricant in a core-annular flow, the first fluid can flow with an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%). )flow.

[0260] Channel efficiency ( Efficiency can be expressed as the ratio of the theoretical pressure required to drive the flow through the channel outlet to the actual pressure required to drive the flow through that outlet. For example, efficiency can be viewed as the ratio of the theoretical pressure required to drive the flow through the channel (e.g., a device channel) outlet under laminar, ideal, fully expanded, or fully concentric annular flow conditions. ) and the actual pressure required for the drive flow to pass through the entire channel ( The ratio of ) to: .efficiency( It can also be expressed as a constant specified in the given time. The flow rate of the first fluid through the channel ( ) and the ideal flow rate of the first fluid in the core annular flow ( The ratio of ) to: Efficiency of core-to-circuit flow equipment ( This can also be expressed as the pressure reduction factor under ideal core annular flow and the actual channel pressure reduction factor: .

[0261] Equipment efficiency ( Efficiency can be expressed as the ratio of the theoretical pressure required to drive the flow through the equipment outlet to the actual pressure required to drive the flow through that outlet. For example, efficiency can be viewed as the ratio of the theoretical pressure required to drive the flow through the equipment outlet under laminar flow, ideal flow, fully expanded flow, and fully concentric annular flow conditions. ) and the actual pressure required for the drive flow to pass through the entire device ( The ratio of ) to: .efficiency( It can also be expressed as a constant specified in the given time. The flow rate of the first fluid through the device ( ) and the ideal flow rate of the first fluid in the core annular flow ( The ratio of ) to: Efficiency of core-to-circuit flow equipment ( This can also be expressed as the pressure drop factor under ideal core annular flow and the actual equipment pressure drop factor: .

[0262] In some embodiments, the channel has a maximum inner diameter not greater than 5 cm, 4 cm, 3 cm, 2 cm, or 1 cm (e.g., the maximum inner diameter of the cylinder). In some embodiments, the device has a maximum inner diameter not greater than 5 cm, 4 cm, 3 cm, 2 cm, or 1 cm (e.g., the maximum inner diameter of the cylinder). In some embodiments, the constricting portion has a maximum inner diameter not greater than 5 cm, 4 cm, 3 cm, 2 cm, 1 cm, 0.9 cm, 0.8 cm, 0.7 cm, 0.6 cm, 0.5 cm, 0.4 cm, 0.3 cm, 0.2 cm, or 0.1 cm. In some embodiments, the needle hub has a maximum inner diameter not exceeding 5 cm, 4 cm, 3 cm, 2 cm, 1 cm, 0.9 cm, 0.8 cm, 0.7 cm, 0.6 cm, 0.5 cm, 0.4 cm, 0.3 cm, 0.2 cm, or 0.1 cm. In some embodiments, the maximum inner diameter of the needle hub is the same as the maximum inner diameter of the contraction portion. In some implementations, the needle hub has a minimum inner diameter of no more than 5 cm, no more than 4 cm, no more than 3 cm, no more than 2 cm, no more than 1 cm, no more than 0.9 cm, no more than 0.8 cm, no more than 0.7 cm, no more than 0.6 cm, no more than 0.5 cm, no more than 0.4 cm, no more than 0.3 cm, no more than 0.2 cm, no more than 0.1 cm, no more than 0.9 mm, no more than 0.8 mm, no more than 0.7 mm, no more than 0.65 mm, no more than 0.6 mm, no more than 0.55 mm, no more than 0.5 mm, no more than 0.45 mm, or no more than 0.4 mm (e.g., at the needle hub-needle interface) (e.g., at the needle hub outlet). In some embodiments, the needle has a minimum inner diameter (e.g., needle lumen size) of no more than 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.65 mm, 0.6 mm, 0.55 mm, 0.5 mm, 0.45 mm, or 0.4 mm (e.g., at the needle outlet).In some embodiments, the syringe barrel has a minimum inner diameter (e.g., at the tip) of no more than 5 cm, no more than 4 cm, no more than 3 cm, no more than 2 cm, no more than 1 cm, no more than 0.9 cm, no more than 0.8 cm, no more than 0.7 cm, no more than 0.6 cm, no more than 0.5 cm, no more than 0.4 cm, no more than 0.3 cm, no more than 0.2 cm, or no more than 0.1 cm.

[0263] In some embodiments, the channel includes two or more separate contraction portions. In some embodiments, the needle hub includes two or more separate contraction portions. In some embodiments, two adjacent contraction portions are spaced apart along the channel (e.g., in the needle hub or barrel) by no more than 5 mm, no more than 4 mm, no more than 3 mm, no more than 2 mm, no more than 1 mm, or no more than 0.5 mm. In some embodiments, the device or apparatus includes two or more contraction portions along the channel contained therein. For example, in some embodiments, the needle hub includes two contraction portions. As another example, in some embodiments, the needle hub includes a first contraction portion and the needle tip includes a second contraction portion. In some embodiments, the barrel includes a first contraction portion (e.g., at the tip of the barrel) and the needle hub includes a second contraction portion. In some embodiments, the barrel includes two contraction portions. This document discusses exemplary contraction portions according to some embodiments with respect to contraction portions in the needle hub, but these contraction portions are not necessarily limited to those located in such needle hubs.

[0264] In some embodiments, the needle hub includes an inlet for a channel. In some embodiments, the needle hub includes an outlet for a channel. In some embodiments, the needle tip includes an outlet for a channel. In some embodiments, the needle tip includes an inlet for a channel. In some embodiments, the barrel includes an inlet for a channel. In some embodiments, the needle hub includes two inlets, for example, one for a first fluid and one for a lubricant. In some embodiments, the barrel includes two inlets, for example, one for a first fluid and one for a lubricant, at the tip of the barrel. In some embodiments, the needle hub is attached to the needle tip (e.g., bonded to the needle tip or compressed into or on the needle tip).

[0265] As used herein, the term "pharmaceutical composition" refers to a composition in which an active agent is formulated together with one or more pharmaceutically acceptable carriers. Pharmaceutical compositions (e.g., formulations) may include small molecules and / or biological products. Pharmaceutical compositions may include monoclonal antibodies (mAbs), polyclonal antibodies (pAbs), enzymes, peptides, recombinant therapeutic protein formulations, or combinations thereof. In some embodiments, the active agent is present in a unit dose suitable for administration in a treatment regimen that, when administered to the relevant population, shows a statistically significant probability of achieving the intended therapeutic effect. In some embodiments, the pharmaceutical composition may be specifically formulated for administration in a liquid form. The pharmaceutical composition may be a concentrated formulation in which one or more active ingredients [e.g., one or more antibodies (e.g., comprising one or more monoclonal antibodies and / or one or more polyclonal antibodies), enzymes, peptides, proteins, or combinations thereof] are present in high concentrations, such as at least 25 mg / mL (solvent, e.g., water), at least 30 mg / mL, at least 40 mg / mL, at least 50 mg / mL, at least 60 mg / mL, at least 70 mg / mL, at least 75 mg / mL, at least 80 mg / mL, at least 90 mg / mL, at least 100 mg / mL, at least 125 mg / mL, at least 150 mg / mL, at least 175 mg / mL, or at least 200 mg / mL (e.g., and not exceeding 500 mg / mL). The pharmaceutical composition may be formulated for parenteral administration, such as by subcutaneous, intramuscular, intravenous, or epidural injection, for example, using a syringe or injector (e.g., an auto-injector). The pharmaceutical composition may be formulated as, for example, a sterile solution or suspension. The pharmaceutical composition may be formulated for transdermal administration (e.g., using a patch comprising one or more needles). The pharmaceutical compositions disclosed herein are generally fluids. A first fluid may be or contain the pharmaceutical composition. The pharmaceutical composition may be referred to as a drug. The pharmaceutical composition may be or contain a drug, monoclonal antibody, enzyme, peptide, recombinant therapeutic protein, biological product, bone putty, hydrogel, cell, biopharmaceutical, or a combination thereof. For example, in some embodiments, the first fluid contains a pharmaceutical composition that is or contains a concentrated pharmaceutical formulation (e.g., a biological product).

[0266] Example

[0267] To provide a fuller understanding of this application, the following embodiments are described. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting in any way.

[0268] Example 1

[0269] Many needle holders with different profiles have been manufactured and their performance tested. Consistent with the simulations discussed above, it has been found that the convex needle holder profile, which tapers more drastically at the large diameter and then less drastically at the small diameter, performs best. Figure 14 Subplot AC illustrates images of three selected pin headers. Subplot D plots the metrics of their respective performance.

[0270] Subfigure A illustrates a needle hub with right-angle discontinuities and a rapidly tapering section. This needle hub is manufactured using a standard drill bit. Subfigure B illustrates a needle hub with an extended section that tapers at a gentler angle, manufactured using a custom-modified drill bit. Subfigure C illustrates a needle hub with a convex exponential needle hub profile manufactured using 3D printing. The exponential needle hub profile in Subfigure C best matches the profile for n = -1.

[0271] Subplot D provides the minimum Q that can be achieved at a range of viscosities without inducing viscous displacement. o / Q i (This is a graph measuring the performance of the pin header shown in subgraph AC.) Q o For the flow rate of (external) lubricant, and Q i The flow rate of the first (internal) fluid. The minimum Qo / Qi achievable across a range of viscosities without inducing viscous displacement. Lower Qo / Qi. o / Q i This represents better performance. The exponential profile needle holder (sub-figure C) performs significantly better than the other two needle holders.

[0272] Example 2

[0273] This section outlines the details regarding the calculation of the efficiency of the core-annular flow in the embodiments of this disclosure. As shown in Table 2, this disclosure proposes a core-annular flow that requires lower pressure compared to other designs under the same flow rate and viscosity conditions.

[0274] Some devices can generate core-ring flow more efficiently than others, depending on the flow geometry before the two fluids merge and / or during fluid contraction. That is, even with the same needle outlet (needle) diameter and length, the same fluid viscosity, and the same flow rate, some devices will have lower pressure requirements than others, depending on the efficiency with which the flow can be contracted and the degree to which the flow is coaxial. The channel geometry disclosed herein (e.g., with a certain curvature) is significantly more efficient than other designs (e.g., the designs in Table 2).

[0275]

[0276] Table 2

[0277] Equipment efficiency ( ) can be expressed as the theoretical pressure required to drive the flow through an outlet (e.g., the outlet of a needle) under laminar, ideal, fully expanded, or fully concentric annular flow conditions. ) and the actual pressure required for the drive flow to pass through the entire device ( The ratio of ) to:

[0278]

[0279] The value can be measured using a pressure sensor, or by dividing the injection force of the device by the cross-sectional area of ​​the applied force. Since there is a linear relationship between pressure drop and flow rate, efficiency can also be defined as the efficiency at a given constant pressure. The flow rate of the first viscous fluid passing through the device ( ) and the ideal flow rate of the first viscous fluid in a core-annular flow ( The ratio of ) to:

[0280]

[0281] In both cases, an efficiency of 1 indicates a fully efficient device whose pressure drop will not exceed the pressure drop required for the core-ring flow to pass through the outlet (e.g., the needle outlet). Higher efficiency is preferred to reduce actuation pressure, shorten injection time, or both.

[0282] For a cylindrical geometry, the ideal flow rate versus pressure drop relationship can be calculated by considering the Navier-Stokes equations for the first and second fluids under laminar flow conditions in cylindrical coordinates:

[0283]

[0284] in It is the radius of the first fluid inside, and It is the radius of the cylindrical wall, such as the inner diameter of a needle. Here and Indicates the internal and external fluid viscosity, and This is the pressure gradient along the axis of the cylindrical geometry. Assuming the pressure gradient is constant, integrating the expressions and applying appropriate boundary conditions (no wall slip, shear and velocity continuity at the interface between the two fluids, and symmetry), we obtain the following expressions for the flow rates of the inner first fluid and the outer second fluid in a core-annular flow:

[0285]

[0286] These relationships between pressure drop and flow rate represent the case where the limiting ideal efficiency is 1.0, where And for a certain cylinder length , .

[0287] Another, more convenient method for calculating efficiency is to compare the force reduction factor provided by the core-toroidal flow device with the ideal pressure reduction factor. The pressure reduction factor can be defined as:

[0288]

[0289] in It is the pressure drop of conventional equipment that does not use core-ring flow, and This is the pressure drop of the core-to-loop flow device. This pressure drop factor is assumed to be all other things being equal (i.e., the flow rate of the first internal fluid in the core-to-loop flow is matched with the flow rate of the first fluid in a device without a core-to-loop flow, and the needle diameter, length, and viscosity of the first fluid are also matched).

[0290] Figure 15 The figure shows the pressure reduction factor under ideal conditions, which is based on a first internal viscosity of 100 cP and a second external viscosity of 1 cP. The function.

[0291] The efficiency of a core-annular flow device can therefore be calculated by comparing the pressure drop factor under ideal core-annular flow with the pressure drop factor of the actual device:

[0292]

[0293] The calculated efficiency is a dimensionless number that applies to a range of combinations of force / pressure and flow rate for a given device. In other words, the calculated efficiency characterizes a device operating above a specific flow rate and / or force / pressure (e.g., a needle holder). However, generally, when calculating efficiency, one either chooses force / pressure and measures the flow rate, or chooses the flow rate and measures the required force / pressure. The different formulas previously given for efficiency may have some minor natural variations, but values ​​calculated using different methods remain comparable.

[0294] In the work of Jayaprakash, V. et al., 2020 on water-miscible lubricants, a pressure reduction coefficient was found. The ideal pressure reduction factor under these conditions is 12.75, resulting in an efficiency of 20% for a miscible (in this case, water-based) lubricant.

[0295] For oil-based (immiscible) lubricants, particularly those from Jayaprakash, V. et al., 2020. Figure 3A. The maximum efficiency achieved is in the range of 42% to 52%. However, this efficiency is only achievable when using immiscible lubricants, which limits the applicability of the device. It is worth noting that, as mentioned earlier, the efficiency is much lower (only 20%) when using miscible lubricants.

[0296] Regarding PCT application publication number WO 2013 / 114114, especially Figure 9 The increase in flow rate at a syringe pressure of 0.2 bar can be calculated. Without a core-ring flow, the glycerol flow rate is approximately 64 µL / min. With a core-ring flow, at Q... o / Q i When the flow rate is 2.0, the flow rate is 1500 µL / min, representing a 23.4-fold increase in flow rate (1500 / 64 = 23.4 times). Under these conditions, At that time, the maximum pressure reduction factor is 128. Therefore, the estimated efficiency is 23.4 / 128 = 18.3%.

[0297] For US Patent No. 9,737,662, and specifically according to Table 1, the average core-ring flow injection time is 6.14 seconds. Based on the conservative estimate of 85 seconds for the glycerol run time provided in that work, a flow rate increase of 13.84 times is estimated. The Q values ​​obtained from simultaneously compressed BD 3 mL syringes and BD 1 mL syringes are... o / Q i The coefficient of performance is 0.305. Under these conditions, the maximum pressure reduction factor is 40.45, resulting in an efficiency of 13.84 / 40.45 = 34%. It is worth noting that this result is only achieved when the equipment is running completely vertically. Tilting the equipment will result in lower efficiency. Therefore, this result also limits the applicability of the equipment.

[0298] Figure 2 Subfigure C shows the effect of a flow rate of 6 mL / min through a 27G needle with an inner diameter of 210 µm and a length of 0.0127 m, where the internal viscosity is 500 cP and the external viscosity is 1 cP. Data collected from fluid at a ratio of 0.12. The measured forces are those applied to the two plungers of the device, with the first plunger having a diameter of 1.2 cm. ), and the diameter of the second plunger is 0.467 cm ( For coreless annular flow devices, the expected injection force is:

[0299]

[0300] This yields a pressure reduction factor of 1733 / 20 = 86.66. For a given viscosity ratio and The ideal pressure reduction factor is 161. Therefore, the efficiency of this equipment is: .

[0301] Devices with the features described herein have achieved efficiencies exceeding 70% across a wide range of viscosities and flow rates.

[0302] Figure 16 Tests of a core-loop flow device with a pressure sensor incorporated upstream of the needle hub and constriction section are shown. The viscous internal fluid has a viscosity of 17.8 cP, while the external fluid has a viscosity of 1 cP. Initially, only the viscous fluid was flowed through the device at a flow rate of 1 mL / min, generating a pressure of 6.79 psi. The external low-viscosity flow was then initiated at a flow rate of 1 mL / min, initiating the core-loop flow and generating a pressure of 1.17 psi, with a pressure drop factor of 5.8. The ideal pressure drop factor for this viscosity-to-flow ratio is 7.98. This yields a device efficiency of 73%. Device and channel efficiencies of at least this high value have been achieved using miscible first (internal) fluid and lubricant, immiscible first (internal) fluid and lubricant, and a vertical device / channel orientation.

[0303] Such measurements were performed for a range of viscosity ratios and flow rates, and the results are shown in Table 3.

[0304]

[0305] Table 3

[0306] Some embodiments of this disclosure have been described above. However, it is explicitly stated that this disclosure is not limited to those embodiments, but rather that additions and modifications to the content explicitly described herein are also intended to be included within the scope of this disclosure. Furthermore, it should be understood that the features of the various embodiments described herein are not mutually exclusive and can exist in various combinations and arrangements without departing from the spirit and scope of this disclosure, even if such combinations or arrangements are not explicitly stated. This disclosure has been described in detail with specific reference to certain embodiments, but it should be understood that variations and modifications can be made within the spirit and scope of the claimed invention.

Claims

1. A fluid delivery device comprising a channel extending from an inlet to an outlet (e.g., in a needle hub, optionally also in a needle tip), wherein the channel is sized and shaped such that a first fluid having a viscosity of at least 10 cP can flow from the inlet (e.g., a first end of the channel and / or an initial position within the channel) through the channel to the outlet and flow through the outlet.

2. The device of claim 1, wherein the channel is sized and shaped such that the first fluid having a viscosity greater than 20 cP (e.g., at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP) can flow from the inlet through the channel to the outlet and through the outlet.

3. The device of claim 1, wherein the size and shape of the channel are designed such that the first fluid having a viscosity of at least 15 cP can flow from the inlet through the channel to the outlet and flow through the outlet.

4. A fluid delivery device comprising a channel extending from an inlet to an outlet (e.g., in a needle hub, optionally also in a needle tip), wherein the channel has a curvature such that a first fluid having a viscosity of at least 10 cP (e.g., at least 15 cP, greater than 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP) can flow from the inlet (e.g., a first end of the channel and / or an initial position within the channel) through the channel to the outlet and flow through the outlet.

5. The device as claimed in any of the preceding claims, wherein the channel is sized and shaped such that the first fluid can be delivered through the channel by manually applying force (e.g., with a plunger) at the inlet.

6. The device as claimed in any of the preceding claims, wherein a force of no more than 40 N (e.g., no more than 30 N, no more than 25 N, no more than 20 N, no more than 15 N, no more than 12.5 N, or no more than 10 N) is capable of causing the fluid to flow through the channel and through the outlet.

7. The device as claimed in any of the preceding claims, wherein the channel is sized and shaped such that the first fluid having a viscosity greater than 20 cP (e.g., at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP) can be lubricated in a core-ring flow (e.g., coaxial lubrication) (e.g., stable core-ring flow) [e.g., wherein the lubricant coats the inner surface of the channel (e.g., and is concentric and coaxial with the (more viscous) first fluid flowing through the channel), and wherein the first fluid does not contact the inner surface of the channel, for example, wherein the lubricant has a viscosity less than 10 cP (e.g., in the range of 0.5 cP). At a viscosity of cP to 10 cP, for example, 0.5 cP to 5 cP or 0.5 cP to 2 cP, the fluid flows from the inlet (e.g., the first end of the channel and / or the initial position within the channel) through the channel to the outlet and flows through the outlet.

8. A fluid delivery device comprising a channel extending from an inlet to an outlet (e.g., in a needle hub, optionally also in a needle tip), wherein the size and shape of the channel are designed such that a first fluid can be delivered with the following efficiency ( The fluid flows from the inlet (e.g., the first end of the channel and / or the initial position within the channel) through the channel to the outlet and flows through the outlet in a core-annular flow pattern: greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 80%, or greater than 90% if the first fluid and lubricant are immiscible and / or the channel orientation is perpendicular).

9. The device of claim 8, wherein the dimensions and shape of the channel are designed such that the first fluid can flow with the efficiency when the longitudinal axis of the channel is within 45 degrees of a line perpendicular to gravity and / or when the first fluid exhibiting the core-ring flow and the lubricant are miscible.

10. The device of claim 8 or claim 9, wherein the first fluid has a viscosity of at least 10 cP (e.g., at least 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP).

11. The device as claimed in any of the preceding claims, comprising a constriction portion (e.g., in a needle holder) disposed in the channel between the inlet and the outlet, the constriction portion having an internal shape including a convex portion relative to the interior of the channel (e.g., wherein the second derivative of the internal profile of the constriction portion is positive (> 0) at at least some point along the internal profile).

12. The device of claim 11, wherein the contraction portion has an internal shape that is completely convex relative to the interior of the channel [e.g., having a shape formed by...]. The defined shape, where R is the radius, z is the position along the channel, and -1 < n < -0.1 (e.g., n = -1 / 3)].

13. The device of claim 11 or claim 12, wherein the contraction portion tapers relatively more abruptly with position at the larger diameter end of the contraction portion, and relatively less abruptly with position at the smaller diameter end.

14. The device according to any one of claims 11-13, wherein the length of the retractable portion does not exceed 10 mm (e.g., not exceeding 8 mm, not exceeding 7 mm, not exceeding 6 mm, not exceeding 5 mm, not exceeding 4 mm, not exceeding 3 mm, not exceeding 2.5 mm, or not exceeding 2.0 mm).

15. The device according to any one of claims 11-14, wherein the inlet and the constriction portion are arranged to be spaced no more than 5 mm apart (e.g., no more than 4 mm, no more than 3 mm, no more than 2 mm, no more than 1 mm, no more than 0.8 mm, no more than 0.6 mm, no more than 0.5 mm, or no more than 0.4 mm apart).

16. The device of any one of claims 11-15, wherein the second derivative of the inner contour of the contracted portion is positive (> 0) at every point along the inner contour.

17. The device as claimed in any of the preceding claims, wherein the channel includes an inner surface, and the device comprises the first fluid and a lubricant, the first fluid and the lubricant each being disposed in the channel, wherein the lubricant separates the first fluid from the inner surface (e.g., wherein the inner surface is textured), and the lubricant has a lower viscosity than the first fluid.

18. The device of claim 17, wherein the shear stress of the first fluid does not exceed 1000 times the shear stress of the lubricant (e.g., not exceeding 100 times, 10 times, 5 times, or 2 times the shear stress of the lubricant).

19. The device of claim 17 or claim 18, wherein the first fluid and the lubricant are coaxially disposed in at least a portion of the channel.

20. The device of any one of claims 17-19, wherein the channel, the first fluid, and the lubricant are configured such that, when flowing, the flow of the first fluid is characterized by an eccentricity (E) of E < 1.

21. The device of claim 20, wherein E < 0.05 (e.g., E < 0.02 or E = 0).

22. The device of any one of claims 17-21, wherein the channel includes a second inlet, (ii) the inlet being an inlet for the first fluid, and (iii) the second inlet being an inlet for the lubricant (e.g., wherein, The needle hub, which includes at least a portion of the channel, includes the first inlet and the second inlet (e.g., where the first inlet and the second inlet are spatially separated, e.g., at the needle hub).

23. The device of claim 22, wherein the ratio of the area of ​​the inlet to the area of ​​the second inlet is from 0.02 to 5 (e.g., 0.02 to 2, 0.02 to 4, 0.02 to 3, e.g., 0.04 to 2, 0.04 to 4, 0.04 to 3, 0.05 to 2, 0.06 to 2, 0.07 to 2, 0.02 to 4, 0.02 to 3, 0.02 to 1.8, 0.02 to 1.6, 0.02 to 1.4, 0.04 to 4, 0.04 to 3, 0.04 to 1.8, 0.04 to 1.6, 0.04 to 1.4, 0.06 to 4, 0.06 to 3, 0.06 to 2, 0.06 to 1.8, 0.06 to 1.6, 0.06 to 5). The range is 1.4, 0.07 to 4, 0.07 to 3, 0.07 to 2, 0.07 to 1.8, 0.07 to 1.6, 0.07 to 1.4, 0.1 to 4, 0.1 to 3, 0.1 to 2, 0.1 to 1.8, 0.1 to 1.6, 0.1 to 1.4, 0.2 to 4, 0.2 to 3, 0.2 to 2, 0.3 to 4, 0.3 to 3, 0.3 to 2, 0.4 to 4, 0.4 to 3, 0.4 to 2, 0.5 to 4, 0.5 to 3, 0.5 to 2, 0.5 to 1.8, 0.5 to 1.6, or 0.5 to 1.4).

24. The device according to any one of claims 17-23, wherein the lubricant is water-based.

25. The device according to any one of claims 17-23, wherein the lubricant is non-aqueous.

26. The device of any one of claims 17-25, wherein the lubricant comprises a buffer solution.

27. The device of claim 26, wherein the first fluid comprises the same buffer solution as the buffer solution contained in the lubricant.

28. The device of any one of claims 17-27, wherein the first fluid has a concentration of 5 cP to 10,000 cP (e.g., 5 cP to 5,000 cP, 5 cP to 4,000 cP, 5 cP to 3,000 cP, 5 cP to 2,500 cP, 5 cP to 2,000 cP, 20 cP to 10,000, 20 cP to 5,000 cP, 20 cP to 4,000 cP, 20 cP to 3,000 cP, 20 cP to 2,500 cP, 20 cP to 2,000 cP, 50 cP to 10,000, 50 cP to 5,000 cP, 50 cP to 4,000 cP, 50 cP to 3,000 cP, 50 cP to 2,500 cP, 50 cP to 2,000 cP). 75 cP to 10,000, 75 cP to 5,000 cP, 75 cP to 4,000 cP, 75 cP to 3,000 cP, 75 cP to 2,500 cP, 75 cP to 2,000 cP, 100 cP to 10,000, 100 cP to 5,000 cP, 100 cP to 4,000 cP, 100 cP to 3,000 cP, 100 cP to 2,500 cP, 100 cP to 2,000 cP, 250 cP to 10,000, 250 cP to 5,000 cP, 250 cP to 4,000 cP, 250 cP to 3,000 cP, 250 cP to 2,500 cP, 250 cP to 2,000 cP Viscosities in the range of cP, 500 cP to 10,000, 500 cP to 5,000 cP, 500 cP to 4,000 cP, 500 cP to 3,000 cP, 500 cP to 2,500 cP, 500 cP to 2,000 cP, 1,000 cP to 10,000, 1,000 cP to 5,000 cP, 1,000 cP to 4,000 cP, 1,000 cP to 3,000 cP, 1,000 cP to 2,500 cP, or 1,000 cP to 2,000 cP.

29. The device according to any one of claims 17-28, wherein the lubricant has a viscosity in the range of 0.5 cP to 10 cP (e.g., 0.5 cP to 5 cP or 0.5 cP to 2 cP).

30. The device according to any one of claims 17-29, wherein the lubricant is no more than 50% by volume of the total volume of the material in the channel (e.g., no more than 40% by volume, no more than 30% by volume, no more than 25% by volume, no more than 20% by volume, no more than 15% by volume, no more than 10% by volume, or no more than 5% by volume).

31. The device according to any one of claims 17-30, wherein the volume ratio of the first fluid to the lubricant is not less than 3:1 (e.g., not less than 4:1, not less than 5:1, not less than 6:1, not less than 7:1, not less than 8:1 or not less than 9:1).

32. The device of claim 31, wherein the volume ratio of the first fluid to the lubricant does not exceed 200:1 (e.g., not exceeding 100:1).

33. The device as claimed in any of the preceding claims, wherein the first fluid is a pharmaceutical composition (e.g., a formulation) (e.g., comprising small molecules and / or biological products) [e.g., comprising small molecules and / or biological products (e.g., monoclonal antibodies (mAbs), polyclonal antibodies (pAbs), enzymes, peptides, recombinant therapeutic protein formulations, or combinations thereof)].

34. The device as claimed in any of the preceding claims, wherein the size and shape of the channel are designed such that a fluid having a viscosity at any location in the range of at least 5 cP to 10,000 cP (e.g., from 5 cP to 5,000 cP, from 5 cP to 4,000 cP, from 5 cP to 3,000 cP, from 5 cP to 2,500 cP, from 5 cP to 2,000 cP, from 5 cP to 1,500 cP, or from 5 cP to 1,200 cP) can flow from the inlet through the channel to the outlet and through the outlet.

35. The device as claimed in any of the preceding claims, wherein the delivery device comprises an injection cartridge [e.g., operable by manually applying force (e.g., force applied to one or more plungers)].

36. The device of claim 35, wherein the injection cartridge includes a barrel and a needle hub (e.g., a needle hub including the constricted portion) (e.g., a 3D-printed needle hub) in fluid communication with the barrel (e.g., via a tube), the barrel (e.g., the tip of the barrel) and the needle hub each defining a portion of the channel.

37. The device of claim 36, wherein the needle hub includes the inlet.

38. The device of any one of claims 35-37, wherein the syringe includes a needle, the needle includes an outlet, and the body of the needle defines a portion of the channel (e.g., there are no obvious right angles in the fluid path through the needle hub and / or the needle).

39. The device of claim 38, wherein a portion of the needle is disposed within an end of the needle hub, the portion of the needle hub including a needle inlet, and the needle inlet including a gently tapering portion relative to the inner diameter of the needle.

40. The device of claim 38, wherein the outlet of the needle hub is disposed within the needle tip.

41. The device according to any one of claims 38-40, wherein the needle is smaller than 22 (e.g., 25 or 27).

42. The device as claimed in any of the preceding claims, wherein the diameter of any of the channels does not exceed 5 cm (e.g., not exceeding 4 cm, 3 cm, 2 cm, 1 cm or 0.5 cm).

43. The device as claimed in any of the preceding claims, wherein the size and shape of the channel are designed to eliminate viscous displacement during the flow of the fluid (e.g., the first fluid) through the channel.

44. The device as claimed in any of the preceding claims, wherein the size and shape of the channel are designed (e.g., having a certain curvature) such that the flow of the first fluid can occur at a flow rate of at least 1 mL / min (e.g., at least 2 mL / min, at least 3 mL / min, at least 4 mL / min, at least 5 mL / min, at least 6 mL / min, at least 7 mL / min, at least 8 mL / min, at least 9 mL / min or at least 10 mL / min).

45. A method for delivering a first fluid through a channel (e.g., in a needle hub, optionally also in a needle tip), the first fluid having a viscosity of at least 10 cP, the method comprising causing a lubricant and the first fluid to flow simultaneously through the channel and out of an outlet of the channel (e.g., into or out of the needle tip), wherein the viscosity of the lubricant is less than that of the first fluid.

46. ​​The method of claim 45, wherein the viscosity is greater than 20 cP (e.g., at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP).

47. The method of claim 45, wherein the viscosity is at least 15 cP.

48. The method of claim 45, wherein the first fluid has a concentration of 50 cP to 10,000 cP (e.g., 50 cP to 5,000 cP, 50 cP to 4,000 cP, 50 cP to 3,000 cP, 50 cP to 2,500 cP, 50 cP to 2,000 cP, 75 cP to 10,000 cP, 75 cP to 5,000 cP, 75 cP to 4,000 cP, 75 cP to 3,000 cP, 75 cP to 2,500 cP, 75 cP to 2,000 cP, 100 cP to 10,000 cP, 100 cP to 5,000 cP, 100 cP to 4,000 cP, 100 cP to 3,000 cP, 100 cP to 2,500 cP, 100 cP to 2,500 cP, 100 cP to 2,500 cP, 100 cP to 2,0 ... cP to 2,000 cP, 250 cP to 10,000, 250 cP to 5,000 cP, 250 cP to 4,000 cP, 250 cP to 3,000 cP, 250 cP to 2,500 cP, 250 cP to 2,000 cP, 500 cP to 10,000, 500 cP to 5,000 cP, 500 cP to 4,000 cP, 500 cP to 3,000 cP, 500 cP to 2,500 cP, 500 cP to 2,000 cP, 1,000 cP to 10,000, 1,000 cP to 5,000 cP, 1,000 cP to 4,000 cP, 1,000 cP to 3,000 cP, 1,000 cP to 2,5 ...2,000 cP, 1,000 cP to 2,000 cP, 1,000 cP to 2,500 cP, 1,000 cP to 4,000 cP, 1,000 cP to 3,000 cP, 1,000 cP to 2,500 cP, 1,0 Viscosities in the range of 1,000 cP to 2,500 cP, or 1,000 cP to 2,000 cP.

49. The method of any one of claims 45-48, wherein the lubricant has a viscosity of less than 10 cP (e.g., a viscosity in the range of 0.5 cP to 10 cP, for example, 0.5 cP to 5 cP or 0.5 cP to 2 cP).

50. The method of any one of claims 45-49, the method comprising manually applying force to the first fluid (e.g., the lubricant) to cause the first fluid to flow through the channel.

51. The method of claim 50, wherein the force is applied at the entrance by manually applying a force (e.g., with a plunger) at the entrance to the channel.

52. The method of claim 50 or claim 51, wherein the force does not exceed 40 N (e.g., not exceeding 30 N, not exceeding 25 N, not exceeding 20 N, not exceeding 15 N, not exceeding 12.5 N, or not exceeding 10 N).

53. The method of any one of claims 45-52, wherein the lubricant and the first fluid exhibit a core-ring flow (e.g., coaxial lubrication) (e.g., stable core-ring flow) when flowing simultaneously through the channel.

54. The method of any one of claims 45-53, wherein the lubricant and the first fluid flow simultaneously through the channel with the following efficiency ( It exhibits a core-ring flow (e.g., coaxial lubrication) (e.g., stable core-ring flow): greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 80%, or greater than 90% when the first fluid and lubricant are immiscible and / or the channel orientation is perpendicular).

55. The method of claim 54, wherein the longitudinal axis of the channel is located within 45 degrees of a line perpendicular to gravity and / or when the first fluid exhibiting the annular flow and the lubricant are miscible.

56. The method of claim 54 or claim 55, wherein the first fluid has a viscosity of at least 10 cP (e.g., at least 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP).

57. The method of any one of claims 45-56, comprising flowing the lubricant and the first fluid through a constriction portion (e.g., a needle seat) in the channel, the constriction portion having an internal shape including a convex portion relative to the interior of the channel (e.g., wherein the second derivative of the internal profile of the constriction portion is positive (> 0) at at least some point along the internal profile).

58. The method of claim 57, wherein the contraction portion has an internal shape that is completely convex relative to the interior of the channel [e.g., having a shape formed by...]. The defined shape, where R is the radius, z is the position along the channel, and -1 < n < -0.1 (e.g., n = -1 / 3)].

59. The method of claim 57 or claim 58, wherein the contraction portion tapers relatively more abruptly with position at the larger diameter end of the contraction portion, and relatively less abruptly with position at the smaller diameter end.

60. The method of any one of claims 57-59, wherein the length of the contracted portion does not exceed 10 mm (e.g., not more than 8 mm, not more than 7 mm, not more than 6 mm, not more than 5 mm, not more than 4 mm, not more than 3 mm, not more than 2.5 mm, or not more than 2.0 mm).

61. The method of any one of claims 57-60, wherein the inlet and the contraction portion are arranged to be spaced no more than 5 mm apart (e.g., no more than 4 mm, no more than 3 mm, no more than 2 mm, no more than 1 mm, no more than 0.8 mm, no more than 0.6 mm, no more than 0.5 mm, or no more than 0.4 mm apart).

62. The method of any one of claims 57-61, wherein the second derivative of the inner contour of the contracted portion is positive (> 0) at every point along the inner contour.

63. The method of any one of claims 45-62, wherein during the flow, the shear stress of the first fluid does not exceed 1000 times the shear stress of the lubricant (e.g., not exceeding 100 times, 10 times, 5 times, or 2 times the shear stress of the lubricant).

64. The method of any one of claims 45-63, wherein the lubricant separates the first fluid from the inner surface of the channel (e.g., wherein the first fluid and the lubricant are coaxially disposed in at least a portion of the channel).

65. The method of any one of claims 45-64, wherein the flow of the first fluid is characterized by an eccentricity (E) of E < 1.

66. The method of claim 65, wherein E < 0.05 (e.g., E < 0.02 or E = 0).

67. The method of any one of claims 45-66, comprising (e.g., simultaneously) supplying the first fluid to the channel through a first inlet and supplying the lubricant to the channel through a second inlet.

68. The method of any one of claims 45-67, wherein the lubricant is water-based.

69. The method of any one of claims 45-68, wherein the lubricant is non-aqueous.

70. The method of any one of claims 45-69, wherein the lubricant comprises a buffer solution.

71. The method of claim 70, wherein the first fluid comprises the same buffer as the buffer contained in the lubricant.

72. The method of any one of claims 45-71, wherein the lubricant is no more than 50% by volume of the total volume of the material in the channel (e.g., no more than 40% by volume, no more than 30% by volume, no more than 25% by volume, no more than 20% by volume, no more than 15% by volume, no more than 10% by volume, or no more than 5% by volume).

73. The method of any one of claims 45-72, wherein the volume ratio of the first fluid to the lubricant is not less than 1:1 (e.g., not less than 2:1, not less than 3:1, not less than 4:1, not less than 5:1, not less than 6:1, not less than 7:1, not less than 8:1 or not less than 9:1).

74. The method of claim 73, wherein the volume ratio of the first fluid to the lubricant does not exceed 200:1 (e.g., not exceeding 100:1).

75. The method of any one of claims 45-74, wherein the first fluid is a pharmaceutical composition (e.g., a formulation) [e.g., comprising small molecules and / or biological products (e.g., monoclonal antibodies (mAbs), polyclonal antibodies (pAbs), enzymes, peptides, recombinant therapeutic protein formulations, or combinations thereof)] (e.g., and the method comprises subcutaneous administration of the pharmaceutical composition through the channel).

76. The method of any one of claims 45-75, wherein the syringe [e.g., operable by manually applying force (e.g., applying force to one or more plungers)] includes the channel.

77. The method of claim 76, wherein the injection cartridge includes a body and a needle hub (e.g., a needle hub including the constricted portion) (e.g., a 3D-printed needle hub) in fluid communication with the body (e.g., via a tube), the body (e.g., the tip of the body) and the needle hub each defining a portion of the channel.

78. The method of claim 77, wherein the cylinder includes an inlet for the first fluid (e.g., and a separate inlet for the lubricant).

79. The method of any one of claims 76-78, wherein the syringe includes a needle, the needle includes an outlet, and the body of the needle defines a portion of the channel.

80. The method of claim 79, wherein a portion of the needle is disposed within an end of the needle hub, the portion of the needle hub including a needle inlet, and the needle inlet including a gently tapering portion relative to the inner diameter of the needle.

81. The method of claim 80, wherein the outlet of the needle hub is disposed within the needle tip.

82. The method of any one of claims 79-81, wherein the needle is smaller than 22 (e.g., 25 or 27).

83. The method of any one of claims 45-82, wherein the diameter of any of the channels does not exceed 5 cm (e.g., not exceeding 4 cm, 3 cm, 2 cm, 1 cm or 0.5 cm).

84. The method of any one of claims 45-83, wherein the first fluid is allowed to flow through the channel such that no viscous displacement occurs.

85. The method of any one of claims 45-84, wherein the flow of the first fluid occurs at a flow rate of at least 2 times (e.g., at least 3 times or at least 4 times) that of the lubricant.

86. The method of claim 85, wherein the flow of the first fluid occurs at a flow rate not exceeding five times the flow rate of the lubricant.

87. The method of any one of claims 45-86, wherein the flow of the first fluid occurs at a flow rate of at least 1 mL / min (e.g., at least 2 mL / min, at least 3 mL / min, at least 4 mL / min, at least 5 mL / min, at least 6 mL / min, at least 7 mL / min, at least 8 mL / min, at least 9 mL / min, or at least 10 mL / min).

88. The method of claim 87, wherein the flow of the first fluid occurs at a flow rate not exceeding 20 mL / min.

89. The method of any one of claims 45-88, wherein the flow of the lubricant occurs at a flow rate of at least 0.5 mL / min (e.g., at least 1 mL / min, at least 1.5 mL / min, at least 2 mL / min, or at least 2.5 mL / min).

90. The method of claim 89, wherein the flow of the lubricant occurs at a flow rate not exceeding 3 mL / min.

91. The method of any one of claims 45-90, wherein the first fluid and the lubricant are miscible.

92. A fluid delivery needle hub (e.g., a plastic needle hub) (e.g., a 3D-printed needle hub), the fluid delivery needle hub including a channel extending from an inlet of the needle hub to an outlet of the needle hub, the channel including a constricted portion having an internal shape including a convex portion relative to the interior of the channel (e.g., wherein the second derivative of the internal profile of the constricted portion is positive (> 0) at at least some point along the internal profile).

93. The needle hub of claim 92, wherein the channel is sized and shaped such that a first fluid having a viscosity of at least 10 cP (e.g., greater than 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP) can flow from the inlet (e.g., a first end of the channel and / or an initial position within the channel) through the channel to the outlet and through the outlet.

94. The needle hub of claim 92, wherein the first fluid has a viscosity of at least 15 cP.

95. The needle hub of claim 91, wherein the channel has a curvature such that a first fluid having a viscosity of at least 10 cP (e.g., at least 20 cP, at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP) can flow from the inlet (e.g., a first end of the channel and / or an initial position within the channel) through the channel to the outlet and flow through the outlet.

96. The needle hub of any one of claims 91-95, wherein the size and shape of the channel are designed such that a fluid having a viscosity at any location in the range of at least 5 cP to 10,000 cP can flow from the inlet through the channel to the outlet and flow through the outlet.

97. The needle hub as claimed in any one of claims 91-96, wherein the contraction portion has an internal shape that is completely convex relative to the interior of the channel [e.g., having a shape formed by...]. The defined shape, where R is the radius, z is the position along the channel, and -1 < n < -0.1 (e.g., n = -1 / 3)].

98. The needle hub as claimed in any one of claims 91-97, wherein the contraction portion tapers relatively more abruptly with position at the larger diameter end of the contraction portion, and relatively less abruptly with position at the smaller diameter end.

99. The needle hub as described in any one of claims 91-98, wherein the length of the contracted portion does not exceed 10 mm (e.g., not exceeding 8 mm, not exceeding 7 mm, not exceeding 6 mm, not exceeding 5 mm, not exceeding 4 mm, not exceeding 3 mm, not exceeding 2.5 mm, or not exceeding 2.0 mm).

100. The needle hub as described in any one of claims 91-99, wherein the inlet and the contraction portion are arranged to be spaced no more than 5 mm apart (e.g., no more than 4 mm, no more than 3 mm, no more than 2 mm, no more than 1 mm, no more than 0.8 mm, no more than 0.6 mm, no more than 0.5 mm, or no more than 0.4 mm apart).

101. The needle hub as claimed in any one of claims 91-100, wherein the second derivative of the contour of the contraction portion is positive (> 0) at every point along the contour.

102. The needle hub of any one of claims 91-101, wherein the flow of the first fluid occurs at a flow rate of at least 1 mL / min (e.g., at least 2 mL / min, at least 3 mL / min, at least 4 mL / min, at least 5 mL / min, at least 6 mL / min, at least 7 mL / min, at least 8 mL / min, at least 9 mL / min, or at least 10 mL / min).

103. An apparatus comprising a needle hub according to any one of claims 91-102 and a needle attached to the needle hub, wherein the lumen of the needle is in fluid communication with the channel.

104. The apparatus of claim 103, wherein the inlet leading to the needle is provided within the channel.

105. The device of claim 104, wherein the needle inlet includes a gently tapering portion relative to the inner diameter of the lumen.

106. The apparatus of claim 103, wherein the outlet of the needle hub is disposed within the lumen.

107. The device according to any one of claims 103-106, wherein the needle is smaller than 22 (e.g., 25 or 27).

108. A fluid delivery device comprising a channel extending from an inlet to an outlet, wherein the channel is sized and shaped such that a fluid having a viscosity at any location in the range of at least 5 cP to 10,000 cP can flow from the inlet (e.g., a first end of the channel and / or an initial location within the channel) through the channel to the outlet and flow through the outlet.

109. A device for delivering a fluid (e.g., a syringe comprising a body, a needle hub, and optionally a needle), wherein the device is shaped to deliver a fluid (e.g., with a viscosity of at least 5 cP, such as at least 10 cP, such as at least 20 cP, such as at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP). When the fluid (cP) flows through the device, a core-ring flow (e.g., coaxial lubrication) is established for delivering the fluid (e.g., delivering the fluid to the subject) through the outlet from the cylinder of the device (e.g., and through the needle hub and / or needle of the device) (e.g., through the operation of the plunger, for example, through the mechanical operation of the plunger by the user, for example, by manual force).

110. The device of claim 109, wherein the flow of the fluid is characterized by an eccentricity (E) of E < 1 (e.g., E < 0.05, E < 0.02, E = 0).

111. The device of claim 109, wherein the fluid is a viscous pharmaceutical formulation, and wherein the device is shaped to establish a stable core-ring flow for delivering the fluid to a subject as the fluid flows through the device.

112. The device of claim 111, wherein the flow of the fluid is characterized by an eccentricity (E) of E < 1 (e.g., E < 0.05, E < 0.02, E = 0).

113. An apparatus (e.g., a syringe comprising a barrel, a needle hub, and optionally a needle) for delivering a viscous pharmaceutical formulation, wherein the apparatus is shaped to deliver the viscous pharmaceutical formulation (e.g., with a viscosity of at least 5 cP, such as at least 10 cP, such as at least 20 cP, such as at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP). When the viscous pharmaceutical formulation (cP) flows through the device, a core-annular flow (e.g., coaxial lubrication) is established to enable delivery of the viscous pharmaceutical formulation (e.g., delivery of the formulation to a subject) through an outlet from the cylinder of the device (e.g., and through the needle hub and / or needle of the device) (e.g., through the operation of a plunger, e.g., through mechanical operation of the plunger by a user, e.g., by hand), wherein, The shear stress of the internal fluid containing the viscous pharmaceutical formulation (e.g., substantially composed of the viscous pharmaceutical formulation, for example, composed of the viscous pharmaceutical formulation) is not significantly greater than the shear stress of the external lubricating fluid (e.g., not greater than 1000 times, 100 times, 10 times, 5 times, 3 times, 2 times, 1.1 times, or 1.0 times the shear stress of the external lubricating fluid).

114. The device of any one of claims 109 to 113, wherein the device comprises a needle holder having a convex profile (e.g., opposite to a concave profile).

115. A device for delivering a fluid (e.g., a syringe comprising a body, a needle hub, and optionally a needle), wherein the device is shaped to deliver a fluid (e.g., with a viscosity of at least 5 cP, such as at least 10 cP, such as at least 20 cP, such as at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP). When the fluid (cP) flows through the device, a core-annular flow is established for delivering the fluid (e.g., delivering the fluid to the subject) through an outlet from the device's cylinder (e.g., and through the device's needle hub and / or needle) (e.g., through the operation of a plunger, such as through mechanical operation of the plunger by a user, e.g., by hand), wherein, The core-annular flow is not perfectly eccentric (e.g., the flow of the fluid is characterized by an eccentricity (E) of E < 1, e.g., E < 0.05, e.g., E < 0.02, e.g., E = 0), and the through flow (e.g., the flow through the outlet) is greater than the total compliance flow (e.g., the compliance flow throughout all sections of the core-annular flow) (e.g., at least twice, e.g., at least five times, e.g., at least ten times).

116. A device for delivering a fluid (e.g., the device of any one of claims 1 to 44, such as the device of claim 115), wherein the device is shaped to establish a non-perfectly eccentric core-ring flow and has associated resistance and compliance components designed to stabilize the core-ring flow (e.g., a dynamic system of core-ring flow) as the fluid flows through the device to prevent viscous displacement.

117. An apparatus for delivering a fluid (e.g., the apparatus of any one of claims 1 to 44, such as the apparatus of claim 115 or 116), wherein the shape of the apparatus is designed to establish a non-perfectly eccentric core-ring flow and to match the ratio of the resistance of one or more lubricant fluid passages to the resistance of one or more viscous fluid passages to within 1000% as the fluid flows through the apparatus (e.g., wherein the ratio of the larger of the two resistances to the smaller of the two resistances is 10 or less, e.g., 5 or less, e.g., 3 or less, e.g., 2 or less, e.g., 1.5 or less, e.g., 1.2 or less, e.g., 1.1 or less).

118. An apparatus for delivering a fluid (e.g., the apparatus of any one of claims 1 to 44, or the apparatus of any one of claims 115-117), wherein the shape of the apparatus is designed to establish a non-perfectly eccentric core-ring flow and to match the ratio of the resistance of one or more lubricant fluid passages to the resistance of one or more viscous fluid passages to within 10,000% as the fluid flows through the apparatus (e.g., wherein the ratio of the larger of the two resistances to the smaller of the two resistances is 100 or less, e.g., 50 or less, e.g., 30 or less, e.g., 20 or less, e.g., 10 or less, e.g., 5 or less, e.g., 2 or less).

119. A device for delivering a fluid (e.g., the device of any one of claims 1 to 44, or the device of any one of claims 115-118), wherein the device is shaped to establish a non-perfectly eccentric core-ring flow, and wherein the device includes one or more fluid dampers to isolate compliant elements, thereby reducing (e.g., preventing) viscous displacement caused by compliant flow as the fluid flows through the device.

120. An apparatus for delivering a fluid (e.g., the apparatus of any one of claims 1 to 44, such as the apparatus of any one of claims 115-119), wherein the shape of the apparatus is designed to establish a non-perfectly eccentric core-ring flow, and wherein the apparatus matches the upstream pressure of a lubricant reservoir and a viscous fluid reservoir as the fluid flows through the apparatus.

121. An apparatus (e.g., an syringe comprising a barrel, a needle hub, and optionally a needle) for delivering a viscous fluid (e.g., a pharmaceutical formulation) (e.g., the apparatus of any one of claims 1 to 44), wherein the apparatus is shaped to deliver the fluid (e.g., with a viscosity of at least 5 cP, e.g., at least 10 cP, e.g., at least 20 cP, e.g., at least 50 cP, at least 100 cP, at least 200 cP, at least 300 cP, at least 500 cP, at least 750 cP, at least 1,000 cP, at least 1,100 cP, at least 1,200 cP, at least 1,300 cP, at least 1,500 cP, at least 2,000 cP, at least 3,000 cP, at least 4,000 cP, or at least 5,000 cP). When the viscous fluid (cP) flows through the device, a core-ring flow (e.g., coaxial lubrication) is established for delivering the viscous fluid (e.g., delivering the fluid to the subject) through an outlet from the cylinder of the device (e.g., and through the needle hub and / or needle of the device) (e.g., through the operation of a plunger, e.g., through mechanical operation of the plunger by a user, e.g., by hand) and wherein the device includes one or more features designed to perform one or more of the following (i) to (iv): (i) Reduce and / or minimize lubricant compliance ( ); (ii) To reduce the upstream resistance of the lubricant and the viscous fluid ( and (For example, matching the upstream resistance of the lubricant and the viscous fluid to a coefficient not greater than 10,000, not greater than 3,000, not greater than 1,000, not greater than 100, not greater than 10, not greater than 5, not greater than 3, not greater than 2, not greater than 1.5, not greater than 1.2, or not greater than 1.1). (iii) Reduce and / or minimize pressure disturbances ( ); as well as (iv) Reduce and / or minimize core annular flow resistance (e.g., maximize through flow and / or minimize compliant flow). ).

122. The device of claim 121, wherein the device includes components designed to reduce and / or minimize lubricant compliance. One or more characteristics of the lubricant, wherein the lubricant compliance is defined as (Volume change corresponding to a unit change in pressure), where No more than 10 -11 [ (For example, no more than 3 × 10) -12 Not greater than 1×10 -12 No more than 3×10 -13 No more than 5×10 -13 or not greater than 1×10 -14 [ ]).

123. The device of claim 122, wherein one or more features designed to reduce or minimize lubricant compliance include mechanisms for eliminating air bubbles in the device (e.g., ventilated surfaces and / or thin fluid channels that are unlikely to trap air bubbles).

124. The device of claim 121, wherein the device includes components designed to reduce upstream resistance of the lubricant and viscous fluid. and One or more characteristics associated with (e.g., matching the upstream resistance of the lubricant and viscous fluid to a coefficient not greater than 10, 5, 3, 2, 1.5, 1.2, or 1.1).

125. The device of claim 124, wherein the device comprises a viscous fluid channel and a lubricant channel, wherein one or more features include a throttling point located within the lubricant channel (e.g., a resistive region in the form of a capillary tube and / or a filter, e.g., comprising densely packed elements with orifices) (e.g., wherein, The cross-sectional area of ​​the lubricant flow channel in a specific region is significantly smaller than the cross-sectional area of ​​the viscous fluid flow channel.

126. The device as claimed in claim 124 or 125, wherein / Not greater than approximately 100,000, for example, not greater than approximately 10,000, for example, not greater than approximately 1,000, for example, not greater than 100, for example, not greater than 10).

127. The device as claimed in claim 124 or 125, wherein... / Not greater than approximately 100, for example, not greater than approximately 50, for example, not greater than approximately 20, for example, not greater than 10, for example, not greater than 5).

128. The device of claim 121, wherein the device includes components designed to reduce and / or minimize pressure disturbances. One or more characteristics of ).

129. The apparatus of claim 128, wherein the apparatus comprises a lubricant reservoir and a viscous substance reservoir, and wherein one or more features designed to reduce and / or minimize disturbances include a common (e.g., a single) pressure headspace shared between the lubricant reservoir and the viscous substance reservoir.

130. The device of claim 128 or 129, wherein one or more features designed to reduce and / or minimize disturbances include flow channels or other regions with a diameter small enough to induce viscous losses (e.g., flow channels with a diameter not greater than 2 mm, not greater than 1 mm, not greater than 0.5 mm, not greater than 0.2 mm, or about 0.2 mm).

131. The device of claim 128, 129, or 130, wherein the device includes a needle hub that initiates the core-ring flow, wherein one or more features designed to reduce and / or minimize disturbances include a damping element disposed between the needle hub and an upstream element of compliance (e.g., the most compliant upstream element) to limit pressure disturbances experienced by the compliant upstream element and reduce the likelihood of viscous displacement.

132. The device of claim 123, wherein the device comprises components designed to reduce and / or minimize core-ring flow resistance (e.g., maximize through flow and / or minimize compliant flow). One or more characteristics of ).

133. The device of claim 132, wherein one or more features designed to reduce and / or minimize core annular flow resistance include a convex pin seat and / or a smooth profile (e.g., a profile with minimal or no discontinuities, e.g., a profile with a continuous (e.g., substantially continuous) derivative).

134. The device according to any one of claims 109-133, wherein the core annular flow has an efficiency greater than 20% (e.g., greater than 34%, greater than 40%, greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 76%, greater than 80%, or greater than 90%) (e.g., greater than 50%, greater than 52%, greater than 60%, greater than 70%, greater than 80%, or greater than 90%, when the first fluid and lubricant are immiscible and / or the channel orientation is perpendicular). ).

135. The device of claim 134, wherein the dimensions and shape of the channel are designed such that the first fluid can flow with the efficiency when the longitudinal axis of the channel is within 45 degrees of a line perpendicular to gravity and / or when the first fluid exhibiting the core-ring flow and the lubricant are miscible.

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