Systems and methods for injection of viscous fluids

Abstract

To provide a system and a method for injecting a viscous fluid.SOLUTION: Disclosed herein are systems and methods for the injection of viscous fluids. For example, systems and methods of the invention for injecting viscous fluids, such as concentrated drug formulations, via droplet lubrication are described. Certain embodiments are directed to an article for delivery of a fluid. In some embodiments, an article for delivery of a fluid comprises a chamber, a needle fluidly connected to the chamber, an inner fluid extending from the chamber into the needle, and an outer fluid extending from the chamber into the needle and axially surrounding the inner fluid, wherein the outer fluid preferentially wets an interior surface of the needle relative to the inner fluid.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority under 35 U.S.C. Section 119(e) of U.S. Provisional Patent Application No. 62 / 967,239, filed January 29, 2020, which is incorporated herein by reference in its entirety.

[0002] SUMMARY OF THE INVENTION Generally, systems and methods for injection of viscous fluids are described. Summary of the Invention [Means for solving the problem]

[0003] Disclosed herein are systems and methods for the injection of viscous fluids. For example, inventive systems and methods are described for injecting viscous fluids, such as concentrated drug formulations, via droplet lubrication. In some embodiments, injectability of an inner fluid (e.g., a concentrated drug formulation) is desired. In certain embodiments, the systems and methods include an outer fluid axially surrounding the inner fluid. In some cases, the outer fluid lubricates the flow of the inner fluid against the inner fluid, the inner surface of the needle, and / or the chamber through which the fluid is transported, by preferential wetting. In some cases, the inner fluid does not contact the inner surface of the needle and / or the chamber through which the inner fluid is transported. The subject matter of the present invention, in some cases, involves interrelated products, alternative solutions to a particular problem, and / or multiple different uses of one or more systems and / or articles.

[0004] Certain embodiments relate to an article for fluid delivery, in some embodiments, the article for fluid delivery comprises a chamber, a needle fluidly connected to the chamber, an inner fluid extending from the chamber into the needle, and an outer fluid extending from the chamber into the needle and axially surrounding the inner fluid, wherein the outer fluid preferentially wets an inner surface of the needle relative to the inner fluid.

[0005] In some embodiments, an article for delivery of a fluid comprises a chamber and a needle fluidly connected to the chamber, the article being configured such that when the inner and outer fluids are transported through the needle, the outer fluid axially surrounds the inner fluid and the outer fluid preferentially wets the inner surface of the needle relative to the inner fluid.

[0006] In one embodiment, an article for delivery of a fluid comprises a chamber, a needle fluidly connected to the chamber, an inner fluid extending from the chamber into the needle and flowing through the needle, and an outer fluid extending from the chamber into the needle, axially surrounding the inner fluid and flowing through the needle, wherein the outer fluid mixes with the inner fluid by up to 50% while in the needle.

[0007] In one embodiment, an article for fluid delivery comprises a chamber and a needle fluidly connected to the chamber, the article being configured such that when the inner and outer fluids are transported through the needle, the outer fluid axially surrounds the inner fluid and the outer fluid mixes with the inner fluid by up to 50% while in the needle.

[0008] In some embodiments, an article for delivery of a fluid comprises a chamber, a needle fluidly connected to the chamber, an inner fluid extending from the chamber into the needle and flowing through the needle, and an outer fluid extending from the chamber into the needle, axially surrounding the inner fluid and flowing through the needle, wherein the article has an eccentricity parameter (E) of less than 1 when the longitudinal axis of the needle is within 45 degrees of a line perpendicular to gravity for at least one time period.

[0009] In one embodiment, an article for delivery of fluids comprises a chamber and a needle fluidly connected to the chamber, the inner surface of the needle comprising a texture that confers wettability for at least one fluid when a droplet of that fluid is present on the inner surface of the needle in another fluid.

[0010] In some embodiments, an article for delivery of fluids comprises a chamber and a needle fluidly connected to the chamber, the inner surface of the needle comprising a coating that confers wettability for at least one fluid when a droplet of that fluid is present on the inner surface of the needle in another fluid.

[0011] In some embodiments, an article for delivery of a fluid comprises a chamber, a needle fluidly connected to the chamber, an inner fluid comprising a liquid and a species suspended and / or dissolved in the liquid, the inner fluid extending from the chamber into the needle and flowing through the needle, and an outer fluid comprising the liquid and extending from the chamber into the needle, axially surrounding the inner fluid and flowing through the needle, wherein the outer fluid does not contain the species or contains the species at a molar concentration at least 50% lower than the molar concentration of the species in the inner fluid.

[0012] Other advantages and novel features of the present invention will become apparent from the following detailed description of various non-limiting embodiments of the invention when considered in conjunction with the accompanying drawings. In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control. The present invention provides, for example, the following. (Item 1) 1. An article for the delivery of a fluid, comprising: a chamber; a needle fluidly connected to the chamber; an inner fluid extending from the chamber into the needle and flowing through the needle; an outer fluid extending from the chamber into the needle, axially surrounding the inner fluid, and flowing through the needle; Equipped with The article wherein the outer fluid mixes with the inner fluid by up to 50% while in the needle. (Item 2) 1. An article for the delivery of a fluid, comprising: a chamber; a needle fluidly connected to the chamber; Equipped with The article is configured such that when the inner and outer fluids are transported through the needle, the outer fluid axially surrounds the inner fluid and the outer fluid mixes with the inner fluid by up to 50% while within the needle. (Item 3) 1. An article for the delivery of a fluid, comprising: a chamber; a needle fluidly connected to the chamber; an inner fluid containing a liquid and a species suspended and / or dissolved in the liquid, the inner fluid extending from the chamber into the needle and flowing through the needle; an outer fluid containing the liquid and extending from the chamber into the needle, the outer fluid axially surrounding the inner fluid and flowing through the needle; Equipped with The article, wherein the outer fluid is free of the species or contains the species at a molar concentration that is at least 50% lower than the molar concentration of the species in the inner fluid. (Item 4) 10. The article of any preceding item, wherein the outer fluid and / or the inner fluid are soluble in the other in an amount greater than 0.001 mass fraction. (Item 5) 1. An article for the delivery of a fluid, comprising: a chamber; a needle fluidly connected to the chamber; an inner fluid extending from the chamber into the needle and flowing through the needle; an outer fluid extending from the chamber into the needle, axially surrounding the inner fluid, and flowing through the needle; Equipped with The article has an eccentricity parameter (E) of less than 1 when the longitudinal axis of the needle is within 45 degrees of a line perpendicular to gravity for at least one period of time. (Item 6) Item 6. The article of item 5, wherein the article has an eccentricity parameter (E) of less than 1 when the longitudinal axis of the needle is within 15 degrees of a line perpendicular to gravity for at least one period of time. (Item 7) 1. An article for the delivery of a fluid, comprising: a chamber; a needle fluidly connected to the chamber; an inner fluid extending from the chamber into the needle; an outer fluid extending from the chamber into the needle and axially surrounding the inner fluid; Equipped with The article wherein the outer fluid preferentially wets the interior surface of the needle relative to the inner fluid. (Item 8) 1. An article for the delivery of a fluid, comprising: a chamber; a needle fluidly connected to the chamber; Equipped with The article is configured such that when the inner and outer fluids are transported through the needle, the outer fluid axially surrounds the inner fluid and the outer fluid preferentially wets the inner surface of the needle relative to the inner fluid. (Item 9) 10. The article of any preceding item, wherein neither the outer fluid nor the inner fluid is soluble in the other in an amount greater than 0.001 mass fraction. (Item 10) 10. The article of any preceding item, wherein the outer fluid is a Newtonian fluid. (Item 11) 10. The article of any preceding item, wherein the outer fluid is a yield stress fluid. (Item 12) The ratio of the viscosity of the inner fluid to the viscosity of the outer fluid (μ i / μ o ) may contain more than one of the articles described in any of the preceding items. (Item 13) The ratio of the viscosity of the inner fluid to the viscosity of the outer fluid (μ i / μ o) is more than 10. (Item 14) With respect to the inner fluid, the outer fluid, and the inner surface of the needle, S on(i) ≧0. (Item 15) 10. The article of any preceding item, wherein the capillary number of the inner fluid is greater than or equal to 0.01 and the capillary number of the outer fluid is greater than or equal to 0.001. (Item 16) Item 16. The article of item 15, wherein the capillary number of the inner fluid is greater than the capillary number of the outer fluid. (Item 17) 10. The article of any preceding item, wherein the inner surface of the needle comprises a texture. (Item 18) With respect to the inner fluid, the outer fluid, and the texture, S on(i) Item 18. The article of item 17, wherein ≧0. (Item 19) 10. The article of any preceding item, wherein the inner surface of the needle comprises a coating. (Item 20) With respect to the inner fluid, the outer fluid, and the coating, S on(i) 20. The article of item 19, wherein .gtoreq.0. (Item 21) The inner surface of the needle is φ s Item 10. The article of any preceding item, having a texture that is ≦0.5. (Item 22) The inner surface of the needle is φ s Item 10. The article of any preceding item, having a texture where R is ≦0.1. (Item 23) 10. The article of any preceding item, wherein the outer fluid preferentially wets the interior surfaces of the chamber. (Item 24) 10. The article of any preceding item, wherein the inner fluid and the outer fluid comprise one or more components that are the same. (Item 25) 10. The article of any preceding item, wherein the inner fluid and / or the outer fluid comprise one or more different components. (Item 26) 10. The article of any preceding item, wherein the inner fluid and the outer fluid comprise exactly the same components, except that the inner fluid has an additional component. (Item 27) 1. An article for the delivery of a fluid, comprising: a chamber; a needle fluidly connected to the chamber; Equipped with An article wherein the interior surface of the needle comprises a texture that imparts wettability for at least one fluid when a droplet of that fluid is present on the interior surface of the needle in another fluid. (Item 28) The inner surface of the needle is φ s 28. The article of item 27, having a texture that is ≦0.5. (Item 29) φ s 29. The article of item 28, wherein the ρ is ≦0.1. (Item 30) 1. An article for the delivery of a fluid, comprising: a chamber; a needle fluidly connected to the chamber; Equipped with An article wherein the interior surface of the needle comprises a coating that confers wettability for at least one fluid when a droplet of that fluid is present on the interior surface of the needle in another fluid. (Item 31) Item 10. The article of any preceding item, wherein the needles have a length greater than or equal to 5 microns. (Item 32) Item 10. The article of any preceding item, wherein the needle has a length of at least 10 mm. (Item 33) 10. The article of any preceding item, wherein the article is a syringe needle system. (Item 34) 10. The article of any preceding item, wherein the article is non-manually actuated. (Item 35) 1. A method of fluid delivery comprising: Initiating flow of at least a portion of the inner fluid and at least a portion of the outer fluid within the article according to any of the preceding items so that at least a portion of the inner fluid and at least a portion of the outer fluid are transported from the chamber to the needle and expelled from the needle. A method comprising: (Item 36) Item 36. The method of item 35, wherein the longitudinal axis of the needle is within 45 degrees of a line perpendicular to gravity for at least one time period between initiating the flow and ejection from the needle. (Item 37) Item 37. The method of item 36, wherein the longitudinal axis of the needle is within 15 degrees of the line perpendicular to gravity for at least one period of time between initiating the flow and ejection from the needle. (Item 38) 38. The method of any one of items 35-37, wherein the at least one time period is the entire time between initiating the flow and ejection from the needle. (Item 39) 39. The method of any one of items 35-38, wherein the ratio (Φ) of the volume of the inner fluid expelled from the needle to the total volume expelled from the needle is ≧0.5. (Item 40) 40. The method of any one of items 35-39, wherein the inner and outer fluids have a timescale of convection within the article and a timescale of eccentricity within the article, the timescale of convection being less than or equal to the timescale of eccentricity. (Item 41) 41. The method of any one of items 35-40, wherein the inner fluid and the outer fluid have a timescale of convection within the article and a timescale of mixing within the article, the timescale of convection being less than or equal to the timescale of mixing. (Item 42) 1. A method of fluid delivery comprising: Initiating the flow of at least a portion of the inner fluid and at least a portion of the outer fluid in the article according to any one of items 1-34, such that at least a portion of the inner fluid and at least a portion of the outer fluid are transported from the chamber to the needle and expelled from the needle. Including, The volumetric flow rate of the inner fluid is ≥ 10 -2 ×γπd n 2 / μ i and the volumetric flow rate of the outer fluid is ≥ 10 -3 ×γπd n 2 / μ o That's the method. (Item 43) The volumetric flow rate of the inner fluid is ≥ 10 -1 ×γπd n 2 / μ i and the volumetric flow rate of the outer fluid is ≥ 10 -3 ×γπd n 2 / μ o Item 43. The method according to Item 42, wherein (Item 44) 1. A method of fluid delivery comprising: Initiating the flow of at least a portion of the inner fluid and at least a portion of the outer fluid in the article according to any one of items 1-34, such that at least a portion of the inner fluid and at least a portion of the outer fluid are transported from the chamber to the needle and expelled from the needle. Including, The volumetric flow rate of the outer fluid (Q o ) the volumetric flow rate (Q i ) is greater than 0.2, method. (Item 45) 10. The method of claim 1, wherein the inner fluid and the outer fluid comprise one or more components that are the same. (Item 46) 10. The method of claim 1, wherein the inner fluid and / or the outer fluid comprise one or more different components. (Item 47) 10. The method of claim 9, wherein the inner fluid and the outer fluid contain exactly the same components, except that the inner fluid has an additional component. [Brief explanation of the drawings]

[0013] Non-limiting embodiments of the present invention will now be described, by way of example, with reference to the accompanying drawings, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component shown is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor every component of every embodiment of the invention is shown, unless illustration is necessary to enable those skilled in the art to understand the invention.

[0014] [Figure 1A] FIG. 1A is a schematic diagram of an article for fluid delivery comprising a chamber 101, a needle 102, an inner fluid 103, and an outer fluid 104, according to some embodiments. [Figure 1B] FIG. 1B is a cross-sectional view of a needle depicting the outer and inner fluids within the needle, according to some embodiments. [Figure 2A] Figure 2A is a time-lapse image demonstrating the difficulty of manually injecting a high-viscosity solution (52 cP glycerin / water, top) compared to a low-viscosity solution (1 cP water, bottom) through a 27 G needle. The time-lapse images were taken over 7 seconds of manual injection into the absorbent sponge. The operator applied the maximum possible clamping force (approximately 50 N). [Figure 2B] FIG. 2B is a plot of the manual injection force required to inject 11 highly concentrated monoclonal antibody solutions of the IgG1 isotype. [Figure 2C]FIG. 2C is a schematic illustration of unlubricated and axially lubricated flow through a needle, according to some embodiments. [Figure 2D] FIG. 2D is a plot of pressure reduction factor (η) versus the ratio of volumetric flow rate of the outer fluid to that of the inner fluid (Qo / Qi) over various viscosity ratios (λ), according to some embodiments. [Figure 3A] FIG. 3A is a schematic illustration of an article used to inject a viscous fluid, according to some embodiments. [Figure 3B] Figure 3B plots the viscosity ratio (λ) versus the ratio of the volumetric flow rate of the outer fluid to that of the inner fluid (Qo / Qi), according to some embodiments, for systems that exhibited axially lubricated flow and systems that exhibited viscosity displacement. Volume fractions below 55% have not been experimentally explored. [Figure 3C] Figure 3C shows a time diagram of a cross section of a needle (needle inner diameter = 304.8 μm) combined with a pressure vs. time plot highlighting the viscous displacement regime, according to some embodiments. This regime involved periodic switching between a primary state, in which the viscous fluid filled the entire cross section of the needle, and a secondary state, in which the two fluids flowed as intermittent axially lubricated flows. This resulted in a high and unstable pressure drop within the needle. The scale bar is 100 μm wide. [Figure 3D] FIG. 3D is a time diagram of a needle cross section combined with a pressure versus time plot highlighting the axially lubricated flow regime, according to some embodiments. The axially lubricated flow regime was stable over time and resulted in a much lower steady-state pressure drop. The scale bar is 100 μm wide. [Figure 4A] FIG. 4A is a plot of pressure reduction factor (η) versus the ratio of volumetric flow rate of the outer fluid to that of the inner fluid (Qo / Qi) over different viscosity ratios (λ), according to some embodiments. [Figure 4B]FIG. 4B is a digital photograph of a needle (needle inner diameter = 304.8 μm, scale bar is 100 μm wide) with eccentric inner and outer fluids, which resulted in a lower maximum pressure reduction coefficient than in a system with concentric flow, according to some embodiments. [Figure 5A] FIG. 5A is an exploded view of a proof-of-concept dual-barreled syringe, according to some embodiments. [Figure 5B] FIG. 5B is a photograph of a dual-barrel syringe, according to some embodiments. [Figure 5C] FIG. 5C is a set of time-lapse images comparing the injectability of a high viscosity formulation through a commercially available syringe (top) and a syringe constructed and used in accordance with certain embodiments (bottom). [Figure 5D] FIG. 5D shows a comparison of the force reduction coefficient of the entire dual-barreled syringe (ηDBS) and the force reduction coefficient of the needle alone (ηneedle) from one experiment compared to the corresponding control experiment in a comparator syringe-needle system. [Figure 5E] FIG. 5E shows that by using a syringe (e.g., a dual-barrel syringe) configured and used in accordance with certain embodiments described herein, an increase in concentration is possible for a nominal injection force of 25 N. [Figure 5F] FIG. 5F plots injection force versus monoclonal antibody concentration in a dual-barreled syringe, according to some embodiments. [Figure 6A] FIG. 6A is an image showing axially lubricated flow in a needle connected to an axially lubricated flow injector, according to some embodiments. [Figure 6B] FIG. 6B is a schematic diagram of the experimental setup used to measure the pressure reduction coefficient of a dual-barreled syringe, according to some embodiments. [Figure 7] FIG. 7 shows contact angle measurements of HFE-7500 on a PTFE surface in the environment of a 26 cP glycerin / water mixture, according to some embodiments. [Figure 8A]FIG. 8A shows a plot of convective timescale / eccentricity timescale (Tc / te) versus density difference between the inner and outer fluids over different average volumetric flow rates (Qavg), according to an embodiment. [Figure 8B] FIG. 8B shows a plot of convective timescale / eccentricity timescale (Tc / te) versus orientation of the system (e.g., needle and / or chamber) when the density difference between the inner and outer fluids is 0.05 kg / m3 over different average volumetric flow rates (Qavg), according to an embodiment. [Figure 9] FIG. 9 is a schematic diagram of a droplet on a surface in a medium that can be used to illustrate how a diffusion coefficient is determined, according to an embodiment. [Figure 10A] FIG. 10A is a cross-sectional view of an embodiment of a needle with inner and outer fluids in concentric annular flow. [Figure 10B] FIG. 10B is a cross-sectional view of an embodiment of a needle with inner and outer fluids in a fully eccentric annular flow. [Figure 10C] FIG. 10C is a cross-sectional view of an embodiment of a needle with inner and outer fluids in a partially eccentric annular flow. [Figure 11] FIG. 11 plots the capillary number of the inner fluid versus the capillary number of the outer fluid for a system that exhibited axially lubricated flow and a system that exhibited viscous displacement, according to one embodiment. [Figure 12A] FIG. 12A is a top view schematic of an inner surface of a needle with a texture, according to an embodiment. [Figure 12B] FIG. 12B is a three-dimensional perspective view of the interior surface of a needle with a texture, according to an embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description Disclosed herein are articles, systems, and methods for the injection of viscous fluids. For example, inventive articles, systems, and methods for injecting viscous fluids, such as concentrated drug formulations, via lubrication are described. In some embodiments, the injectability of internal fluids, such as concentrated drug formulations, is desirable. However, the nonlinear relationship between formulation concentration and viscosity can significantly limit the ability to inject high-concentration drug formulations, frequently required for biologics and / or subcutaneous administration. As drug concentrations increase above 50 mg / mL, the corresponding viscosities frequently range from 20 cP to 1,000 cP, making injection through conventional delivery methods (e.g., syringes) extremely cumbersome. For example, the high hydraulic resistance presented by flow through a needle at such high concentrations frequently induces high backpressure. In some embodiments, the articles, systems, and / or methods described herein reduce these resistances by achieving axially lubricated flow with a fluid of interest (e.g., an inner fluid) and a lubricating fluid (e.g., an outer fluid), improving the injectability of such high concentration drug formulations and other high viscosity fluids.

[0016] However, axially lubricated flow can be very difficult to achieve in practical systems. For example, if the densities of the inner and outer fluids are not substantially identical, eccentricity frequently occurs (e.g., as shown in Figures 10B and 10C compared to the concentric system of Figure 10A), such that the inner fluid contacts the interior surfaces of the needle and / or chamber, reducing the lubricating effect from the outer fluid. However, attempting to match the densities of the inner and outer fluids can often be extremely impractical. Avoiding eccentricity can be particularly difficult when the inner and outer fluids are miscible. While vertical motion can be used to avoid eccentricity in some cases, this is also impractical because most hypodermic injections are not typically administered vertically. Furthermore, vertical motion only facilitates the injection of miscible inner and outer fluids and, in some cases, typically will not work with immiscible fluids. Some of the embodiments disclosed herein are capable of achieving axially lubricated flow in practical systems despite these challenges.

[0017] In certain embodiments, the articles, systems, and / or methods include an outer fluid that axially surrounds the inner fluid. In some cases, the outer fluid preferentially wets the interior surfaces of the needle and / or chamber through which the fluid flows, helping to ensure that the inner fluid does not contact the interior surfaces of the needle and / or chamber even when the fluid flow is highly eccentric and the needle is approximately horizontal during administration. In some embodiments, the interior surface of the needle is textured to promote preferential wetting by the outer fluid. In some cases, the interior surface of the needle is coated to promote preferential wetting by the outer fluid.

[0018] Articles for fluid delivery are described herein. One such article is illustrated diagrammatically in FIGS. 1A-1B. In some embodiments, the article comprises a chamber. For example, according to some embodiments, article 100 of FIG. 1A comprises chamber 101. In some embodiments, the diameter of the chamber exceeds the diameter of the needle. In some embodiments, the chamber comprises a biocompatible material. In some embodiments, the material of the chamber is selected such that when the inner and outer fluids contact each other and the chamber, the outer fluid preferentially wets the interior surface of the chamber relative to the inner fluid.

[0019] In some embodiments, the article comprises a needle. For example, according to one embodiment, article 100 of FIG. 1A comprises needle 102. In some embodiments, the article is a syringe needle system. In some embodiments, the article comprises a plurality of needles. For example, in some cases, the article comprises more than or equal to 1, more than or equal to 2, more than or equal to 3, more than or equal to 10, more than or equal to 50, or more than or equal to 100 needles. In some cases, the article comprises less than or equal to 1,000, less than or equal to 500, less than or equal to 100, less than or equal to 50, less than or equal to 10, or less than or equal to 5 needles. Combinations of these ranges (e.g., 1 to 1,000) are also possible.

[0020] According to some embodiments, the article comprises a microneedle patch. In some embodiments, the microneedle patch comprises an array of needles, optionally arranged in a periodic pattern. In some such embodiments, the inner fluid and the outer fluid can be delivered to a subject (e.g., a patient) through the needles of the microneedle patch.

[0021] In some embodiments, the article is manually actuated. For example, in some embodiments, injection of the inner fluid can be achieved by applying pressure by hand. While manual actuation is required, however, in some embodiments, the article is non-manually actuated. For example, in some embodiments, the article is actuated by a mechanical spring and / or an electric motor.

[0022] According to some embodiments, a needle is fluidly connected to a chamber. For example, in the exemplary embodiment shown in FIG. 1A, needle 102 is fluidly connected to chamber 101. The needle may be directly connected to the chamber (e.g., with nothing between them), or it may be indirectly connected to the chamber (e.g., with an additional chamber between them). According to some embodiments, the chamber is upstream of the needle such that fluid within the chamber can flow and / or be transported to the needle. For example, in the example shown in FIG. 1A, chamber 101 is upstream of needle 102 such that fluid within chamber 101 can flow from chamber 101 to needle 102.

[0023] In some embodiments, the article comprises an inner fluid. For example, according to one embodiment, article 100 of FIG. 1A comprises inner fluid 103. According to some embodiments, the inner fluid extends from the chamber into the needle. For example, as illustrated in FIG. 1A, inner fluid 103 extends from chamber 101 into needle 102. In some embodiments, the inner fluid flows through the needle. For example, as shown in FIG. 1A, inner fluid 103 flows through needle 102 in the direction of arrow 106.

[0024] In some embodiments, the article comprises an outer fluid. For example, in some instances, article 100 of FIG. 1A comprises outer fluid 104. According to some embodiments, the outer fluid extends from the chamber into the needle. For example, as illustrated in FIG. 1A, outer fluid 104 extends from chamber 101 into needle 102. In some embodiments, the outer fluid axially surrounds the inner fluid, as described in more detail below. According to some embodiments, the outer fluid flows through the needle. For example, as shown in FIG. 1A, outer fluid 104 flows through needle 102 in the direction of arrow 106.

[0025] Examples of fluids include liquids, such as pure liquids, and mixtures of liquids, as well as liquids combined with non-liquids, such as liquid / gas mixtures, and liquid / solid mixtures, such as suspensions.

[0026] According to certain embodiments, the article is configured so that the outer fluid axially surrounds the inner fluid as they are transported through the needle. A first fluid is said to "axially surround" a second fluid when a continuous path can be traced through the first fluid that surrounds the longitudinal axis of the second fluid. For example, as illustrated in FIGS. 1A-1B, outer fluid 104 axially surrounds inner fluid 103. In some embodiments, the outer fluid is positioned around the circumference of the inner fluid but does not surround the inner fluid at the end of the flow exiting the needle (or other fluid path). In the non-limiting example shown in FIG. 1A, for example, outer fluid 104 is positioned around the circumference of inner fluid 103 but does not surround inner fluid 103 at point 107 (the end of needle 105). In certain embodiments, the outer fluid can axially surround the inner fluid such that the inner fluid is in an elongated shape having a length to cross-sectional dimension ratio of, for example, at least 5:1, at least 10:1, at least 25:1, or greater.

[0027] According to some embodiments, the outer fluid preferentially wets the interior surface of the needle and / or chamber relative to the inner fluid. For example, referring to the example shown in Figure 1A, in one embodiment, the outer fluid 104 preferentially wets the interior surface 105 of the needle 102 relative to the inner fluid 103.

[0028] In some embodiments, the outer fluid has a diffusion coefficient (S on(i) ) is greater than or equal to 0, the inner surface of the needle is preferentially wetted by the inner fluid. Figure 9 is a schematic diagram of a droplet of outer fluid on the inner surface of a needle, where the outer droplet is surrounded by the inner fluid. The diffusion coefficient can be determined according to the following equation:

number

number

[0029] In some embodiments, the inner fluid does not contact the inner surface of the needle. For example, in some embodiments, the inner fluid 103 in FIG. 1A does not contact the inner surface 105 of the needle 102. According to some embodiments, the inner fluid does not contact the inner surface of the needle for a period of time. For example, in some cases, the period of time is between initiating the flow of the inner and / or outer fluid and ejecting the inner and / or outer fluid from the needle. In some cases, the period of time is at least a portion (e.g., at least 50%, at least 75%, at least 90%, or the entirety of the time) of the time between initiating the flow of the fluid and ejecting the fluid from the needle.

[0030] According to some embodiments, the inner fluid comprises a drug, a monoclonal antibody, an enzyme, a peptide, a recombinant therapeutic protein, a biologic, a bone putty, a hydrogel, a cell, and / or a biopharmaceutical. For example, in certain embodiments, the inner fluid comprises a concentrated drug formulation (e.g., a biologic).

[0031] According to certain embodiments, the outer fluid has a lower viscosity than the inner fluid. In some embodiments, the ratio of the viscosity of the inner fluid to the viscosity of the outer fluid (μ i / μ o ) is >1. In some embodiments, the ratio of the viscosity of the inner fluid to the viscosity of the outer fluid (μ i / μ o ) is greater than or equal to 3, greater than or equal to 5, greater than or equal to 8, or greater than or equal to 10.

[0032] In some cases, the external fluid comprises water, a buffer (e.g., a pharmaceutically acceptable buffer such as a buffer used in a pharmaceutical product such as a biologic), a formulation (e.g., a pharmaceutical formulation such as a biologic), a water-based solution, saline, a biocompatible oil (e.g., squalene, a fluorinated oil (e.g., HFE-7500), a mineral oil, and / or a triglyceride oil), benzyl benzoate, a metabolizable oil, an immunological adjuvant (e.g., MF59, AS02, AS03, and / or AS04), and / or safflower oil.

[0033] In some embodiments, the outer and inner fluids are immiscible. For example, according to certain embodiments, neither the outer nor the inner fluid is soluble in the other at a mass fraction greater than 0.001, a mass fraction greater than 0.0001, or a mass fraction greater than 0.00001. In certain embodiments, the outer and inner fluids are immiscible at the temperature at which the fluids are flowed. In some cases, the outer and inner fluids are immiscible at 25°C.

[0034] The use of immiscible inner and outer fluids is not necessarily required, and in some embodiments, the outer and inner fluids are miscible. For example, according to some embodiments, the outer and / or inner fluids are soluble in the other at a mass fraction greater than 0.001, a mass fraction greater than 0.01, or a mass fraction greater than 0.1. In some embodiments, the outer and inner fluids are miscible at the temperature at which the fluids are flowed. In some cases, the outer and inner fluids are miscible at 25°C.

[0035] For the systems and methods described herein, the timescale of convection (T c ) is the time it takes for the inner and outer fluids to travel through the system (e.g., needle and / or chamber) while in direct contact with each other. The convective timescale is calculated by estimating the average volumetric flow rate of the multi-fluid system. Specifically, the average volumetric flow rate and timescale of the conventional method are calculated using the following equations:

number

[0036] For the systems and methods described herein, the timescale of eccentricity (t e ) is the time for spatially stable eccentricity to occur within any portion of the system (e.g., needle and / or chamber) comprising the inner and outer fluids. The timescale of eccentricity can be measured according to the following equation:

number

[0037] In one embodiment, the timescale of convection (T c ) is the timescale of eccentricity (t e ) for the inner and outer fluids. For example, in some embodiments, the timescale of convection (T c ) and the eccentricity timescales (t e ) is less than or equal to 1, less than or equal to 0.75, less than or equal to 0.5, or less than or equal to 0.1. In some embodiments, the ratio of the convective timescale (T c ) is the timescale of eccentricity (t e ), the fluid does not exhibit substantial eccentricity while in the system (e.g., needle and / or chamber).

[0038] For the systems and methods described herein, the timescale of mixing (t m) is the time required for 50% of the outer fluid to mix with the inner fluid as they progress through the system or part thereof (e.g., needle and / or chamber) while the outer and inner fluids are in direct contact with each other. The timescale for mixing can be calculated using the following equation:

number

[0039] In one embodiment, the timescale of convection (T c ) is the timescale (t) of mixing within one or more portions of the system (e.g., within the needle and / or within the chamber) or within the system as a whole. m ) for example, in some embodiments, the timescale of convection is less than the timescale of mixing within the needle, and / or the timescale of convection is less than the timescale of mixing within the chamber. For example, in some embodiments, the timescale of convection for the inner and outer fluids (T c ) and the mixing timescales (t m ) is less than or equal to 1, less than or equal to 0.75, less than or equal to 0.5, less than or equal to 0.1, or less than or equal to 0.01. In some embodiments, the ratio of the convective timescale (Tc ) is the mixing timescale (t m ), the fluids do not substantially mix while in the system or portions thereof (e.g., needle and / or chamber).

[0040] In some embodiments, the density and / or volumetric flow rate (Q) of the inner and outer fluids influence the convective timescale and / or the ratio of the convective timescale to the eccentricity timescale. For example, FIG. 8A illustrates a convective timescale with a t of less than or equal to 1, according to one embodiment. c / t e However, a smaller density difference between the inner and outer fluids and / or a higher mean volumetric flow rate (Q i ) is easier to achieve.

[0041] In some embodiments, when the outer fluid flow rate is too low compared to the inner fluid flow rate, a viscosity displacement regime is observed rather than an axially lubricated flow regime. In the viscosity displacement regime, the outer fluid fills the entire cross section of the needle, forcing both the inner and outer fluids to flow back into the outer fluid inlet. However, in some cases, the backflow cannot be maintained due to the constant mass flux imposed on the outer fluid, resulting in a sudden overflow of the outer fluid into the needle. In some cases, the flow decreases until it is completely blocked again, and the process repeats. In some embodiments, this cyclic behavior (as shown in FIG. 3C) results in unstable and significantly worse lubrication compared to the axially lubricated flow regime (as shown in FIG. 3D).

[0042] According to some embodiments, the volumetric flow rate of the outer fluid (Q o ) and the volumetric flow rate of the inner fluid (Q i ) is greater than 0.1. In some embodiments, the volumetric flow rate of the outer fluid (Q o ) and the volumetric flow rate of the inner fluid (Q i) is greater than or equal to 0.2, greater than or equal to 0.4, or greater than or equal to 0.6. In certain embodiments, the volumetric flow rate (Q o ) and the volumetric flow rate of the inner fluid (Q i ) is less than or equal to 1.

[0043] In some embodiments, the outer and inner fluids do not substantially mix within the needle and / or chamber because the mixing step dilutes the inner fluid and reduces the benefits of axially lubricated flow. In certain embodiments, the timescale of convection is shorter than the time it takes for the inner and outer fluids to substantially mix within the needle and / or chamber. According to some embodiments, the outer fluid mixes with the inner fluid by up to 50% while in the needle and / or chamber. That is, up to 50% of the outer fluid mixes with the inner fluid while in the needle and / or chamber, while the remainder of the outer fluid remains unmixed with the inner fluid. For example, in certain embodiments, the outer fluid mixes with the inner fluid by up to 40%, up to 30%, up to 20%, or up to 10% while in the needle and / or chamber. According to certain embodiments, the degree of mixing can be determined by visual inspection. In some embodiments, this can be accomplished by staining the inner and / or outer fluids, taking photographs at the needle exit, and measuring the degree of mixing of the two fluids from the diffusion and / or exhalation of the dye. In certain embodiments, the degree of mixing can be measured at different lengths by cutting the needle to a length of interest and photographing the fluid at the outlet.

[0044] In some embodiments, the inner and outer fluids comprise completely different components. For example, in some embodiments, the inner and outer fluids have no components in common. One such example would be where the inner fluid comprises a drug and water, while the outer fluid comprises an organic solvent.

[0045] In some embodiments, the inner and outer fluids comprise one or more components (e.g., solvents and / or buffers) that are the same. For example, in certain embodiments, the inner and outer fluids both comprise water.

[0046] In certain embodiments, the inner fluid and / or the outer fluid comprise one or more different components, for example, in some embodiments, the inner fluid comprises water and the outer fluid does not.

[0047] In some embodiments, the inner and outer fluids contain one or more components that are different and one or more components that are the same. For example, in some embodiments, the inner and outer fluids contain the same components, except that the inner fluid also contains a drug (e.g., a biologic). For example, in some embodiments, the inner and outer fluids both contain water, but the inner fluid contains a drug (e.g., a biologic) and the outer fluid does not. In some embodiments, the inner and outer fluids contain exactly the same components (e.g., a buffer) except that one of the fluids (e.g., the inner fluid) contains an additional component (e.g., a drug).

[0048] In some embodiments, the inner and outer fluids contain exactly the same components (e.g., buffer and drug), but the concentration of one or more of the components (e.g., drug) is different. For example, in some embodiments, the inner and outer fluids contain exactly the same components (e.g., buffer and drug), but the concentration of one or more of the components (e.g., drug) is higher than in the inner fluid. As one skilled in the art will understand, in some embodiments, the different concentrations of one or more of the components may result in different physical and / or chemical properties. For example, in embodiments where the inner fluid has a high concentration of a biological drug and the outer fluid has a low concentration of a biological drug, but the inner and outer fluids are otherwise the same, the viscosity and / or density of the inner fluid may be much higher than that of the outer fluid.

[0049] In some embodiments, the molar concentration of one component (e.g., a drug) in the outer fluid 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 that component in the inner fluid. In some embodiments, the molar concentration of one component (e.g., a drug) in the outer fluid 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 that component in the inner 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 a component is 1 M in the inner fluid and 0.1 M in the outer fluid, the molar concentration of the component in the outer fluid will be 90% less than that in the inner fluid.

[0050] When the inner and outer fluids are in concentric contact and moving, one or more components of the inner fluid (e.g., a drug such as a biologic) may begin to diffuse into the outer fluid. The radial position (R(x)) of the separation between the inner and outer fluids is given by the following equation:

number

[0051] According to some embodiments, the outer fluid is a Newtonian fluid. For example, according to certain embodiments, the viscosity stress resulting from the flow of the outer fluid at each point is linearly related to the local strain rate. Examples of suitable Newtonian fluids include water, water-based solutions, buffers (e.g., pharmaceutically acceptable buffers such as those used in pharmaceutical products, such as biologics), formulations (e.g., pharmaceutical formulations, such as biologics), saline, biocompatible oils (e.g., squalene, fluorinated oils (e.g., HFE-7500), mineral oil, and / or triglyceride oil), benzyl benzoate, metabolizable oils, immunological adjuvants (e.g., MF59, AS02, AS03, and / or AS04), and / or safflower oil.

[0052] In some embodiments, the outer fluid is a stress-relieving fluid. For example, in some embodiments, the outer fluid deforms and / or flows only when subjected to stress above a critical value specific to the stress-relieving fluid. Examples of suitable stress-relieving fluids include bone putty, hydrogels, hydrogel microbeads, and / or polymer solutions (e.g., polyethylene glycol).

[0053] In some embodiments, an additional fluid is present. In some embodiments, the additional fluid is an additional lubrication layer. In some embodiments, the outer fluid and / or the additional fluid comprises a surfactant. In some cases, the surfactant reduces and / or prevents healing and / or degradation. In some cases, the additional fluid is more biocompatible than the outer fluid. In some embodiments, the use of an additional fluid results in improved biocompatibility. In some embodiments, the additional fluid (e.g., an additional fluid comprising a surfactant) increases the diffusion coefficient. In some embodiments, the additional fluid (e.g., an additional fluid comprising a surfactant) increases the capillary number of the inner fluid and / or the outer fluid.

[0054] In some embodiments, the needle comprises an inner surface. For example, in some instances, needle 102 of FIG. 1A comprises inner surface 105.

[0055] In some embodiments, the interior surface of the needle comprises a texture. For example, in some embodiments, the interior surface of the needle comprises a plurality of features. For example, in some embodiments, the exterior surface of the conduit comprises milliscale, microscale, and / or nanoscale features. The texture, in some embodiments, may be used to control the wettability of the surface. Any of a variety of features may be used. Non-limiting examples of protrusions include spherical or hemispherical protrusions. In some embodiments, the features include protrusions such as ridges, spikes, and / or pillars. The features may be formed, for example, in some embodiments, by etching away or otherwise removing the material from which the surface is made. In other embodiments, the features may be added to the surface (e.g., by depositing the features on the interior surface of the needle and / or chamber). The features may be made from the same or different material from which the interior surface is made. In some embodiments, the features may be dispersed on the interior surface in a random (e.g., fractal) or patterned manner.

[0056] According to some embodiments, the maximum height of the millimeter-scale features is greater than 100 micrometers up to 1 millimeter, greater than 100 micrometers up to 200 micrometers, 200 micrometers to 300 micrometers, 300 micrometers to 500 micrometers, 500 micrometers to 700 micrometers, 700 micrometers to 1 millimeter, 1 millimeter to 3 millimeters, 3 millimeters to 5 millimeters, and / or 5 millimeters to 10 millimeters. Combinations of the above-cited ranges (e.g., 300 micrometers to 700 micrometers or 200 micrometers to 1 millimeter) are also possible.

[0057] According to some embodiments, the maximum height of the microscale features is between 1 micrometer and 10 micrometers, between 10 micrometers and 20 micrometers, between 20 micrometers and 30 micrometers, between 30 micrometers and 50 micrometers, between 50 micrometers and 70 micrometers, or between 70 micrometers and 100 micrometers. Combinations of the above-cited ranges (e.g., between 30 micrometers and 70 micrometers or between 20 micrometers and 100 micrometers) are also possible.

[0058] According to some embodiments, the maximum height of the nanoscale features is between 1 nm and 100 nm, between 100 nm and 200 nm, between 200 nm and 300 nm, between 300 nm and 500 nm, between 500 nm and 700 nm, or between 700 nm and 1 micrometer. Combinations of the above-cited ranges (e.g., between 300 nm and 700 nm or between 200 nm and 1 micrometer) are also possible.

[0059] According to certain embodiments, features (e.g., millimeter-scale features, microscale features, and / or nanoscale features) are distributed across the interior surface and / or chamber of the needle and / or chamber such that the features occupy a particular solid fraction of the interior surface. The term "solid fraction" (φ) refers to the fraction of solids occupied by multiple features on a surface. s As used herein, solid fraction (also referred to as solid area) refers to the area fraction of a surface occupied by a feature. Solid fraction can be calculated by dividing the sum of the areas that features occupy on an interior surface by the geometric surface area of ​​the interior surface over which they are distributed. For example, with reference to FIGS. 12A-12B, an interior surface portion 1400 (e.g., a portion of the interior surface of a needle) comprises a plurality of features 1406. The features 1406 in FIGS. 12A-12B are squares with side length a, and therefore each has a 2 The remaining area of ​​the interior surface is not occupied by features. In the set of embodiments illustrated in Figures 12A-12B, the features 1406 each have the same side length a and the same nearest neighbor spacing b. Therefore, the surface solid fraction (φ) occupied by the features in Figures 12A-12B is s ) would be calculated as follows:

number

[0060] In certain embodiments, the interior surface of the needle comprises a texture having a solids fraction (φs) therethrough of less than or equal to 0.5, hi some embodiments, the interior surface of the needle comprises a texture having a solids fraction (φs) therethrough of less than or equal to 0.25, or less than or equal to 0.1.

[0061] In some embodiments, the interior surface of the chamber is defined by a solid fraction (φ s In some embodiments, the interior surface of the needle comprises a texture having a solid fraction (φ) therethrough of less than or equal to 0.5. s) is less than or equal to 0.25 or less than or equal to 0.1.

[0062] In certain embodiments, a third fluid (in addition to the inner and outer fluids) can be impregnated between features on the interior surface of the needle and / or chamber. The third fluid, in some embodiments, can be stably contained between features such that the third fluid remains contained between the features while the inner and outer fluids are transported through the needle (and / or chamber). The third fluid can be stably contained between features, for example, by spacing the features sufficiently closely together so that the third liquid is stably contained between the features (e.g., via surface tension). In certain embodiments, the third fluid is contained between the features but does not coat the top of the features. In some embodiments, the properties of the third fluid can be tailored to control the wettability of the interior surface of the needle and / or chamber.

[0063] According to some embodiments, for a given inner fluid, outer fluid, and textured surface inside the needle and / or chamber, the diffusion coefficient (S on(i) ) is greater than or equal to 0. In some embodiments, the texture confers wettability across at least one fluid (e.g., outer fluid) when a droplet of that fluid is present on the interior surface of a needle in another fluid (e.g., inner fluid). That is, in some cases, at least one fluid (e.g., outer fluid) is wetted when the texture is present, but would not be wetted in the same system without the texture.

[0064] According to certain embodiments, the interior surface of the needle comprises a coating. For example, in some embodiments, the interior surface of the needle comprises a conformal smooth coating with limited discontinuities. In some embodiments, the conformal smooth coating with limited discontinuities is 1 m 2 10 per 8 Less than or equal to 10 6 Less than or equal to or 104 The coating is considered conformal if 90% of the facial area of ​​the coating is within 20% of the average thickness of the coating. According to some embodiments, the diffusion coefficient (S on(i) ) is greater than or equal to 0. In some embodiments, the coating confers wettability across at least one fluid (e.g., outer fluid) when a droplet of that fluid is present on the interior surface of the needle in the other fluid (e.g., inner fluid). That is, in some cases, at least one fluid (e.g., outer fluid) is wetted when the texture is present, but would not be wetted in the same system without the texture.

[0065] According to certain embodiments, the needle can have any of a variety of lengths. Some of the embodiments described herein can be used to achieve stable core-sheath flow within needles with relatively long lengths. According to certain embodiments, the needle has a length greater than or equal to 5 microns, greater than or equal to 10 microns, greater than or equal to 25 microns, greater than or equal to 50 microns, greater than or equal to 100 microns, greater than or equal to 1 mm, greater than or equal to 5 mm, greater than or equal to 10 mm, or greater than or equal to 100 mm. According to some embodiments, the needle has a length less than or equal to 250 mm, less than or equal to 100 mm, less than or equal to 50 mm, less than or equal to 10 mm, less than or equal to 5 mm, less than or equal to 1 mm, less than or equal to 500 microns, less than or equal to 100 microns, less than or equal to 50 microns, or less than or equal to 25 microns. Combinations of these ranges (e.g., 5 microns to 5 mm or 5 mm to 10 mm) are also possible.

[0066] It should be understood that the use of relatively long needles is not required, and that in other embodiments the needles are relatively short, for example, in some embodiments the needles have a length of less than 5 mm, less than or equal to 1 mm, less than or equal to 500 microns, or less than or equal to 100 microns.

[0067] In some embodiments, the needle is thin. For example, in some cases, the needle has an inner diameter of greater than or equal to 5 microns, greater than or equal to 10 microns, greater than or equal to 25 microns, greater than or equal to 50 microns, greater than or equal to 100 microns, greater than or equal to 250 microns, greater than or equal to 500 microns, or greater than or equal to 750 microns. In some embodiments, the needle has an inner diameter of less than or equal to 1 mm, less than or equal to 750 microns, less than or equal to 500 microns, less than or equal to 310 microns, less than or equal to 250 microns, less than or equal to 100 microns, less than or equal to 50 microns, less than or equal to 25 microns, or less than or equal to 10 microns. Combinations of these ranges (e.g., greater than or equal to 5 microns and less than or equal to 1 mm, or greater than or equal to 10 microns and less than or equal to 310 microns) are also possible.

[0068] Methods are also described herein. In some embodiments, the methods include initiating flow of at least a portion (e.g., at least 50%, at least 75%, at least 90%, or all) of an internal fluid within an article described herein (e.g., an internal fluid described herein). According to some embodiments, at least a portion (e.g., at least 50%, at least 75%, at least 90%, or all) of the internal fluid is transported from the chamber to the needle. In certain embodiments, at least a portion (e.g., at least 50%, at least 75%, at least 90%, or all) of the internal fluid is expelled from the needle. For example, in some embodiments, at least a portion of internal fluid 103 of FIG. 1A is transported from chamber 101 to needle 102 and expelled from needle 102.

[0069] In some embodiments, the method includes initiating flow of at least a portion (e.g., at least 50%, at least 75%, at least 90%, or all) of an outer fluid (e.g., an outer fluid described herein) within an article described herein. According to some embodiments, at least a portion (e.g., at least 50%, at least 75%, at least 90%, or all) of the outer fluid is transported from the chamber to the needle. In some embodiments, at least a portion (e.g., at least 50%, at least 75%, at least 90%, or all) of the outer fluid is expelled from the needle. For example, in some embodiments, at least a portion of outer fluid 104 of FIG. 1A is transported from chamber 101 to needle 102 and expelled from needle 102.

[0070] In some embodiments, it is beneficial to eject a smaller amount of outer fluid compared to the amount of inner fluid ejected (e.g., so that the patient is not exposed to a large amount of lubricating fluid). According to certain embodiments, the ratio (Φ) (volume fraction) of the volume of inner fluid ejected from the needle to the total volume (e.g., inner and outer fluid) ejected from the needle is greater than or equal to 0.5, greater than or equal to 0.6, greater than or equal to 0.7, greater than or equal to 0.8, or greater than or equal to 0.9. The volume fraction (Φ) can also be expressed as:

number

[0071] According to some embodiments, when the inner fluid has a certain capillary number and the outer fluid has a certain capillary number, axially lubricated flow can be observed, whereas otherwise, viscosity shifts can be observed. For example, Figure 11 plots the capillary number of the inner fluid versus the capillary number of the outer fluid, according to certain embodiments, showing systems that exhibited axially lubricated flow and systems that exhibited viscosity shifts.

[0072] According to certain embodiments, the capillary number of the inner fluid is greater than or equal to 0.01, greater than or equal to 0.1, greater than or equal to 1, greater than or equal to 10, greater than or equal to 20, or greater than or equal to 25. In some embodiments, the capillary number of the inner fluid is less than or equal to 30, less than or equal to 25, less than or equal to 10, less than or equal to 1, or less than or equal to 0.1. Combinations of these ranges (e.g., greater than or equal to 0.01 to less than or equal to 30) are also possible.

[0073] In some embodiments, the capillary number of the outer fluid is greater than or equal to 0.001, greater than or equal to 0.01, greater than or equal to 0.1, greater than or equal to 1, greater than or equal to 10, or greater than or equal to 20. In certain embodiments, the capillary number of the outer fluid is less than or equal to 25, less than or equal to 10, less than or equal to 1, less than or equal to 0.1, or less than or equal to 0.01. Combinations of these ranges (e.g., 0.001 to 25) are also possible. In some embodiments, the capillary number of the inner fluid is greater than the capillary number of the outer fluid. The capillary number of a fluid is expressed as:

number

[0074] In some embodiments, the orientation of the system (e.g., needle and / or chamber) affects the timescale of eccentricity. For example, FIG. 8B shows that, according to one embodiment, T is less than or equal to 1. c / t e demonstrates that this is easier to achieve with systems (e.g., needles and / or chambers) that are closer to vertical (90° from a line perpendicular to gravity) and more difficult to achieve with systems that are closer to horizontal (0° from a line perpendicular to gravity).

[0075] According to some embodiments, the longitudinal axis of the needle is within 45 degrees of a line perpendicular to gravity for at least one time period. For example, in some cases, the longitudinal axis of the needle is within 30 degrees, 15 degrees, or 0 degrees of a line perpendicular to gravity for at least one time period. In some embodiments, the time period is between initiating flow of the inner and / or outer fluid and ejecting the inner and / or outer fluid from the needle. For example, in some cases, the time period is at least a portion (e.g., at least 50%, at least 75%, at least 90%, or the entirety) of the time between initiating flow and ejection from the needle.

[0076] As discussed above, in some embodiments, it is beneficial for a smaller amount of outer fluid to be expelled compared to the amount of inner fluid expelled (e.g., so that the patient is not exposed to large amounts of lubricating fluid). In certain embodiments, the volumetric flow rate of the inner fluid is greater than the volumetric flow rate of the outer fluid. According to some embodiments, the volumetric flow rate of the inner fluid is ≥ 10 -2 ×γπd n 2 / μ i For example, in some cases, the volumetric flow rate of the inner fluid is ≥ 5 × 10 -2 ×γπd n 2 / μ i or ≥ 10 -1 ×γπd n 2 / μ i According to one embodiment, the volumetric flow rate of the outer fluid is ≥ 10 -3 ×γπd n 2 / μ O For example, in some cases, the volumetric flow rate of the outer fluid is ≥ 10 -3 ×γπd n 2 / μ O In terms of volumetric flow rate, d n is the diameter of the needle, γ (gamma) is the surface tension of the two fluids, and μ is the dynamic viscosity of the fluids (where i refers to the inner fluid and o refers to the outer fluid).

[0077] In some embodiments, the concentration of solubilized or suspended species (e.g., drug) in the inner fluid can be significantly higher than in the same article, system, and / or method without the outer fluid axially surrounding the inner fluid. For example, in some cases, the ratio of the concentration of solubilized or suspended species (e.g., drug) in an inner fluid according to an embodiment disclosed herein compared to the same article, system, and / or method without the outer fluid axially surrounding the inner fluid is greater than or equal to 1.1:1, greater than or equal to 1.5:1, greater than or equal to 2:1, greater than or equal to 5:1, greater than or equal to 10:1, greater than or equal to 50:1, greater than or equal to 100:1, or greater than or equal to 250:1. In some embodiments, the ratio of the concentration of solubilized or suspended species (e.g., drug) in an inner fluid according to an embodiment disclosed herein compared to the same article, system, and / or method without an outer fluid axially surrounding the inner fluid is less than or equal to 500:1, less than or equal to 250:1, less than or equal to 100:1, less than or equal to 50:1, less than or equal to 10:1, less than or equal to 5:1, or less than or equal to 2:1. Combinations of these ranges (e.g., 1.1:1 to 500:1) are also possible.

[0078] In some embodiments, the articles, systems, and / or methods disclosed herein have reduced pressure during injection compared to the same article, system, and / or method without an outer fluid axially surrounding the inner fluid. For example, in some cases, the ratio during injection compared to that of the same article, system, and / or method without an outer fluid axially surrounding the inner fluid is less than or equal to 0.9:1, less than or equal to 0.7:1, less than or equal to 0.5:1, less than or equal to 0.3:1, less than or equal to 0.1:1, or less than or equal to 0.01:1. In some embodiments, the ratio of pressure during injection compared to the same article, system, and / or method without an outer fluid axially surrounding the inner fluid is greater than or equal to 0.001:1, greater than or equal to 0.01:1, or greater than or equal to 0.1:1. Combinations of these ranges (eg, 0.001:1 to 0.9:1 or 0.1:1 to 0.3:1) are also possible.

[0079] Certain embodiments disclosed herein may provide one or more of several advantages, including reduced contamination, reduced needle blockage, reduced protein inactivation (e.g., when the internal fluid contains proteins), increased concentration of the formulation (e.g., the internal fluid may be a highly concentrated drug formulation), increased viscosity of the fluid, increased feasibility of subcutaneous administration (as opposed to intravenous administration), smaller needles, shorter injection times, reduced pain, smaller dosages, reduced hydrodynamic resistance within the needle, reduced shear forces on the internal fluid, and / or reduced pressure. Examples of benefits that may result from subcutaneous administration (which often requires higher concentrations) as opposed to intravenous administration include, in some embodiments, increased feasibility of self-administration, reduced hospitalization, reduced treatment costs, and / or increased patient compliance.

[0080] In some embodiments, the systems described herein can inject viscous fluids without the use of larger needle gauges or long injection times, which can cause pain. Also, in certain embodiments, the systems described herein can inject highly concentrated formulations without the use of syringe pumps, which can cause pain and require a hospital environment. Additionally, according to some embodiments, the systems described herein can inject viscous fluids without the use of needleless jet injectors, which frequently result in contamination and high costs. Furthermore, according to certain embodiments, the systems described herein can inject viscous fluids without particle encapsulation, which frequently result in protein inactivation, density-based separation, needle clogging, and higher manufacturing complexity. The lack of a practical methodology for injecting highly viscous formulations not only limits the availability of subcutaneous biologics but also hinders the development of new formulations, as developers are forced to design formulations with lower viscosities. Therefore, there remains a compelling need to achieve injectability through simple and inexpensive injection techniques with minimal additions to the pharmaceutical manufacturing process and no risk of cross-contamination.

[0081] The following examples are intended to illustrate certain embodiments of the present invention, but do not exemplify the full scope of the invention. [Example]

[0082] Highly concentrated biological drug formulations that can be delivered via subcutaneous injection offer tremendous benefits to global health, but they generally cannot be injected through commercially available syringes and needles due to their high viscosity. Current approaches to solving this problem face several challenges, ranging from cross-contamination and high cost to needle blockage and protein inactivation. Discussed herein is a simple method for improving injectability using axially lubricated flow, in which coaxial lubrication with a lower viscosity fluid makes transport of highly viscous drugs through needles easier. A phase diagram was established to minimize the lubricant volume fraction while obtaining axially lubricated flow. This technique resulted in up to a sevenfold reduction in injection pressure for the highest viscosity ratio tested. Finally, these findings were implemented in the design and fabrication of a dual-barreled syringe that significantly extends the range of injectable concentrations of several biological agents.

[0083] Biologics are primarily administered via intravenous infusion at low concentrations (<30 mg / ml), with dosages ranging from 5 to 700 milligrams. However, over the past few years, subcutaneous injection has emerged as an alternative delivery route because it (i) enables self-administration, (ii) reduces hospitalization and treatment costs, and (iii) increases patient compliance. Unlike intravenous infusion, subcutaneous injection generally requires much more concentrated (>100 mg / ml) formulations because injection volumes are limited to 1–1.5 ml per dose. This limitation is due to the high backpressure that can develop within the subcutaneous tissue at larger volumes. The nonlinear relationship between formulation concentration and viscosity makes subcutaneous formulations very viscous and therefore more difficult to inject, as illustrated in Figure 2A. Highly viscous fluids (top) wick significantly less than low-viscosity fluids (bottom) when injected intracavernously at the maximum force that can be applied manually (approximately 50 N). As a result, the force that can be applied sets a limit to the concentration of this formulation (Figure 2B). Figure 2B shows the injection force (for a flow rate of 4 ml / min through a 27 G needle) as a function of concentration for 11 monoclonal antibody solutions of the IgG1 isotype. This figure highlights the fact that a wide range of formulation concentrations requires a force of 50 N to be injected, exceeding the average maximum force that can be applied in a pinch motion. [Example]

[0084] Discussed herein is a technique for improving the injectability of highly concentrated drug formulations using axially lubricated flow. In this technique, a low-viscosity fluid axially lubricated the transport of an immiscible, viscous drug through a needle (FIG. 2C). This not only reduced the hydrodynamic resistance within the needle, but also reduced the shear force on the payload material (inner fluid).

[0085] The goal of this technology was to develop a device that uses axially lubricated flow to more easily inject viscous formulations. To achieve this, the observable flow regime within the device was reported, and a regime map was established to show the flow rates and viscosity ratios that axially lubricated flow was achievable within the needle. Finally, a coaxial, double-barreled syringe was designed, fabricated, and tested to demonstrate the capability of this technique for injecting highly concentrated drugs. result

[0086] The setup shown in Figure 3A was used to investigate the dynamics of axially lubricated flow through a needle. Two syringe pumps were used to drive the inner viscous fluid and the outer lubricating fluid through the fluid intersection to establish axially lubricated flow. A digital pressure sensor at the intersection measured the pressure drop through the needle. A transparent needle was used to visualize the flow rate, and the dimensions of all components were chosen so that their hydrodynamic resistance was negligible compared to that of the needle.

[0087] Due to the volumetric and dosage constraints of subcutaneous biologic injections mentioned above, volume fractions (of the viscous payload) below 55% were not considered. Therefore, the viscous fluid flow rate was fixed at 1 ml / min, and the lubricant flow rate was varied from 0.1 to 0.8 ml / min. These flow rates were selected to be within the range of flow rates that would be required for practical injections. Figure 3B shows a map of the flow regimes observed for different flow rates and viscosity ratios. Two regimes emerged in phase space: a viscosity displacement regime at low external fluid flow rates and an axially lubricated flow regime as the lubricant flow rate increased. In the viscosity displacement regime, the viscous fluid initially filled the entire cross section of the needle, forcing both fluids to flow back into the lubricant inlet. However, this backflow could not be sustained due to the constant mass flux imposed on the lubricant, resulting in a sudden overflow of the lubricant into the needle. The flow then decreased until it was again completely blocked, and the process repeated. This cyclic behavior was shown in the time diagram of the needle cross section (Figure 3C), which led to unstable and significantly worse lubrication compared to the axially lubricated flow regime (Figure 3D).

[0088] Figure 4A reports the experimental pressure reduction coefficient (mean ± standard error) as a function of the ratio between the lubricant flow rate and the viscous fluid flow rate for different viscosity ratios. o / Q i Experiments corresponding to (Q ≦0.2) exhibited larger errors due to the periodic nature of the regime. Therefore, the mean pressure reduction coefficient in this regime is significantly higher than that in the axially lubricated flow regime (Q o / Q i >0.2), which was much lower than that in the

[0089] A system with buoyancy-induced eccentricity was investigated, as shown in Figure 4B, a digital photograph of a side view of the needle. Experimental measurements of the pressure reduction coefficient are shown in Figure 4A. While pressure reduction was still observed, a significant difference in the magnitude of the pressure reduction coefficient was observed compared to the concentric system. This lower performance resulted from eccentricity caused by density differences between the two phases. Consideration

[0090] To implement this knowledge into a practical device, a dual-barreled syringe, shown in Figures 5A-5B, was designed and fabricated. The dual-barreled syringe included an outer barrel containing a lubricant and an inner barrel holding a viscous payload. A 6 milliliter syringe barrel was used as the outer barrel. Fluid was driven by corresponding outer and inner plungers with a movable outer gasket that facilitated leak-tight operation. The barrel dimensions were selected to provide a ratio of lubricant flow rate to viscous fluid flow rate of approximately 0.59, significantly above the threshold of 0.2 observed to be required to sustain axial lubricated flow during plunger displacement. The simplicity of this design made it easy to manufacture, as it could be fabricated using injection molding or blow-fill-seal processes, facilitating ease of use and cost similar to commercially available medical syringes and needles. FIG. 6A shows axially lubricated flow established in a needle connected to a double-barreled syringe, demonstrating that this indeed operated within the axially lubricated flow regime.

[0091] Visual evidence of improved manual injectability is shown in Figure 5C, which demonstrates better liquid wicking within the sponge cavern when a high-viscosity fluid was injected using the dual-barreled syringe (top) compared to the commercial syringe (bottom). To quantify this improvement, the force required to inject a water / glycerin solution (26.3 cP) using the dual-barreled syringe and the commercial syringe over the same volumetric flow rate was compared. Injection force was quantified using a load cell mounted on the syringe pump (Figure 6B). The measured force was calculated using the force reduction factor η DBS and η needle was used to calculate, which is defined as follows:

number

[0092] Figure 5D shows the experimental force reduction coefficient obtained with the present dual-barreled syringe. Both the comparator and the dual-barreled syringe were run with and without a needle to quantify the resistance of the barrels. The present proof-of-concept design suffered from significant friction between the barrel and plunger, η DBS This resulted in low values ​​for . However, this friction can be largely eliminated by using existing syringe manufacturing techniques (such as injection molding to create a more properly sized gasket). The greater variability observed for the needle was due to the error propagation operation performed to isolate only the needle resistance. After the barrel contribution was removed, a force reduction factor of 5 at the needle was observed.

[0093] Such significant force reduction factors demonstrated the promise of this technique for increasing the threshold concentration of biological drugs. To further emphasize this, Figure 5E shows the increase in concentration that was possible for 11 monoclonal antibody solutions reported in the literature while maintaining the nominal injection force of 25 N. This revealed that using this dual-barreled syringe, it was possible to double (formulation 6) and even triple (formulation 3) the injectable concentration for one monoclonal antibody formulation. Finally, considering the maximum force (50 N) that can be applied in a pinch motion, Figure 5F demonstrates that the regime of manually injectable formulations can be significantly expanded by using a dual-barreled syringe. Furthermore, the reduction in force for lower-concentration formulations may facilitate more rapid injections or the use of smaller needles, resulting in less pain for the patient.

[0094] It was discovered that the relative wettability of the inner and outer fluids to the chamber and / or the inner surface of the needle is important. In fact, if the inner fluid preferentially wets the inner needle surface, the outer lubricant flow will fail, leading to unstable axially lubricated flow and therefore a tremendous loss of pressure reduction. This, combined with its biocompatibility, led to HFE-7500 being selected as the lubricant for further experiments because HFE 7500 wetted toward the needle more than the adhesive water-soluble payload. This is shown in Figure 7, where HFE 7500 was observed to completely wet on PTFE in the presence of glycerin (a model adhesive payload). While not wishing to be bound by any particular theory or mode of operation, it is believed that this preferred wetting may be the reason why flow was not completely eccentric in these experiments (E = 0.98). Other biocompatible oils, such as squalene, which have been shown to promote adjuvant activity, resulting in a more rapid immune response to injection, may also be used as lubricants.

[0095] The advantages observed in axially lubricated flow-based injection techniques can be similarly extended to other subcutaneous delivery methods. For example, microneedle patches can be made with smaller needles or used for shorter time periods if the resistance to flow is reduced using axially lubricated flow. This methodology also holds substantial promise for applications beyond biopharmaceuticals. For example, the lubricating effect of axially lubricated flow can be extended to other high-viscosity or non-Newtonian fluids that need to be injected, such as bone putty or hydrogels. The reduced shear in such flow rates can also be applied to handle and dispense sensitive or primary cells, where low shear is essential to prevent damage.

[0096] Demonstrated here is a simple yet effective technique for improving the injectability of high-concentration biopharmaceuticals using axially lubricated flow. A regime map of flow rate and viscosity ratio required to achieve stable axially lubricated flow while minimizing lubricant flow rate was established. Significant pressure reduction was achieved in axially lubricated flow across a range of payload viscosities. Experimentally, [ka] Up to a 7-fold reduction in pressure over λ = 26 was achieved. In addition, the role of buoyancy-based eccentricity was explored. Finally, the knowledge was applied to design, fabricate, and test a prototype dual-barreled syringe. Substantial pressure reduction in this syringe, i.e., up to a 5-fold reduction over λ = 26, was demonstrated, thus significantly extending the injectable viscosity regime for biologics without increasing cost, cross-contamination risk, or manufacturing complexity.

[0097] method Fluid preparation and characterization Fluid preparation Glycerin and water mixtures of different viscosities were used as the inner fluid in all experiments. HFE-7500 + 2 wt% fluorosurfactant (RAN Biotechnologies) was used as the lubricant (outer fluid).

[0098] Rheology A TI ARG-2 rheometer was used to measure the viscosity of all samples. A 40 mm 2° cone geometry was used to measure the viscosity of all glycerin solutions. A step flow test was performed, where the shear rate was 10 s -1 500 seconds from -1 A 60 mm plate geometry was used to measure the viscosity of HFE 7500, where the shear rate was varied from 1 s -1 100 seconds from -1 It was fluctuated up to.

[0099] interfacial tension Interfacial tension measurements were performed using a Rame'-Hart contact angle goniometer. The pendant drop method was used to measure interfacial tension, where a glycerin drop was suspended in a bath of HFE 7500 + 2 wt% fluorosurfactant.

[0100] Experimental setup Pressure reduction measurement PHD ULTRA manufactured by Harvard apparatus TM A syringe pump was used to drive the fluid. A fluid intersection with a 1 / 8" NPT female fitting was used to establish axially lubricated flow. Specifically, the high viscosity fluid flowed through a 1 / 16" OD tubing that entered through the entire intersection and a Luer adapter before entering the needle hub. Lubricant was introduced through one of the branches within the intersection and allowed to exit the needle coaxially with the inner viscous fluid. A 2" long PTFE needle with an ID of 304.8 μm was used in all experiments. The final branch of the intersection was fitted with a Honeywell (R) The pressure sensor housed a Keithley 26PC series pressure sensor. The sensor was connected to a DC power supply and its output was measured using a voltmeter. (R) Measured using a 2450 SourceMeter.

[0101] Testing double-barreled syringes An Omega Engineering LC 307 series load cell was used to measure the force on the plunger. The load cell was attached to the drive plate of the syringe pump, and a 3D-printed adapter was used so that the plunger only contacted the load cell during operation.

[0102] While several embodiments of the present invention have been described and illustrated herein, those skilled in the art will readily envision various other means and / or structures for performing the functions and / or obtaining one or more of the results and / or advantages described herein, and each such variation and / or modification is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are intended to be exemplary, and that the actual parameters, dimensions, materials, and / or configurations will depend on the specific application or applications for which the teachings of the present invention are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Accordingly, it is to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and their equivalents, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, and / or methods is included within the scope of the present invention, if such features, systems, articles, materials, and / or methods are not mutually inconsistent.

[0103] The indefinite articles "a" and "an," as used herein in the specification and claims, unless expressly indicated otherwise, should be understood to mean "at least one."

[0104] The phrase "and / or," as used herein in the specification and claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements present conjunctively in some cases and disjunctively in other cases. Other elements other than the elements specifically identified by the "and / or" clause, whether related or unrelated to those elements specifically identified, may optionally be present, unless clearly indicated otherwise. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0105] As used herein in the specification and claims, "or" shall be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" shall be construed as inclusive, i.e., the inclusion of at least one, but more than one, of several elements or lists of elements, optionally including additional unlisted items. Only terms clearly indicated to the contrary, such as "only one of" or "exactly one of," or, when used in the claims, "consisting of," will refer to the inclusion of exactly one element of several elements or lists of elements. In general, the term "or" as used herein shall be construed as indicating only exclusive alternatives (i.e., "one or the other, but not both") when preceded by terms of exclusivity, such as "either," "one of," "only one of," or "exactly one of." When used in the claims, "consisting essentially of" shall have its ordinary meaning as used in the field of patent law.

[0106] As used herein in the specification and claims, the phrase "at least one" in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically recited within the list of elements, and not excluding any combinations of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements. Thus, as a non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently, "at least one of A and / or B") can refer in one embodiment to at least one A, optionally including more than one A, with no B present (optionally including elements other than B); in another embodiment to at least one B, optionally including more than one B, with no A present (optionally including elements other than A); in yet another embodiment to at least one A, optionally including more than one A, and at least one B (optionally including other elements), optionally including more than one B, etc.

[0107] In the claims, as well as in the above specification, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding," and the like, are to be understood to be open-ended, i.e., meaning "including, but not limited to." Only the transitional phrases "consisting of" and "consisting essentially of" shall be closed or semi-closed transitional phrases, respectively, as set forth in the U.S. Patent Office Manual of Patent Examining Procedures, Section 2111.03.

Claims

[Claim 1] The invention described in this specification.

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