Abstract:
Core annular flow is used to enable the subcutaneous delivery of a viscous fluid such as a protein therapeutic formulation. The high-viscosity fluid is surrounded by a low-viscosity fluid, and the low-viscosity fluid lubricates the passage of the high-viscosity fluid. This allows the use of protein formulations that have a higher concentration and a higher viscosity at comparatively reduced injection forces and reduced injection times. Several different embodiments of injection devices that provide core annular flow are described herein.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims priority to U.S. Provisional Patent Application Ser. No. 61/556,491, filed on Nov. 7, 2011, and to U.S. Provisional Patent Application Ser. No. 61/673,864, filed on Jul. 20, 2012. The entireties of those disclosures are fully incorporated by reference herein. 
     
    
     BACKGROUND 
       [0002]    The present disclosure relates to injection devices, compositions and processes for delivering viscous fluids, such as pharmaceutical protein formulations, to a patient using core annular flow. This reduces the injection force needed to deliver the fluid, and can reduce the amount of fluid without changing the amount of delivered therapy. 
         [0003]    Protein therapeutics is an emerging class of drug therapy that promises to provide treatment for a broad range of diseases, such as autoimmune disorders, cardiovascular diseases, and cancer. The dominant delivery method for protein therapeutics, particularly monoclonal antibodies, is through intravenous infusion, in which large volumes of dilute solutions are delivered over time. Intravenous infusion usually requires the supervision of a doctor or nurse and is performed in a clinical setting. This can be inconvenient for a patient, and so efforts are being made to permit the delivery of protein therapeutics at home. Desirably, a protein therapeutic formulation can be administered using a syringe for subcutaneous delivery instead of requiring intravenous administration. Subcutaneous injections are commonly administered by laypersons, for example in the administration of insulin by diabetics. 
         [0004]    Transitioning therapeutic protein formulations from intravenous delivery to injection devices like syringes requires addressing challenges associated with delivering high concentrations of high molecular weight molecules in a manner that is easy, reliable, and causes minimal pain to the patient. In this regard, while intravenous bags typically have a volume of 1 liter, the standard volume for a syringe ranges from 0.3 milliliters up to 25 milliliters. Thus, depending on the drug, to deliver the same amount of therapeutic proteins, the concentration may have to increase by a factor of 40 or more. Also, injection therapy is moving towards smaller needle diameters and faster delivery times for purposes of patient comfort and compliance. 
         [0005]    Delivery of protein therapeutics by injection is also complicated by the high molecular weight of such proteins. The high molecular weight results in a high viscosity for the therapeutic formulation. For example, many monoclonal antibody formulations would be delivered in concentrations greater than 150 mg/mL when injection is used, and this results in the formulation having an absolute viscosity exceeding 5 centipoise (cP). The dosages required for some therapeutic proteins can necessitate a protein concentration in the range of 150 to 500 mg/mL or higher. These concentrations can have absolute viscosities exceeding 50 cP, making them unsuitable for delivery by conventional injection devices. 
         [0006]    Some methods have been considered to improve protein delivery via injection. For example, U.S. Pat. No. 7,666,413 describes a method of reducing the viscosity of high concentration protein formulations by adding a salt that increases the ionic strength of the formulation, thereby decreasing self-association between protein molecules. However, this method only extends the usable concentration range of the formulation to about 100 mg/mL, at which point the viscosity still exceeds 20 cP. Estimates of the injection force required to inject a 20 cP formulation through a common 27 gauge needle with a syringe in 10 to 20 seconds is approximately 40 N or 20 N, respectively, which is higher than suitable for most injection devices. Furthermore, higher concentration protein formulations are unstable and will aggregate over time, losing their activity. 
         [0007]    PCT Publication No. WO2010/056657 discloses the use of protein suspensions to achieve low viscosity, high concentration protein formulations of up to 200 mg/mL. An insoluble protein particle is suspended in a non-solvent; depending on the non-solvent, viscosity as low as 3 cP is claimed. However, this approach requires identifying a non-solvent that is safe for injection and does not cause pain. In addition, the stability of the protein in contact with the non-solvent is not demonstrated. 
         [0008]    The interior of the syringe barrel and the exterior of the plunger are commonly lubricated with silicone oil (in a layer having a thickness of approximately 100 nanometers) to reduce the friction at the interface of the two parts. This approach may reduce the gliding force and/or injection force associated with boundary layer fluid flow within the barrel. In addition, the silicone oil can migrate from the barrel surface into the solution being injected, which could adversely influence the stability and activity of the protein in the protein therapeutic formulation. Other coating technologies have been developed more recently, such as TriboGlide®, from Tribo Film Research, Inc. and IVEK Corporation, which provides more effective friction reduction. The major pressure source however is fluid flow through the needle, and these lubricants do not address that issue. Thus, substantial force is still required to inject high-viscosity solutions. 
         [0009]    It would be desirable to provide processes and devices by which a high-viscosity fluid could be administered through a conventional syringe with reduced injection force in a reasonable injection time. These could be used to deliver high-concentration protein, or other high viscosity pharmaceutical formulations. 
       BRIEF DESCRIPTION 
       [0010]    Devices, compositions, and processes to enable subcutaneous delivery of viscous fluids with reduced injection force using available volumes and injection times are described herein. Briefly, core annular flow is used to deliver such viscous fluids. Highly viscous fluid is located in the “core” and is lubricated by a lower viscosity fluid which forms an annulus around the highly viscous fluid. This significantly reduces the amount of force required for injection, and can enable the use of current injection technologies for the delivery of highly viscous fluids as well as enabling the development of new delivery strategies. The injection devices described herein can be used to deliver a high-viscosity fluid to a patient. 
         [0011]    Disclosed in some embodiments is an injection device for delivering a high-viscosity fluid, comprising: a barrel and a plunger operating within the barrel. The barrel has an interior space for containing the high-viscosity fluid to be, dispensed by the injection device, the interior space being formed by a sidewall. The barrel also has an open end and a closed plunger end, and the open end includes a nozzle having a constriction point and an orifice. The barrel also includes an inner concentric wall within the sidewall, an opening being positioned between a bottom edge of the inner concentric wall and the nozzle. The inner concentric wall defines an inner compartment having the high-viscosity fluid and an outer compartment having a low-viscosity fluid within the barrel. The inner concentric wall has one or more openings permitting fluid communication between the inner and outer compartments. The plunger is adapted to provide a depressing force substantially concurrently to a high-viscosity fluid within the inner compartment and a low-viscosity fluid within the outer compartment, thereby producing an annulus of the low-viscosity fluid around a core of the high-viscosity fluid as the fluids are dispensed from the orifice. 
         [0012]    The ratio of the viscosity of the high-viscosity fluid to the viscosity of the low-viscosity fluid may be from about 60 to about 200. In other embodiments, the ratio of a cross-sectional area of the inner compartment to a cross-sectional area of the outer compartment is from about 2:1 to about 9:1. Sometimes, the nozzle tapers from the constriction point to the orifice. 
         [0013]    The injection device may further comprise a means for sealing located at the constriction point which ruptures when the plunger is depressed. The means for sealing may be located across only the inner concentric wall. 
         [0014]    In some embodiments, a valve mechanism is located at the bottom edge of the inner concentric wall. In other embodiments, the inner concentric wall includes a lower wall that tapers to form an aperture, and a means for sealing is located at the aperture. The injection device can sometimes further comprise a wire extending longitudinally at the aperture. The injection device may also further comprise grooves at the open end of the barrel. 
         [0015]    Disclosed in other embodiments is an injection device for delivering a high-viscosity fluid, comprising a barrel having an interior space formed from a sidewall, an open end, and a closed plunger end. The open end has an orifice. The barrel also has a rupturable sealing membrane that separates the interior space of the barrel into an upper compartment and a lower compartment. The high-viscosity fluid is located in the upper compartment, and a low-viscosity fluid is located in the lower compartment. A plunger can move within the barrel. Depressing the plunger produces an annulus of the low-viscosity fluid around a core of the high-viscosity fluid as the fluids are dispensed from the orifice. 
         [0016]    Disclosed in other embodiments is an injection device for delivering a high-viscosity fluid, comprising a barrel having an interior space formed from a sidewall, an open end, and a closed plunger end. The open end has an orifice. The barrel also has a radial wall that separates the interior space of the barrel into an upper compartment and a lower compartment. The radial wall includes an aperture aligned with the orifice in the open end of the barrel, the aperture being sealed with a sealing means. The high-viscosity fluid is located in the upper compartment, and a low-viscosity fluid is located in the lower compartment. A plunger can move within the barrel. Depressing the plunger produces a pressure which pushes the high-viscosity fluid through the aperture and produces an annulus of the low-viscosity fluid around a core of the high-viscosity fluid as the fluids are dispensed from the orifice. 
         [0017]    The injection device may further comprise grooves at the open end of the barrel to promote core annular flow. 
         [0018]    In yet other embodiments disclosed herein, an injection device for delivering a high-viscosity fluid is described that comprises: a barrel and a plunger, having an open end and a closed end; and a plunger operating within the barrel. The barrel has an interior space formed from a sidewall, an open end, and a closed plunger end. The open end has an orifice. The interior space of the barrel contains one or more beads, wherein each bead includes a core and a shell, the high-viscosity fluid being located in the core. Depressing the plunger produces an annulus of low-viscosity fluid around a core of the high-viscosity fluid as the fluids are dispensed from the orifice. 
         [0019]    In some embodiments, the interior space of the barrel further includes the low-viscosity fluid. The shell is a biocompatible polymer which is insoluble in the low-viscosity fluid, and the injection device further includes a means for breaking the shell. In other embodiments, the shell is soluble in the low-viscosity fluid. 
         [0020]    In some different embodiments, the injection device further comprises an inlet at the open end and a fluid reservoir connected to the barrel through the inlet, the low-viscosity fluid being located within the fluid reservoir; and the bead is shaped to create an annulus within the barrel. This injection device may further comprise a sealing means within the inlet. Withdrawing the plunger from the barrel causes the low-viscosity fluid to enter the interior space of the barrel and interact with the bead(s). In other embodiments, this injection device may further comprise an outlet at the closed end and an outlet reservoir connected to the barrel through the outlet. Excess low-viscosity fluid can enter the outlet reservoir as the plunger is withdrawn beyond the outlet. The injection device can be generally stored with the plunger partially depressed into the barrel. 
         [0021]    The injection device may further comprise a sonic generator located at the open end of the barrel, or may further comprise grooves at the open end of the barrel, both of which can be used to promote core annular flow. 
         [0022]    Also disclosed in various embodiments is an injection device, comprising: a barrel having an open end and a closed end; a plunger operating within the barrel; and an inlet at the open end and a fluid reservoir connected to the barrel through the inlet. 
         [0023]    This injection device may further comprise a sealing means within the inlet. In other embodiments, this injection device may further comprise an outlet at the closed end and an outlet reservoir connected to the barrel through the outlet. This injection device may also further comprise a bead within the barrel, the bead being shaped to create an annulus within the barrel, wherein the bead includes a core and a shell, the high-viscosity fluid being located in the core and the shell surrounding the high-viscosity fluid. The injection device may further comprise grooves at the open end of the barrel. 
         [0024]    Also disclosed in various embodiments herein is an injection device for delivering a high-viscosity fluid, comprising: a barrel having an interior space formed from a sidewall, an open end, and a closed plunger end, the interior space containing a low-viscosity fluid and a high-viscosity fluid, and the open end having an orifice; a plunger movably operable within the barrel; and a sonic generator located at the open end of the barrel for producing an annulus of the low-viscosity fluid around a core of the high-viscosity fluid as the fluids are dispensed from the orifice. If desired, the injection device may further comprise grooves at the open end of the barrel. 
         [0025]    The present disclosure also relates in various embodiments to an injection device for delivering a high-viscosity fluid, comprising: a barrel having an open end and a closed end, the open end having an orifice; and a plunger operating within the barrel; wherein the barrel is formed from a sidewall, and the sidewall includes grooves at the open end. When the barrel contains a low-viscosity fluid and a high-viscosity fluid, the grooves can be used to produce an annulus of the low-viscosity fluid around a core of the high-viscosity fluid as the fluids are dispensed from the orifice. 
         [0026]    The sidewall may taper at the open end to an orifice. Sometimes, the injection device further comprises an inner wall within the barrel that separates the barrel into a first compartment and a second compartment. The injection device can alternatively further comprise a sealing means at a bottom edge of the inner wall. 
         [0027]    Also disclosed herein is an injection device for creating core annular flow, comprising: a barrel; a plunger operating within the barrel; and a flow diverter. The barrel has an interior space formed from a sidewall, an open end having an orifice, and an inner concentric wall within the sidewall. The inner concentric wall divides the interior space into an inner compartment and an outer compartment. The flow diverter is located between the inner compartment and an orifice. The flow diverter is adapted so that fluid flows from the inner compartment to an annulus of the barrel and so that fluid flows from the outer compartment as a core. 
         [0028]    In some embodiments, the flow diverter can be formed from a flow cap and a flow base. A center of the flow cap connects to the inner concentric wall. At least one radial spoke extends from the center of the flow cap to an annular ring. An underside of the annular ring includes a circumferential groove, the circumferential groove creating an inner ring wall and an outer ring wall. The flow base includes a central surface with at least one radial spoke extending from the central surface to an annular wall. The at least one radial spoke of the flow cap and the at least one radial spoke of the flow base cooperate to form a tunnel that channels fluid from the inner compartment to the circumferential groove. The central surface of the flow base may have a diameter equal to an outer diameter of the inner concentric wall. The annular wall of the flow base may have an outer diameter equal to the outer diameter of the inner ring wall of the flow cap. The inner concentric wall and the flow cap can be formed as one integral component or as two separate components. The flow cap may include throughbores between the inner concentric wall and the inner ring wall; and the flow base may include throughbores between the central surface and the annular wall. In some embodiments, the flow cap may rest upon a horizontal stop surface within a needle hub, and the flow base may be seated within the needle hub. 
         [0029]    The plunger may comprise a central piston located within the inner compartment and a ring piston located within the outer compartment, the central piston and the ring piston being connected to a common shaft. 
         [0030]    Also disclosed herein is an injection device for creating core annular flow, comprising: a barrel formed by a sidewall and having a lower volume and an upper volume; a core container located within the lower volume, the core container comprising a sidewall and a floor with a central hole; a plunger rod extending through the barrel upper volume and contacting a core plunger in the core container; a needle hub at an end of the barrel opposite the plunger rod, the needle hub having an internal passage and an annular passage; and a hollow pin having at least one side port at an upper tip, the at least one side port being covered by the floor of the core container, the hollow pin regulating flow from the core container to the internal passage of the needle hub; wherein an annular compartment is formed between the sidewall, the core container, the plunger rod, and the needle hub. High-viscosity fluid can flow from the core container through the hollow pin and the internal passage, and wherein low-viscosity fluid can flow from the annular compartment through the annular passage. 
         [0031]    The core plunger and the plunger rod may be connected to each other. The core plunger may cooperate with at least one groove at a top of the core container sidewall. The upper volume of the barrel may have a smaller diameter than the lower volume of the barrel. The core container may divide the lower volume into an upper space, a lower space, and a lower annular space fluidly connecting the upper space and the lower space. The needle hub may comprise an internal surface upon which the hollow pin sits, the internal surface having a central hole that communicates with the internal passage and at least one slit spaced apart from the central hole that communicates with the annular passage. A base of the hollow pin may include a radial flange. The internal passage and the annular passage of the needle hub may bee separated by an internal cylindrical wall. 
         [0032]    Also disclosed herein in different embodiments is an injection device for delivering a high-viscosity pharmaceutical formulation, comprising: a barrel; a needle attached to an orifice in the barrel; and a plunger operating within the barrel. An interior surface of the needle is coated with a low-viscosity fluid surrounding the high-viscosity fluid such that the high-viscosity fluid does not contact the needle. The low-viscosity fluid may be a phase change material. 
         [0033]    Also disclosed herein is an injection device for delivering a high-viscosity pharmaceutical formulation, comprising: a hollow barrel having an orifice; and a plunger operating within the barrel. The barrel includes a first compartment, a second compartment, and at least one channel connecting the second compartment to the first compartment, the channel being shaped so that fluid flows from the second compartment circumferentially against a sidewall of the first compartment to create core annular flow. The first compartment contains the high-viscosity formulation. The second compartment contains a low-viscosity fluid. 
         [0034]    In some embodiments, the barrel is an outer barrel containing the first compartment, and the device further comprises an inner barrel that slides within the outer barrel, the inner barrel containing the second compartment. 
         [0035]    Alternatively, the barrel may include an inner wall that divides an interior space of the barrel into the first compartment and the second compartment, the orifice being located within the first compartment. 
         [0036]    Also disclosed herein in various embodiments is a process for delivering a high-viscosity pharmaceutical formulation, comprising: receiving the high-viscosity pharmaceutical formulation in an injection device barrel; and injecting the pharmaceutical formulation into a patient, wherein a low-viscosity fluid forms an annulus about the high-viscosity formulation as the pharmaceutical formulation is injected. 
         [0037]    The low-viscosity fluid may comprise water, a water based solution, saline, a perfluoroalkane solvent, safflower oil, or benzyl benzoate. A ratio of the viscosity of the high-viscosity formulation to the viscosity of the low-viscosity fluid may be from about 60 to about 200. A fraction of the width of the injection device barrel occupied by the high-viscosity formulation may be from about 0.70 to less than 1. The high-viscosity formulation can have an absolute viscosity of from about 5 centipoise to about 1000 centipoise. 
         [0038]    In some embodiments, the high-viscosity formulation contains a protein having a concentration of from about 150 mg/mL to about 500 mg/mL. In other embodiments, a velocity gradient of the low-viscosity fluid is greater than a velocity gradient of the high-viscosity formulation during injection. 
         [0039]    Sometimes, the pharmaceutical formulation is injected with a pressure of 20 Newtons or less. Other times, the pharmaceutical formulation is injected within an injection time of 30 seconds or less. 
         [0040]    The low-viscosity fluid may be stored in a different compartment from the high-viscosity formulation, and the low-viscosity fluid flows circumferentially about the high-viscosity formulation during the injecting. 
         [0041]    These and other non-limiting aspects and/or objects of the disclosure are more particularly described below. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0042]    The following is a brief description of the drawings, which are presented for the purposes of illustrating the exemplary embodiments disclosed herein and not for the purposes of limiting the same. 
           [0043]      FIG. 1  is a diagram showing the various components of a conventional hypodermic syringe. 
           [0044]      FIG. 2  is a diagram showing an exemplary embodiment of an injection device containing a high-viscosity fluid and a low-viscosity fluid for injection. 
           [0045]      FIG. 3  is a diagram showing an injection device having two compartments, one for a high-viscosity fluid and one for a low-viscosity fluid. The compartments are made in the form of an inner barrel and an outer barrel. 
           [0046]      FIG. 4  is a diagram showing an injection device having two compartments, one for a high-viscosity fluid and one for a low-viscosity fluid. The compartments are formed from an inner wall running longitudinally within the barrel of the injection device. 
           [0047]      FIG. 5A  is a first potential velocity profile for core annular flow, with a linear velocity profile in the annular fluid. 
           [0048]      FIG. 5B  is a second potential velocity profile for core annular flow, with a parabolic velocity profile in the annular fluid. 
           [0049]      FIG. 6  is a graph showing the effect of the core fraction and the viscosity ratio on the pressure drop. 
           [0050]      FIG. 7  is a graph showing the maximum concentration vs. viscosity obtainable when different low-viscosity fluids are used as an annular fluid for an auto-injector and a manual syringe. 
           [0051]      FIG. 8  is a diagram showing a Y-shaped apparatus used to simulate core annular flow. 
           [0052]      FIG. 9  is a graph showing the pressure drop vs. flow rate for different solutions, some with core annular flow (open symbols) and some without core annular flow (filled symbols). 
           [0053]      FIG. 10  is an illustration of an injection device having a concentric wall that separates the barrel into two compartments. An opening at the bottom of the concentric wall permits the fluids in the two compartments to achieve core annular flow. 
           [0054]      FIG. 11  is a variation on the injection device of  FIG. 10 , with a nozzle or tapered end. 
           [0055]      FIG. 12  is a top view of the closed end of the injection device of  FIG. 10  and  FIG. 11 , where the plunger is inserted, showing how inner walls within the barrel are supported. 
           [0056]      FIG. 13  is a variation on the injection device of  FIG. 10 , having a valve mechanism for the inner compartment to release high-viscosity fluid in the form of drops that are surrounded by low-viscosity fluid. 
           [0057]      FIG. 14  is a variation on the injection device of  FIG. 10 , with the inner wall tapered and including a sealing means at the bottom. This embodiment acts as a “syringe within a syringe”. 
           [0058]      FIG. 15  is an illustration of an injection device having a sealing membrane that separates the barrel into an upper compartment and a lower compartment. The lower compartment contains an expandable pouch containing low-viscosity fluid. 
           [0059]      FIG. 16  is an illustration of an injection device in which the high-viscosity fluid is in the core of a bead and is surrounded by a shell that separates it from the low-viscosity fluid. 
           [0060]      FIG. 17  is an illustration of an injection device in which the high-viscosity fluid is in the form of a core/shell bead stored in the barrel. The low-viscosity fluid is stored in a fluid reservoir outside the barrel and is drawn into the barrel during usage. If desired, an outlet reservoir may also be present. 
           [0061]      FIG. 18  is an illustration of an injection device having a sonic generator at the base. 
           [0062]      FIG. 19  is an illustration of an injection device having a floor that separates the barrel into an upper compartment and a lower compartment. An aperture in the floor is aligned with the orifice leading to the needle. 
           [0063]      FIG. 20  is an illustration of the injection device of  FIG. 19  being injected. The high-viscosity fluid from the upper compartment shoots at high speed through the lower compartment, drawing low-viscosity fluid along with it to create core annular flow. 
           [0064]      FIG. 21  is a perspective illustration of an injection device having grooves in the sidewall leading to the needle to encourage low-viscosity fluid to remain along the wall and high-viscosity fluid to remain in the core. 
           [0065]      FIG. 22  is a top view of the closed end of an injection device showing a first possible construction for an inner wall. 
           [0066]      FIG. 23  is a top view of the closed end of an injection device showing a second possible construction for an inner wall. 
           [0067]      FIG. 24  is a top view of the closed end of an injection device showing a third possible construction for an inner wall. 
           [0068]      FIG. 25  is an illustration of an experimental setup for an injection device having core annular flow. 
           [0069]      FIG. 26  is a magnified view of the test cell of the setup of  FIG. 25  showing the portion that induces core annular flow. 
           [0070]      FIG. 27  is a perspective interior view of an exemplary embodiment of an injection device that uses flow inversion. 
           [0071]      FIG. 28  is a perspective view of some internal components of the injection device. 
           [0072]      FIG. 29  is a bottom view of a flow cap of the injection device. 
           [0073]      FIG. 30  is a perspective view of a flow base of the injection device. 
           [0074]      FIG. 31  is a perspective view of a needle hub of the injection device. 
           [0075]      FIG. 32  is a side cross-sectional view of the injection device showing fluid flow. 
           [0076]      FIG. 33  is a perspective view of the internal components of another exemplary embodiment of a “stacked” injection device. 
           [0077]      FIG. 34  is a side view of the internal components of the injection device. 
           [0078]      FIG. 35  is a side cross-sectional view of the internal components of the injection device. 
           [0079]      FIG. 36  is a plan cross-sectional view showing the diameters of various internal components of the injection device. 
           [0080]      FIG. 37  is a view of the plunger rod of the injection device. 
           [0081]      FIG. 38  is a view of the core container of the injection device. 
           [0082]      FIG. 39  is a view of the hollow pin which is located within the base of the injection device. 
           [0083]      FIG. 40  is a perspective view of the needle hub. 
       
    
    
     DETAILED DESCRIPTION 
       [0084]    A more complete understanding of the processes and apparatuses disclosed herein can be obtained by reference to the accompanying drawings. These figures are merely schematic representations based on convenience and the ease of demonstrating the existing art and/or the present development, and are, therefore, not intended to indicate relative size and dimensions of the assemblies or components thereof. 
         [0085]    Although specific terms are used in the following description for the sake of clarity, these terms are intended to refer only to the particular structure of the embodiments selected for illustration in the drawings, and are not intended to define or limit the scope of the disclosure. In the drawings and the following description below, it is to be understood that like numeric designations refer to components of like function. In the following specification and the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings. 
         [0086]    The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. 
         [0087]    Numerical values in the specification and claims of this application should be understood to include numerical values which are the same when reduced to the same number of significant figures and numerical values which differ from the stated value by less than the experimental error of conventional measurement technique of the type described in the present application to determine the value. 
         [0088]    All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 2 grams to 10 grams” is inclusive of the endpoints, 2 grams and 10 grams, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and/or values. 
         [0089]    As used herein, approximating language may be applied to modify any quantitative representation that may vary without resulting in a change in the basic function to which it is related. Accordingly, a value modified by a term or terms, such as “about” and “substantially,” may not be limited to the precise value specified, in some cases. In at least some instances, the approximating language may correspond to the precision of an instrument for measuring the value. The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” 
         [0090]    The term “room temperature” refers to a temperature from 23° C. to 25° C. 
         [0091]    Viscosity can be defined in two ways: “kinematic viscosity” or “absolute viscosity.” Kinematic viscosity is a measure of the resistive flow of a fluid under an applied force. The SI unit of kinematic viscosity is mm 2 /sec, which is 1 centistoke (cSt). Absolute viscosity, sometimes called dynamic or simple viscosity, is the product of kinematic viscosity and fluid density. The SI unit of absolute viscosity is the millipascal-second (mPa-sec) or centipoise (cP), where 1 cP=1 mPa-sec. 
         [0092]    A “protein” is a sequence of amino acids that is of sufficient chain length to produce a tertiary or quaternary structure. Examples of proteins include monoclonal antibodies, insulin, human growth hormone, and erythropoietin. 
         [0093]    The present disclosure discloses processes for achieving low injection force with high-concentration protein solutions and maintaining the protein stability and activity. The phenomenon of core annular flow (CAF) is used to reduce the pressure required to deliver a given volumetric flow rate. Generally, a highly viscous fluid is delivered in the core of a flow field along with a lower viscosity fluid in an annular region (i.e. between the core and the walls of the delivery system) to lubricate flow and reduce the pressure required relative to non-lubricated flow. The processes of the present disclosure can be used with both manual syringes or auto-injectors and is not limited to cylindrical geometries. For the purposes of this disclosure, the term “injection device” is used to refer to both manual syringes and auto-injectors of any size or shape. 
         [0094]      FIG. 1  is a diagram showing the various components of a conventional hypodermic syringe  100 . The syringe includes a barrel  110 , a plunger  140 , and a needle  160 . 
         [0095]    The barrel  110  is the part of the hypodermic syringe that contains the fluid to be injected into a patient. The barrel  110  is hollow and has a plunger end  112  and a needle end  114 . The plunger end may also be referred to as a closed end  112  of the barrel, because fluid will not pass through this end when the plunger  140  is inserted. Similarly, the needle end may also be referred to as an open end  114  of the barrel because fluid can pass through this end when the needle  160  is attached. The barrel is formed from a sidewall  120  that surrounds an interior space  130 . The sidewall  120  includes an interior surface  122  and an exterior surface  124 . The barrel itself is usually transparent for viewing of fluid within the interior space, and a scale can also be imprinted on the exterior surface. The needle end  114  can be tapered towards an orifice  116  through which fluid exits the interior space  130 . The length  132  and width  134  of the barrel is variable, as is its shape, although generally the barrel is cylindrical. In this regard, the diameter of the barrel corresponds to the width  134  when the barrel is cylindrical. The needle end  114  also includes a female fitting  118  to form a leak-free connection with the needle  160 . The plunger end  112  also includes a finger flange  115  which flares out from the barrel, and allows the user to press on the plunger  140  with the thumb while holding the barrel in place with two fingers. 
         [0096]    The plunger  140  is used to discharge fluid present in the barrel  110  of the syringe. The plunger  140  includes a shaft  150  with a thumbrest  152  on one end  142  and a stopper or piston  154  on the other end  144 . The shaft is long enough for the stopper  154  to travel the length of the interior space  130  of the barrel. The stopper  154  fits snugly against the interior surface  122  of the barrel to make an airtight seal. As previously mentioned, a lubricant (not visible) is typically present between the stopper  154  and the interior surface  122  of the barrel to reduce the gliding force. 
         [0097]    The needle  160  is essentially a small thin tube, and is the part of the syringe that actually pierces the skin of the patient. On one end  162  is a hub  170 , which includes a male fitting  172  for attachment to the needle end of the barrel, such as a Luer lock. The other end of the needle  164  is beveled to increase the ease of insertion into the patient. 
         [0098]    In the processes of the present disclosure, core annular flow is used to reduce the pressure needed to dispense a viscous fluid from an injection device.  FIG. 2  shows an illustrative embodiment of one means for obtaining core annular flow. This figure shows an injection device barrel  210  with the plunger  212  inserted and the stopper  214  visible. Located in the interior space of the barrel is a high-viscosity pharmaceutical formulation  220  which is surrounded by a low-viscosity fluid  230 . The high-viscosity formulation has a greater absolute viscosity than the low-viscosity fluid. The high-viscosity formulation here can be considered to have a core shape. The low-viscosity fluid, which surrounds the high-viscosity formulation, can be described as having an annular shape or forming an annulus around the high-viscosity formulation. The use of the term “annular” here does not exclude the low-viscosity fluid from being located above or below the core formed from the high-viscosity formulation. An interface region  240  exists in the longitudinal direction (along the axis of the injection device) where the low-viscosity fluid and the high-viscosity fluid meet. 
         [0099]    It should be noted that the high-viscosity formulation  220  does not contact the sidewall  216  of the barrel. Only the low-viscosity fluid  230  contacts the sidewall  216 . In other words, the low-viscosity fluid  230  is between the core  220  (formed by the high-viscosity fluid) and the walls  214  of the barrel. When the plunger is depressed, the low-viscosity fluid lubricates the flow and reduces the pressure required to eject the fluid from the barrel. 
         [0100]    Generally, the low-viscosity annulus and high-viscosity core is produced during flow, and may not always be present within the structure. However, it is possible to create trapped high-viscosity core/low-viscosity annular structures through the use of phase change materials such as ice, thermally sensitive emulsions, etc. 
         [0101]    The contents of the injection device can be arranged to obtain core annular flow by several methods. Some exemplary methods are depicted in the following figures. 
         [0102]    In one method, the high-viscosity fluid and the low-viscosity fluid may be stored in two separate compartments, and then combined when the injection device is depressed. The core annular flow may be generated by directing the flow of the two fluids such that the low-viscosity fluid forms an annulus around the high-viscosity core. This may occur in the needle or within a section of the injection device barrel where the two compartments meet. Again, the injection device barrel need not be cylindrical. If an injection device barrel with an initial compartment containing a square cross section is used, the fluids could be injected on different sides a small distance apart, in order to create the core and annulus once the cylindrical section is reached. 
         [0103]    An example of this method is depicted in  FIG. 3 . Syringes having two compartments are known in the art. Here, the injection device  300  contains two separate telescoping barrels. An outer barrel  310  is hollow and has a closed end  312  and an open end  314 . The open end  314  may also be referred to as a needle end because a needle  302  is attached to this end, and fluid may exit the outer barrel  310  through the needle. The outer barrel  310  is formed from a sidewall  320  having an interior surface  322  and surrounding an interior space  325 . The interior space of the outer barrel contains the high-viscosity fluid and can be considered a first compartment of the injection device. The open end  314  of the outer barrel includes an orifice  316  through which fluid exits the interior space/first compartment  325 , and to which the needle is attached. The closed end of the outer barrel includes a first finger flange  315  that flares out radially from the outer barrel and provides one end of a grip for the user. Disposed within the outer barrel  310  is an inner barrel  340  which can slide within the outer barrel  310 . The inner barrel is hollow, and has a plunger end  342  and a stopper end  344 . The inner barrel is also formed from a sidewall  350  that surrounds an interior space  355 . The interior space of the inner barrel contains the low-viscosity fluid and can be considered a second compartment of the injection device. The stopper end  344  forms an airtight seal with the outer barrel  310 , and acts to push fluid contained in the interior space  325  of the outer barrel through the needle  302 . The stopper end  344  notably contains one or more discrete channels  346  which permit fluid within the inner barrel  340  to be injected into the outer barrel  310 . This channel flow is directed against the interior surface  322  of the outer barrel so that the low-viscosity fluid from the inner barrel travels circumferentially against the sidewall  320  and downwards towards the needle. The plunger end  342  of the inner barrel receives the plunger  360 . The plunger end also includes a second finger flange  345  that flares out radially from the inner barrel. The plunger  360  itself includes a shaft  370  with a thumbrest  372  on one end  362  and a piston  374  on the other end  364 . The piston  374  fits snugly against the interior surface  352  of the inner barrel  340  to make an airtight seal. The plunger  360  travels the length of the inner barrel as well. 
         [0104]    In use, the plunger  360  is depressed to inject the low-viscosity fluid (not shown) from the interior space  355  of the inner barrel  340  into the interior space  325  of the outer barrel  310  and form an annulus about the high-viscosity fluid located in the outer barrel (indicated by circumferential arrow  305 ). It is believed that the inner barrel  340  itself should not depress significantly while the plunger  360  is being depressed, because the force required to move the low-viscosity fluid within the inner barrel should be less than the force required to move the high-viscosity fluid within the outer barrel through the needle. Rather, the force of the low-viscosity fluid in a circumferential manner about the sidewall of the outer barrel should eject some of the high-viscosity fluid through the needle until core annular flow is established. 
         [0105]    In another method, the two fluids will naturally adopt a core annular arrangement if they undergo steady flow. When the low-viscosity fluid is injected into a flowing high-viscosity stream, the low-viscosity fluid naturally migrates to the wall to minimize stress (lower energy state) in a process called flow inversion. This results in core annular flow. Such arrangements can be accomplished by taking advantage of non-Newtonian fluid behaviors. For example, the low-viscosity fluid may be a lubricant that has a yield stress that is greater than what can be overcome by buoyancy forces (e.g. density difference between fluids). 
         [0106]      FIG. 4  illustrates this method. Here, the injection device  400  is formed from a barrel  410 , plunger  440 , and needle  460 . The barrel  410  is hollow and has a closed end  412  and an open end  414 . The barrel is formed from a sidewall  420  that surrounds an interior space  430 . The open end  414  includes an orifice  416  through which fluid exits the interior space  430 , and to which the needle  460  is attached. An inner wall  425  is located inside the barrel that extends longitudinally between the open end  414  and the closed end  412 . The inner wall  425  separates the interior space into a first compartment  432  and a second compartment  434 . The inner wall is located to one side, so that the orifice  416  is wholly contained within the first compartment  432 . There is a channel  426  located in the inner wall  425  that runs from the second compartment  434  into the first compartment  432 , and the channel  426  is directed towards a circumference of the orifice  416 . It is contemplated that the high-viscosity fluid will be located in the first compartment, and the low-viscosity fluid will be located in the second compartment. The second compartment may be relatively small, for example about 1% of the volume of the barrel. The plunger  440  includes a shaft  450  with a thumbrest  452  on one end  442  and two pistons  454 ,  456  on the other end  444 . The plunger also contains a tunnel  445  that receives the inner wall  425  of the barrel. As seen here, a first piston  454  is located within the first compartment  432  and a second piston  456  is located within the second compartment  434 . 
         [0107]    In use, it is contemplated that pushing on the plunger  440  will cause both fluids to flow. The low-viscosity fluid is injected through the channel  426  of the inner wall into the high-viscosity fluid, and will naturally migrate against the wall of the needle to create core annular flow. 
         [0108]    In a third method, it is possible to generate core annular flow using a phase change material as the low-viscosity fluid. For example, a thin coating of water is placed on the inside of the barrel or the needle, then captured in place by lowering the temperature to convert the water from its liquid phase into ice. In another section of the injection device, the high-viscosity fluid is captured. This filled injection device would be stored at a temperature below the phase change temperature (in this case, the melting point of the ice). Additives such as salts could be incorporated into the high-viscosity fluid to depress its melting point below that of the water. Upon use, applied heat from the user&#39;s hand or an external source would melt the ice, creating an annulus of low-viscosity fluid. 
         [0109]    The core annular flow can be generated in either the injection device barrel, or the needle, or both. 
         [0110]    It is known that suspensions (particles and fluid) will phase separate during flow. The particles will move to the center as the low-viscosity fluid moves to the walls. In the present disclosure, a distinct interface is created between the high-viscosity fluid and the low-viscosity fluid. The two fluids may be miscible, or even composed of the same solvent, but the interface will be present as a distinct boundary between the two fluids. Such a boundary may be defined, for example, by a step change in the concentration of solute in each fluid. The solute is defined as the species responsible for the viscosity, such as a high molecular weight protein. This distinct boundary is in contrast to the continuous concentration gradient that forms due to natural flow-induced phase separation in a suspension. 
         [0111]    It is contemplated that the high-viscosity formulation can be a solution, dispersion, suspension, emulsion, etc. The high-viscosity formulation may contain a protein, such as a monoclonal antibody or some other protein which is therapeutically useful. The protein may have a concentration of from about 150 mg/mL to about 500 mg/mL. The high-viscosity formulation may have an absolute viscosity of from about 5 centipoise to about 1000 centipoise. The high-viscosity formulation may further contain a solvent or non-solvent, such as water, perfluoroalkane solvent, safflower oil, or benzyl benzoate. 
         [0112]    The low-viscosity fluid may be water or an aqueous solution. Alternatively, the low-viscosity fluid may be an organic solvent appropriate for injection, such as a perfluoroalkane solvent, safflower oil, or benzyl benzoate. In embodiments, the low-viscosity fluid has a lower absolute viscosity than the high-viscosity formulation, and has an absolute viscosity of from about 0.3 to about 1000 centipoise. 
         [0113]    The high-viscosity fluid and the low-viscosity fluid may be miscible or immiscible with each other. 
         [0114]    It has been observed that the pressure reduction is proportional to the ratio of the viscosities of the two fluids. Put another way, an increased magnitude in the difference between the viscosities increases the pressure reduction. In some embodiments, the ratio of the viscosity of the high-viscosity formulation to the viscosity of the low-viscosity fluid (i.e. μ H /μ L ) is from 1 to about 100 thousand, including from about 60 to about 200. 
         [0115]    The velocities of the high-viscosity formulation and the low-viscosity fluid are substantially identical at the interface region, as required by physics. Desirably, the velocity gradient of the low-viscosity fluid (i.e. in the annular flow region) is greater than the velocity gradient of the high-viscosity formulation (i.e. in the core flow region). The velocity gradient may be determined theoretically by the equation of motion and rheological properties of the fluids. Velocity gradients can be determined experimentally by visual studies, such as particle image velocimetry of impulse injections of a dyed fluid, or by observation of a pressure drop. 
         [0116]      FIG. 5A  and  FIG. 5B  show two potential velocity profiles for the core fluid (high-viscosity) and the annular fluid (low-viscosity). In  FIG. 5A , the velocity of the annular fluid near the injection device barrel is lowest (no slip boundary condition at the wall), and the velocity increases linearly for the annular fluid as one moves away from the barrel wall towards the center of the barrel. At the core-annular fluid interface, the velocities are substantially identical. In  FIG. 5B , the velocity profile of the annular fluid is parabolic, such as can occur in pressure driven flows. The velocity of the annular fluid is a maximum between the barrel wall and the interface region with a location that depends on the rheological behaviors of the fluids and the stresses placed on them. 
         [0117]    The benefit of the processes of the present disclosure is supported with an analysis considering fully developed annular flow of Newtonian fluids in a cylindrical geometry. The governing equation relating the flow rate to the pressure drop is given by Equation (1): 
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         [0000]    where Q is the flow rate, ΔPIL is the pressure gradient, λ is the fraction of the diameter occupied by the core fluid, R is the channel radius, and μ 1  and μ 2  are the viscosities of the core and the annular fluids, respectively. 
         [0118]    Results from the analysis are shown in  FIG. 6 . The benefit from core annular flow (pressure required to generate a given flow rate relative to the pressure required to produce the same flow rate without the annular fluid) is shown for a series of Newtonian fluids (viscosity ratios) and annular layer thicknesses. These results are subject to the constraints of the Newtonian assumption and are expressed in relative terms, so the benefit is independent of flow rate and channel width. The results indicate that the pressure reduction is greatest for large viscosity ratios and large lubricant thicknesses. It should be noted that the dependence on those variables, especially λ, is nonlinear, indicating that significant benefit can be realized even for thin annular layers and lower viscosity core fluids. The highest pressure reduction obtained was 99.3% at a core fraction of 70% and a viscosity ratio of 200. At a viscosity ratio of 1 or a core fraction of 1, the relative pressure reduction was zero. 
         [0119]    As seen in  FIG. 6 , the core fraction, i.e. the cross-sectional area occupied by the core fluid, affects the pressure drop. In embodiments, the fraction of the width of the injection device barrel occupied by the high-viscosity formulation is from about 0.70 to less than 1. The fraction is always less than 1. It should be noted that in a cylindrical barrel, the width of the injection device barrel is the diameter of the cylinder. 
         [0120]    The required injection force to inject a protein formulation of a given concentration or viscosity is reduced by the processes of the present disclosure. In embodiments, the high-viscosity pharmaceutical formulation is injected with a force of 20 newtons or less. In embodiments, the high-viscosity pharmaceutical formulation is injected within an injection time of 30 seconds or less. 
         [0121]    The embodiment depicted in  FIG. 2  may be considered to have a finite volume of the low-viscosity fluid. In another preferred embodiment, the low-viscosity fluid in the annular region is replenished from an external source while the plunger is being depressed, or in other words during the injection of the high-viscosity fluid or during the dispensing process. This would allow for additional flow control to deliver a relatively constant ratio of core fluid to lubricant (within the context of an Eulerian reference frame) to be maintained. 
         [0122]    Another embodiment of an injection device  1000  which is capable of core annular flow is depicted in  FIG. 10 . The needle is not depicted here. The barrel  1010  is hollow, and has an open end/needle end  1014  and a closed end/plunger end  1012 . A finger flange  1015  is located at the closed end of the barrel. 
         [0123]    The barrel  1010  is formed from a sidewall  1020  that has an internal diameter  1025 . An inner concentric wall  1030  is located within the barrel. An inner compartment  1034  and an outer compartment  1036  within the barrel are defined by the inner concentric wall. In this regard, the inner compartment  1034  has an inner diameter  1031  equal to the internal diameter of the concentric wall. The outer compartment has an annular shape, with a width  1037  that is the difference between the internal diameter  1031  of the sidewall and the external diameter  1033  of the inner concentric wall. 
         [0124]    The open end  1014  of the barrel includes a front wall  1040  that extends from a constriction point  1022  to an orifice  1016 . The “constriction point” is used here to refer to the location on the sidewall  1020  where the barrel begins to reduce from the internal diameter  1025  down to a smaller diameter for fluid to be injected through the orifice  1016 . As illustrated here, the constriction point  1022  is the intersection of the sidewall  1020  and the front wall  1040 , with the front wall being located in essentially a radial plane (reference numeral  1045 ). A nipple  1050  is present at the open end  1014  of the barrel to which the needle is attached. The nipple has a smaller diameter  1055  than the barrel  1025 . 
         [0125]    The inner concentric wall  1030  includes a bottom edge  1038 . An opening  1042  is formed between the inner concentric wall  1030  and the front wall  1040 , which permits fluid in the outer compartment  1036  to flow towards the orifice  1016  when the plunger is depressed. Here in  FIG. 10 , the opening is a vertical opening. The inner concentric wall  1030  is not connected to the front wall  1040 , but rather is supported at the closed end  1012  of the barrel. 
         [0126]      FIG. 11  is a variation on  FIG. 10 . Here, the front wall  1040  in  FIG. 11  can be described as tapering from the constriction point  1022  to the orifice  1016 , from a larger diameter to a smaller diameter. The bottom edge  1038  of the inner concentric wall and the constriction point are located about the same radial plane  1045 . Here, the opening  1042  that permits fluid in the outer compartment to flow is a radial opening. The degree of tapering is measured longitudinally, and is denoted here as angle ω. In particular embodiments, the angle ω is from about 20° to about 45°, and in some specific embodiments is about 30°. 
         [0127]    In the embodiments of  FIG. 10  and  FIG. 11 , the plunger  1060  provides a depressing force concurrently to the inner compartment  1034  and the outer compartment  1036 . The low-viscosity fluid flows preferentially against the wall of the barrel, so that the high-viscosity fluid is in the core and does not contact the wall. 
         [0128]    Desirably, the volume ratio of high-viscosity fluid to low-viscosity fluid is as high as possible, since it is the high-viscosity fluid that delivers the desired medication and the low-viscosity fluid essentially serves as a lubricant within the injection device. The radial cross-sectional areas of the inner compartment  1034  and the outer compartment  1036  can be controlled to control the volumetric flow of the two fluids. In this regard, the cross-sectional areas for the two compartments can be determined using the interior diameter of the concentric wall, the internal diameter of the sidewall, and the exterior diameter of the inner concentric wall. In embodiments, the ratio of the cross-sectional area of the inner compartment to the cross-sectional area of the outer compartment is from about 2:1 to about 9:1. In ideal circumstances, the flows of the low-viscosity and high-viscosity fluids meet at the constriction point. 
         [0129]    A means for sealing, such as a sealing membrane, may be used to locate the low-viscosity fluid and the high-viscosity fluid in desired locations prior to the injection device being used (or the plunger being depressed), or to keep the two fluids separated to prevent mixing during storage. In  FIG. 10 , a sealing membrane  1018  is located across only the inner concentric wall  1030 , to separate the inner compartment  1034  from the outer compartment  1036  and the nipple  1050 . It is contemplated that the nipple is filled with only the low-viscosity fluid. 
         [0130]    In  FIG. 11 , the sealing means  1018  is located across the barrel sidewall  1020  at approximately the constriction point  1022 , so that the inner compartment  1034  and the outer compartment  1036  are separated from the nipple  1050 . Again, the nipple is filled with only the low-viscosity fluid. 
         [0131]      FIG. 12  is a top view of the closed end of the barrel, with the plunger removed so the structure can be seen. As seen here, the inner concentric wall  1030  is connected to the barrel sidewall  1020  and supported by radial walls  1028 . Finger flange  1015  extends from the sidewall  1020 . 
         [0132]    Two different types of plungers are contemplated. In  FIG. 10 , the plunger  1060  is constructed so that the high-viscosity fluid and low-viscosity fluid are pushed together at the same time and at the same rate. In  FIG. 11 , the plunger  1060  is designed to push some low-viscosity fluid out before the high-viscosity fluid is pushed out. As seen here, the piston  1062  in the outer compartment is at a lower level compared to the piston  1064  in the inner compartment. Put another way, the piston  1062  of the outer compartment is located further from the thumbrest  1066  than the piston  1064  in the inner compartment. In this embodiment, there is usually air between the piston  1064  and the fluid. Thus, some of the high-viscosity fluid generally remains within the injection device after the plunger is fully depressed so that air is not injected. 
         [0133]    Another variation is shown in  FIG. 13 . In this variation, the inner compartment  1034  is closed at the bottom by a valve mechanism  1070 . Again, the high-viscosity fluid is located within the inner compartment  1034  and the low-viscosity fluid is contained in the outer compartment  1036 . When the plunger is depressed, the valve mechanism operates to release the high-viscosity fluid as a series of small drops which can be surrounded by the low-viscosity fluid, so that core annular flow occurs. 
         [0134]    In another variation, illustrated in  FIG. 14 , the inner concentric wall  1030  includes a lower wall  1072  that is tapered to form an aperture  1074 . A means for sealing  1075 , such as a sealing membrane or a valve, is located at the aperture. This embodiment can be described as a “syringe within a syringe”. When the plunger is depressed, the sealing means is ruptured and injection of the high-viscosity fluid begins. In some embodiments, a wire  1076  may be present along the longitudinal axis. It is contemplated that the high-viscosity fluid will preferentially “attach” to the wire, which aids in maintaining the core annular flow of the injection device. The wire can be supported by the wall  1030 ,  1072 . 
         [0135]    Another embodiment of an injection device that is capable of core annular flow is illustrated in  FIG. 15 . This figure focuses on the open end  1514  of the barrel  1510 , and the plunger and the needle are not shown. A sealing membrane or film barrier  1518  is located here, which separates the internal volume of the barrel into an upper compartment  1534  and a lower compartment  1536 . The high-viscosity fluid is located in the upper compartment  1534 . A wetted foil pouch  1540  is present in the lower compartment, which is connected at its upper end to the sidewall  1520 . The foil pouch is configured so that it can expand upon the application of pressure, i.e. is an expandable pouch. The bottom  1542  of the expandable pouch  1540  is configured to preferentially split open upon the application of pressure beyond a given threshold value. The expandable pouch contains low-viscosity fluid. When pressure is applied (by pressing the plunger), the sealing membrane/film barrier  1518  ruptures and the high-viscosity fluid enters the expandable pouch  1540 . The bottom of the expandable pouch  1542  then ruptures. The low-viscosity fluid is adjacent the sides of the pouch, and lubricates the flow of the high-viscosity fluid, creating core annular flow. 
         [0136]      FIG. 16  illustrates another embodiment in which an injection device  1600  can be made capable of core annular flow. The barrel  1610  is formed from a sidewall  1620  and has an open end  1614 . The concept here is that the high-viscosity fluid is provided as a bead  1630 , having a core  1632  with a shell  1634  surrounding the high-viscosity fluid. The shell is used to separate the high-viscosity fluid (in core  1632 ) from the low-viscosity fluid until the injection device is used. The shell is then broken and core annular flow can occur. 
         [0137]    In this regard, it is contemplated that the injection device here can be a conventional syringe, as seen in  FIG. 1 . The bead  1630  containing the high-viscosity fluid core is deposited into the barrel  1610  of the injection device by removing the plunger. The plunger is then depressed towards the open end  1614 , and can be filled with low-viscosity fluid through the open end. Any air in the barrel can be removed by flipping the injection device needle-side up and pushing the plunger in. 
         [0138]    Different shells are contemplated for the bead containing the high-viscosity fluid. In some embodiments, the shell is a biocompatible polymer that is insoluble in the low-viscosity fluid. This shell could be cracked or broken by the application of an external force. For example, acoustic cavitation or a laser could be used to penetrate the shell once the bead is within the low-viscosity fluid. Alternatively, the shell could be made from a material that is soluble in the low-viscosity fluid. In such embodiments, it is contemplated that upon dissolution of the shell, the low-viscosity fluid and high-viscosity fluid would be immediately injected into the patient (so that the two fluids do not mix together). 
         [0139]      FIG. 17  shows another injection device  1700  that can be used for core annular flow. The barrel  1710  is hollow, and has an open end/needle end  1714  and a closed end/plunger end  1712 . A finger flange  1715  is located at the closed end of the barrel. In this embodiment, the barrel  1710  of the injection device contains the high-viscosity fluid. The high-viscosity fluid is in the form of a bead  1730 , having a core  1732  with a shell  1734  surrounding the high-viscosity fluid as described above. The bead is constructed such that an open annulus  1736  is present within the barrel around the bead (e.g. the bead may be in the shape of an X). The cross-sectional area of the annulus should be larger than the orifice  1716  that leads to the needle. Alternatively, the orifice  1716  to the needle can be closed off with a means for sealing  1718 , such as a sealing membrane or valve. 
         [0140]    While the barrel already includes openings for the needle ( 1716 ) and for the plunger ( 1712 ), one additional opening is also present. An inlet  1740  is present at the open end of the injection device and is connected to a fluid reservoir  1742  containing the low-viscosity fluid. In this embodiment, the low-viscosity fluid is stored in the fluid reservoir and the high-viscosity fluid is stored in the form of a bead in the barrel until the injection device is to be used. The injection device  1700  is also stored with the plunger  1760  being partially depressed within the barrel. As illustrated here, the plunger  1760  is a shaft  1762  with a thumbrest  1764  on one end and a piston  1766  at the other end (shown here as resting upon the bead  1730 ). To prevent flow of the low-viscosity fluid into the barrel, the inlet  1740  may be closed off with a means for closing  1744 , such as a sealing membrane (not depicted) or a one-way valve that only permits flow in the direction from the fluid reservoir into the barrel. 
         [0141]    It is contemplated that the injection device is used by first pulling the plunger  1760  out of the barrel  1710 . This creates low pressure within the barrel, causing the closing means  1744  to open, i.e. the sealing membrane would be broken or the one-way valve would open. This permits the low-viscosity fluid to enter the barrel and fill the annulus  1736  surrounding the bead of high-viscosity fluid. The low-viscosity fluid rises and surrounds the bead  1730  containing the high-viscosity fluid. The shell  1734  dissolves upon exposure to the low-viscosity fluid, releasing the core of high-viscosity fluid. The plunger  1760  is then depressed (pushed into the barrel), and core annular flow occurs. If the orifice  1716  is sealed off, the pressure will break the seal and permit the fluids to flow into the needle. It is contemplated that the plunger may be shaped so that it cannot entirely depress, leaving some fluid within the injection device. This ensures that any air in the injection device is not injected into the user. 
         [0142]    If desired, an outlet  1750  can be located at the closed end of the injection device, which is connected to an outlet reservoir  1752 . It is contemplated that the injection device could be used with beads of different sizes, in which case the needed amount of low-viscosity fluid may vary. If the amount of low-viscosity fluid is too great for the bead that is used, the extra fluid could flow into the outlet reservoir. When present, the fluid reservoir and outlet reservoir can be placed in any orientation around the barrel relative to each other, for example on the same side or on opposite sides. There should be sufficient room left between the finger flange  1715  and the outlet reservoir  1750  to accept the finger of the user. 
         [0143]      FIG. 18  describes another injection device  1800  that can be used for core annular flow. In this view, the open end  1814  of the injection device is magnified. Low-viscosity fluid  1804  and high-viscosity fluid  1802  are present in the barrel  1810 , with the low-viscosity fluid surrounding the high-viscosity fluid. At the open end of the barrel is a sonic generator  1820  that surrounds the orifice  1816  through which fluid flows into the needle. The sonic generator creates sound waves that travel radially inwards through the material making up the barrel towards the longitudinal axis of the injection device. It is contemplated that the sound waves can create a “wall” of pressure that prevents high-viscosity fluid from contacting the sides of the orifice. This minimizes flow resistance, permitting core annular flow. Alternatively, the vibrations created by the sound waves may reduce the viscosity of the high-viscosity fluid, minimizing flow resistance and permitting it to flow more easily. The high-viscosity fluid can be stored in the form of a core/shell bead as previously described, or can be added in any of the other variations described herein. 
         [0144]      FIG. 19  and  FIG. 20  show another variation of an injection device  1900  that provides for core annular flow. The barrel  1910  is formed from a sidewall  1920 . Here, a floor  1930  is present in the barrel. In contrast to for example the membrane in  FIG. 15 , the floor here is relatively solid or rigid, and is not intended to break. The floor extends radially to the sidewall  1920 , separating the barrel into an upper compartment  1932  and a lower compartment  1934 . An aperture  1936  is present in the center of the floor, and is aligned with the orifice  1916  leading to the needle. The aperture is sealed with a sealing means  1938 , for example with a sealing membrane or a valve. The high-viscosity fluid  1902  is present in the upper compartment  1932 , and the low-viscosity fluid  1904  is present in the lower compartment  1934 . 
         [0145]    As illustrated in  FIG. 20 , when the plunger is depressed, the high-viscosity fluid  1902  is pushed through the aperture  1936  and shoots through the low-viscosity fluid  1904  into the needle. The low-viscosity fluid is “pulled” along with the high-viscosity fluid (represented by the arrows) so that core annular flow occurs. 
         [0146]      FIG. 21  illustrates an additional concept that can be applied to many of the embodiments described above. In many embodiments, the low-viscosity fluid is separated from the high-viscosity fluid, and the two fluids are brought together during injection. In this figure, the barrel  2110  is formed from a sidewall  2120 . An inner wall  2130  is present that divides the barrel into a first compartment  2132  and a second compartment  2134 . The bottom edge  2136  of the inner wall is free hanging, i.e. does not attach to another wall. A sealing means  2138  (e.g. a membrane) is present at the bottom edge  2136  of the inner wall. Grooves  2140  may be etched into the sidewall area of the open end  2114  of the injection device leading to the orifice  2116 . It is contemplated that such grooves will encourage the low-viscosity fluid to migrate to the boundary, encouraging the development of core annular flow. 
         [0147]    Regarding  FIG. 21 , it should be noted that the first compartment  2132  and the second compartment  2134  can generally take any shape.  FIG. 22 ,  FIG. 23 , and  FIG. 24  are top views of the closed end of an injection device and show different embodiments. In  FIG. 22 , the inner wall  2130  divides the volume of the barrel in half. In  FIG. 23 , the inner wall  2130  is bent so that the first compartment  2132  takes up about 75% of the volume of the barrel. In  FIG. 24 , the barrel contains two separate compartments  2132 ,  2134  which are joined at the bottom near the open end (not visible). 
         [0148]      FIGS. 27-32  are various views of another exemplary embodiment of an injection device that is contemplated for core annular flow and uses flow inversion.  FIG. 27  is a perspective interior view of the injection device.  FIG. 28  is a perspective view of some internal components of the injection device.  FIG. 29  is a bottom view of a flow cap of the injection device.  FIG. 30  is a perspective view of a flow base of the injection device.  FIG. 31  is a perspective view of a needle hub of the injection device.  FIG. 32  is a side cross-sectional view of the injection device that shows fluid flow through the injection device. 
         [0149]    Referring first to  FIG. 27 , the flow inversion injection device  2700  includes a hollow barrel  2710  which is formed from a sidewall  2720 . The base of the injection device is formed from a needle hub  2790  and includes a needle  2702 . It should be noted that this depiction differs from other figures previously described. The needle hub  2790  of the injection device can either be made separately from the sidewall  2720 , or they can be made as one integral component. An inner concentric wall  2730  is located within the barrel  2710 . An inner compartment  2734  and an outer compartment  2736  within the barrel are defined by the inner concentric wall. Located beneath the inner concentric wall is a flow cap  2750  and a flow base  2770 . The plunger is similar to that depicted in  FIG. 10  or  FIG. 11 , with a central piston located within the inner compartment (not depicted) and a ring piston  2742  in the outer compartment. The two pistons are connected to a common shaft (not depicted) and will travel simultaneously at the same rate through the barrel. 
         [0150]    Referring now to  FIG. 28 , the inner concentric wall  2730  and the flow cap  2750  are usually made as one integral piece. The inner concentric wall is at the center of the flow cap. Spokes  2582  extend from the inner concentric wall to an annular ring  2756 . Throughbores  2764  are formed between the center of the flow cap and the annular ring  2756 . Three spokes are depicted here, though this number may vary as desired. 
         [0151]      FIG. 29  is a bottom view of the flow cap  2750 . The inner concentric wall  2730  is at the center of the flow cap. Each spoke  2752  has a radial groove  2754  which extends from the center of the flow cap. A circumferential groove  2762  is present on the underside of the annular ring. The radial grooves  2754  join the inner compartment  2734  of the injection device to the circumferential groove  2762 . The annular ring  2756  includes an inner ring wall  2758  and an outer ring wall  2760  which are separated by the circumferential groove  2762 . Throughbores  2764  are present between the inner concentric wall  2730  and the inner ring wall  2758 , and fluid in the outer compartment will flow through the throughbores. 
         [0152]      FIG. 30  is a perspective view of a topside of the flow base  2770 . The flow base includes a central surface  2776  with spokes  2772  extending to an annular wall  2778 . It should be noted that the annular wall has a height which is greater than that of the central surface. Each spoke  2772  includes a radial groove  2774  which extends to and through the annular wall  2778 . Throughbores  2780  are also present in the flow base  2770  between the annular wall  2778  and the central surface  2776 . 
         [0153]    Referring back to  FIG. 29 , the inner compartment has an inner diameter  2735  equal to the internal diameter of the inner concentric wall  2730 . The central surface  2776  of the flow base has a diameter  2777  equal to the diameter of the outer diameter of the inner concentric wall. The radial spokes of the flow cap are aligned with the radial spokes of the flow base. Similarly, the throughbores of the flow cap are aligned with the throughbores of the flow base. The annular wall  2778  of the flow base has an outer diameter which is equal to the outer diameter  2759  of the inner ring wall  2758  of the flow cap (formed by the circumferential groove  2762 ). 
         [0154]      FIG. 31  is a perspective view of the needle hub  2790 . The needle hub  2790  is formed from a sidewall  2792  and a conical wall  2794  that tapers to form an orifice  2716  through which fluid will pass. The flow base will be seated within the needle hub. The flow cap will rest upon a horizontal stop surface  2796  within the needle hub, or upon the needle hub itself. 
         [0155]    The low-viscosity annular fluid is placed in the inner compartment  2734 , while the high-viscosity core fluid is located in the outer compartment  2736 . 
         [0156]      FIG. 32  illustrates how the core fluid and the annular fluid reverse their orientation as they pass through a flow diverter formed by the flow cap  2750  and the flow base  2770 . The flow cap  2750  and the flow base  2770  cooperate together so that each radial spoke forms a tunnel through which fluid in the inner compartment  2734  is channeled to the circumferential groove  2762 . There is an annular gap  2798  between the needle hub sidewall  2792  and the annular wall  2778  of the flow base  2770 . When the plunger (not depicted) is depressed, low-viscosity fluid can flow from the inner compartment  2734  through the tunnel  2782  formed in the radial spokes to the annular gap  2798 , and subsequently in an annular form through the needle  2702 . This flow is illustrated in dotted line. The high-viscosity fluid in the outer compartment  2736  flows directly downwards through the throughbores  2764 ,  2780  of the flow diverter into the center of the needle. This flow is illustrated in solid line. Core annular flow is thus created. The term “flow inversion” refers to the low-viscosity fluid being stored in the “core” (i.e. the inner compartment) but subsequently flowing in the annulus, and the high-viscosity fluid being stored in the annular but subsequently flowing in the core. 
         [0157]      FIGS. 33-40  are various views of another exemplary embodiment. This injection device can be described as a “stacked” syringe, in which the low-viscosity fluid is stored above the high-viscosity fluid inside the barrel.  FIG. 33  is a perspective view of the internal components of the injection device.  FIG. 34  is a side view of the internal components of the injection device.  FIG. 35  is a side cross-sectional view of the internal components of the injection device.  FIG. 36  is a plan cross-sectional view showing the diameters of various internal components of the injection device.  FIG. 37  is a view of the plunger rod of the injection device.  FIG. 38  is a view of the core container of the injection device.  FIG. 39  is a view of the pin which is located within the base of the injection device.  FIG. 40  is a view of the needle hub. 
         [0158]    Referring first to  FIGS. 33-35 , the injection device  3300  includes a barrel  3310  which is formed from a sidewall  3312 . A needle hub  3370  is located at the base of the sidewall, and a needle  3302  is connected to the needle hub. A hollow pin  3360  sits upon and is coaxial with the needle hub  3370 . The barrel sidewall  3312  and the needle hub  3370  are shaped to form a lower volume  3318 , which runs for approximately half the height of the sidewall. An upper wall  3326  of the barrel sidewall marks the upper end of the lower volume  3318 . Located within the lower volume  3318  is a core container  3330 . The core container  3330  is formed from a sidewall  3332 , a floor  3336  with a central hole through which the hollow pin  3360  can pass, and a core plunger  3340  at the top of the sidewall. The core plunger  3340  initially cooperates with grooves  3334  located at the top of the core container sidewall  3332 , but with the application of sufficient force can be dislodged from the grooves. A plunger rod  3350  is inserted into the barrel and contacts the core plunger  3340 . The upper end  3354  of the plunger rod includes seals  3356  which prevent fluid from leaking out of the barrel. 
         [0159]    Referring to  FIG. 34 , the lower volume  3318  is more easily visualized. The needle hub  3370  includes an internal surface  3382  upon which the hollow pin sits. The needle hub also includes a sidewall  3384  and a conical wall  3376  that form exterior surfaces. The floor  3336  of the core container is spaced apart from the internal surface  3382 , forming a lower space  3316  in which low-viscosity fluid can be contained. The upper wall  3326  of the barrel sidewall is spaced apart from the top of the sidewall  3332  of the core container, forming an upper space  3322  in which low-viscosity fluid is also contained. The outer diameter of the core container is less than the inner diameter of the lower volume, so that the upper space  3322  and lower space  3316  are joined together by a lower annular space  3314 . The diameter of the plunger rod  3350  is less than the inner diameter of the barrel sidewall  3312  in the upper volume above the lower volume, forming an upper annular space  3320  in which low-viscosity fluid is contained. 
         [0160]    Referring now to  FIG. 35 , this cross-sectional view permits easier visualization of the paths through which fluid will flow. The needle hub  3370  contains an internal cylindrical wall  3378  which defines an internal passage  3380  and an annular passage  3372  surrounding the internal passage. These passages are located below the internal surface  3382 , and permit fluid to flow from one side to the other and to the needle  3302 . The hollow pin  3360  is located above the internal passage  3380 . Side ports  3366  are located at an upper tip  3364  of the hollow pin, and are initially covered by the floor  3336  of the core container. High-viscosity fluid is contained within the core container  3330 . Low-viscosity fluid is contained in the lower space  3316 , the lower annular space  3314 , the upper space  3322 , and the upper annular space  3320 . These four locations together may be considered to form an annular compartment that contains the low-viscosity fluid. The annular compartment can also be considered to be defined by the barrel sidewall  3312 , the plunger rod  3350 , the core container  3330 , and the needle hub  3370 . A series of slits (not visible) in the horizontal surface of the needle hub joins the lower space  3316  to the annular passage  3372 . 
         [0161]      FIG. 36  is a plan cross-sectional view illustrating the various diameters involved. The barrel sidewall has an outer diameter  3311 . The barrel sidewall has an inner diameter  3313  in the lower volume. The core container sidewall has an outer diameter  3331  and an inner diameter  3333 . The barrel sidewall has an inner diameter  3315  in the upper volume. Finally, the plunger rod has a diameter  3355 . The lower annular space  3314  containing low-viscosity fluid is the space between the barrel sidewall lower volume inner diameter  3313  and the core container sidewall outer diameter  3331 . The upper annular space  3320  containing low-viscosity fluid is the space between the barrel sidewall upper volume inner diameter  3315  and the plunger rod diameter  3355 . 
         [0162]      FIG. 37  is a view of the plunger rod  3350  of the injection device. The upper end  3354  of the shaft  3352  includes seals  3356 , typically o-rings, for sealing the barrel. 
         [0163]      FIG. 38  is a view of the core container  3330  of the injection device. The sidewall  3332  is visible, and forms a tube. The floor  3336  of the core container can be formed from any type of sealing means. A central hole  3338  is present in the floor, through which the hollow pin will pass. Grooves  3334  are located at the top of the sidewall. The circumference of the core plunger  3340  interacts with the grooves. It should be noted that the core plunger can be made separately from the plunger rod, or could be integral to the plunger rod. It should be noted that the floor  3336  of the core container is fixed in place, whereas the core plunger  3340  can move up and down within the core container  3330  with the application of sufficient force. A central hole  3342  may also be present in the core plunger, if desired. 
         [0164]      FIG. 39  is a view of the hollow pin. The hollow pin  3360  is made from a tubular wall  3362  that is sealed at the upper tip  3364 . The upper tip includes side ports  3366  which fluidly connect the upper surface of the pin to the lower surface. A flange  3368  extends radially from the base of the tubular wall, and is used to seat the pin. As seen in  FIG. 35 , the floor  3336  of the core container covers the side ports  3366 , preventing fluid flow through the hollow pin when the plunger is not depressed. 
         [0165]      FIG. 40  is a view of the needle hub  3370 . The needle hub is formed from a sidewall  3384  and a conical wall  3376 , with the conical wall tapering to form an orifice  3306  through which fluid can flow. The needle hub includes an internal surface  3382  within the sidewall. The internal surface includes a central hole  3374  which is aligned with the tubular portion of the hollow pin. The internal surface  3382  also includes slits  3386  spaced apart from the central hole  3374 . Referring again to  FIG. 35 , the central hole  3374  feeds the internal passage  3380 , while the slits  3386  feed the annular passage  3372  beneath the internal surface. 
         [0166]    Turning back now to  FIG. 35 , fluid flow begins when the plunger rod  3350  is depressed. Initially, due to the joinder of the plunger rod  3350  with the core container  3330  through the core plunger  3340 , the core container also travels downwards towards the flange  3368  of the hollow pin. As the core container travels downwards, the lower space  3316  decreases in volume. The low-viscosity fluid present in the lower space flows through the slits  3386  into the annular passage  3372  and into the needle  3302 . As the plunger rod  3350  and the core container  3330  travel downwards, the upper space  3322  increases in volume and the upper annular space  3320  decreases in volume. The low-viscosity fluid in the upper annular space  3320  is pushed downwards by the seals  3356  at the top of the plunger rod into the upper space  3322 . Low-viscosity fluid also travels from the upper volume  3324  through the lower annular space  3314  around the core container  3330  into the lower space  3316 . The core container  3330  finally stops atop the flange  3368  of the hollow pin. At this point, the side ports  3366  of the hollow pin are exposed. As the plunger rod  3350  continues to be depressed, the force eventually disengages the core plunger  3340  from the grooves at the top of the core container sidewall  3332 . The core plunger then pushes high-viscosity fluid through the side ports  3366  and down the internal passage  3380  of the needle hub. The seals at the top of the plunger rod continue to push low-viscosity fluid from the upper space  3322  down around the core container and through the annular passage  3372  of the needle hub. This creates the core annular flow. The core plunger  3340  can be depressed until it contacts the floor  3336  and the hollow pin  3360  enters the central hole  3342  in the core plunger. The seals  3356  of the plunger rod should remain above the upper space  3322  of the barrel. 
         [0167]    Materials for making the various components of the different injection devices disclosed herein are known in the art, as are methods for making such injection devices. 
         [0168]    The processes and devices described herein may be used to deliver as part of the high-viscosity fluid, protein microparticles made using the processes described in U.S. Provisional Patent Application Ser. No. 61/556,047, filed Nov. 4, 2011, the disclosure of which is hereby incorporated by reference in its entirety. They can also be used as part of the systems described in U.S. Provisional Patent Application Ser. No. 61/556,542, filed Nov. 4, 2011, or in the devices described in U.S. Provisional Patent Application Ser. No. 61/556,709, filed Nov. 4, 2011, the disclosures of which are hereby incorporated by reference in their entirety. 
         [0169]    The following examples are for purposes of further illustrating the present disclosure. The examples are merely illustrative and are not intended to limit processes or devices made in accordance with the disclosure to the materials, conditions, or process parameters set forth therein. 
       Example 1 
       [0170]    Rheological constitutive models describing the relationship between protein concentration and viscosity were constructed to assess the magnitude of concentrations which might be delivered with core annular flow. It was assumed that the maximum allowable forces for an auto-injector and a manual syringe were 10 newtons and 20 newtons, respectively. Two potential low viscosity annular fluids, perfluorohexane (1.1 cP) and perfluorooctyl bromide (0.9 cP), were modeled in the annular region. The maximum concentration of protein in the core region was then calculated for a given viscosity. As a baseline, a lubricant having a viscosity of 10 cP was modeled in the annular region. The results are shown in  FIG. 7 . The top two lines are accomplished with manual injection, the next two lines are done with an auto-injector, and the bottommost line (circles) is for manual injection. As seen here, it is possible to deliver a protein solution at a concentration of more than 450 mg/mL and having a viscosity of up to 1000 cP using a manual syringe with an injection force of 20N. 
       Example 2 
       [0171]    Experiments were performed to measure the pressure drop during delivery of a viscous fluid with core annular flow. 
         [0172]    Two high-viscosity fluids were prepared. The first high-viscosity fluid was an aqueous solution of xanthan gum. The xanthan gum was mixed into water at 0.15 weight percent and had an absolute viscosity of 88 cP at 10/s (i.e. 10 Hz). This solution decreased in viscosity with increasing shear rate following a power law curve (n=0.39 and m=357). The core fraction occupied by the xanthan gum during flow experiments was 0.63. The second high-viscosity fluid was an aqueous solution of bovine serum albumin (BSA). BSA was mixed into phosphate buffered saline (PBS) at a concentration of 200 mg/mL and had an absolute viscosity of 10.3 cP at 10/s. This solution decreased in viscosity with increased shear rate following a power law curve (n=0.21 and m=18). The core fraction occupied by the BSA solution during flow experiments was 0.63. The low-viscosity fluid used in the annular region was water. 
         [0173]    The high-viscosity fluids and the water were run through a slit flow apparatus. The apparatus provided a rectangular cross section. The apparatus is depicted in  FIG. 8 . Briefly, the apparatus  800  included a Y-shaped channel. A core fluid inlet  810  flowed directly into the stem  802 , while the annular fluid flowed from an annular fluid inlet  820  through the arms  804  and then into the stem  802 . Through the stem, core annular flow was present. The fluids then flowed through an outlet  830  that was located at the bottom of the stem of the Y. 
         [0174]    The pressure drop was measured with a glass capillary manometer for various flow rates. For comparison, experiments were also performed where only the high-viscosity fluid was run through the slit flow apparatus, i.e. no low-viscosity lubricant was provided. 
         [0175]    The results are shown in  FIG. 9 . The labels here are marked as “core fluid/annular fluid”. The examples where the core fluid and annular fluid are the same did not show core annular flow. As seen here, when comparing Gum/Water to Gum/Gum, the Gum/Water results showed a lower pressure drop. Similarly, when comparing BSA/Water to BSA/BSA, the BSA/Water results showed a lower pressure drop. The Gum/Water and BSA/Water results used water as a low-viscosity fluid in the annular region, and the lower pressure drop reflects the fact that core annular flow effectively reduces the pressure required for delivery of the viscous fluid at a given flow rate. 
       Example 3 
       [0176]    A test stand was made as seen in  FIG. 25  for proof of concept. The setup included a test cell  2510 , a half-inch tube  2520 , an annular fluid priming syringe  2530 , an annular fluid syringe  2540 , a core fluid priming syringe  2550 , a core fluid syringe  2560 , two 3-way valves  2572 , a gas spring  2580 , a spring latch  2582 , and a fluid catch container  2590 . 
         [0177]      FIG. 26  is a magnified side view of the test cell  2510 , where the annular fluid and the core fluid were combined. The test cell here was designed for a 75/25 core to annulus volumetric flow ratio. In this regard, the right side of the test cell included an inner concentric wall  2512  and an outer wall  2514 . The inner wall formed a straight vertical pipe through which the core fluid flowed straight down. An annulus  2518  was created between the inner wall and the outer wall. The annular fluid entered the annulus from the left side  2516  of the test cell. The inner wall ended where the outer wall began to constrict at a 30° angle, and the two fluids met at the constriction. The triangular shape  2518  illustrates the nipple that would go to a needle. 
         [0178]    Based on this design, a 3 mL plastic Becton-Dickinson (BD) syringe was used for the core fluid syringe. A 1 mL BD syringe was used for the annular fluid syringe. A 5 lbf gas spring with a 2″ stroke was used to drive both fluid syringes simultaneously. A latch held the gas spring in the retracted position until a test was run. Two 3-way valves and priming syringes were used to prime both the fluid syringes and the rest of the test cell between runs. At the bottom of the fixture was the test cell which combined the core and annular flows and directed them through a 27 G half-inch-long stainless steel tube and into the fluid catch container. 
         [0179]    Each test run was performed using the following procedure: The gas spring was retracted and the latch was set. Using the 3-way valve and the core priming syringe, the core fluid syringe was filled with 1 mL of core fluid. Using the 3-way valve and the annular priming syringe, the annular fluid syringe was filled with 0.4 mL of annular fluid. Using the 3-way valve and the core priming syringe, the tubing and test cell was primed with core fluid. Using the 3-way valve and the annular priming syringe, the tubing and test cell was primed with annular fluid. Both 3-way valves were set to allow the fluid syringes to open to the test cell and to close off the priming syringes. The latch was then released to initiate the run, pushing the annular fluid and the core fluid with the same force, and the time was recorded to deliver the fluids. Syringes were used for 10 or less consecutive runs with the same fluid, due to friction problems attributed to silicone lubricant on the plunger wearing off. 
         [0180]    Two different fluids were used. The high-viscosity fluid was a glyercol/water solution with a viscosity of 85 centipoise (cP). The low-viscosity fluid was distilled water, with a viscosity of 1 cP. Viscosity was measured using a TA Ar2000ex rheometer, a 0.5° 20 mm steel cone, Peltier temperature stabilization, at 23° C. with two minutes equilibration time. 
         [0181]    Four different sets of experiments were run. First, water was used as both the core fluid and the annular fluid. Second, glycerol was used as both the core fluid and the annular fluid. Third, glycerol was used as the core fluid and water was used as the annular fluid. Fourth, to show that the combination of water and glycerol is achieving core annular flow rather than merely reducing the total viscosity by combining, the resultant solution from the third set was used as both the core fluid and the annular fluid. The resultant solution had a viscosity of 17 cP. 
         [0182]    The time was recorded by watching when fluid had completely exited the test cell and entered the catch container. However, when running glycerol for both the core and annular fluids, it was difficult to determine exactly when the fluid had completed delivery. As a result, a note was taken when the plungers of both fluid syringes bottomed out for a conservative estimate. 
         [0183]    The results are shown in Table 1. The two fluids are listed in core/annular. 
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                   
                 Water/ 
                 Glycerol/ 
                 Glycerol/ 
                 Resultant/ 
               
               
                   
                   
                 Water 
                 Glycerol 
                 Water 
                 Resultant 
               
               
                   
                   
                 (sec) 
                 (sec) 
                 (sec) 
                 (sec) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Run 1 
                 4 
                 180 
                 6 
                 21 
               
               
                   
                 Run 2 
                 3 
                 176 
                 5 
                 23 
               
               
                   
                 Run 3 
                 4 
                 188 
                 6 
                 20 
               
               
                   
                 Run 4 
                 4 
                 182 
                 6 
                 N/A 
               
               
                   
                 Run 5 
                 4 
                 174 
                 6 
                 N/A 
               
               
                   
                 Run 6 
                 4 
                 N/A 
                 8 
                 N/A 
               
               
                   
                 Run 7 
                 4 
                 N/A 
                 N/A 
                 N/A 
               
               
                   
                 Average 
                 4 
                 180 
                 6 
                 21 
               
               
                   
                   
               
             
          
         
       
     
         [0184]    The conservative estimate for the glycerol/glycerol run was 85 seconds. The core-annular flow provided a 93% reduction in delivery time when compared to this conservative estimate. In contrast, simply reducing the viscosity of the core fluid by mixing in the volume of annular fluid (i.e. the resultant) resulted in only a 75% reduction in delivery time. While these values depend on the two fluids used and their properties, the test clearly showed that core-annular behavior was occurring and demonstrated a significant increase in performance of the system. 
         [0185]    The present disclosure has been described with reference to exemplary embodiments. Obviously, modifications and alterations will occur to others upon reading and understanding the preceding detailed description. It is intended that the present disclosure be construed as including all such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.