A device for microliter-scale lymphatic delivery of coronavirus vaccines

Abstract

A fluid delivery device adapted for microliter-scale injection of a coronavirus vaccine across a patient's skin barrier, e.g., into the patient's lymphatic system, is described. The present disclosure also provides a method of administering a coronavirus vaccine across a patient's skin barrier, e.g., into the patient's lymphatic system. The device includes a microneedle fluid block assembly including a microneedle array including a plurality of microneedles disposed on a distal surface of a base plate, the microneedles having fluid outlet channels defined therein, the microneedles capable of penetrating the stratum corneum of the patient's skin and delivering a fluid composition to a depth below the surface of the patient's skin.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 140670, filed January 22, 2021, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present disclosure relates generally to fluid delivery devices, and more specifically to fluid delivery devices adapted for microliter-scale injection (referred to herein as "microdosing devices"). The present disclosure also relates to methods of applying the fluid delivery device to a patient's skin to deliver a fluid composition across the patient's skin barrier, e.g., to the patient's lymphatic system. The present disclosure more specifically relates to a fluid delivery device adapted for microliter-scale injection of a coronavirus vaccine across the patient's skin barrier, e.g., to the patient's lymphatic system. The present disclosure also relates to methods of administering a coronavirus vaccine across the patient's skin barrier, e.g., to the patient's lymphatic system. [Background technology]

[0003] background Coronaviruses are a group of viruses that cause disease in birds, mammals, and humans. Disease includes respiratory and enteric infections that can be mild or fatal. Coronaviruses are viruses of the subfamily Orthocoronavirinae in the family Coronaviridae of the order Nidovirales. The genus Coronavirus includes Avian infectious bronchitis virus, Bovine coronavirus, Canine coronavirus, Human coronavirus 299E, Human coronavirus OC43, Mouse hepatitis virus, Rat coronavirus, and Porcine hemagglutinating encephalomyelitis virus. The genus Torovirus includes Berne virus and Breda virus. Coronaviruses are enveloped viruses with a positive-sense single-stranded RNA genome and a nucleocapsid with helical symmetry. The genome size of coronaviruses ranges from approximately 26 to 32 kilobases, which is believed to be the largest for an RNA virus.

[0004] The name "coronavirus" is derived from the Latin corona and Greek korone (e.g., "garland" or "wreath"), meaning crown or halo. The corona reference refers to the characteristic appearance of virions (the infectious form of the virus) by electron microscopy, which have a fringe of large bulbous surface projections that create an image reminiscent of a crown or solar corona. This morphology is produced by the viral spike (S) pepillamer, a protein present on the surface of the virus that determines its host tropism. The proteins that contribute to the overall structure of all coronaviruses are the spike (S), envelope (E), membrane (M) and nucleocapsid (N). In the specific case of the SARS coronavirus, a defined receptor-binding domain on S mediates the attachment of the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2). Some coronaviruses (specifically, members of the betacoronavirus subgroup A) also have a shorter spike-like protein called hemagglutinin esterase (HE). The 2019–2020 Chinese pneumonia outbreak in Wuhan originated from a novel coronavirus, labeled 2019-nCoV by the World Health Organization (WHO), and also known as SARS-CoV-2.

[0005] There is a need in the art for methods for preventing or treating coronavirus infections in human and animal patients. Accordingly, the embodiments described herein are provided to meet this need and / or provide other benefits, or at least to provide the public with a useful choice. Summary of the Invention [Means for solving the problem]

[0006] Abstract According to a first aspect, the present disclosure provides a device (also referred to herein as a "microdosing device") configured to deliver a fluid composition across a skin barrier of a patient. The device includes a microneedle fluid block assembly including a microneedle array including a plurality of microneedles disposed on a distal surface of a base plate, the microneedles having fluid outlet channels defined therein, the microneedles capable of penetrating the stratum corneum of the patient's skin and delivering the fluid composition to a depth below the surface of the patient's skin. The device also includes a fluid distribution block having a distal surface coupled to a proximal surface of the base plate of the microneedle array, the fluid distribution block including a fluid distribution manifold defined therein and in fluid communication with the fluid outlet channels of the microneedles and configured to controllably distribute the fluid composition to the plurality of microneedles through the fluid outlet channels. The device also includes a syringe connection assembly having a fluid pathway defined therein, the syringe connection assembly including a distal end coupled to a proximal face of the fluid distribution block, where the fluid pathway of the syringe connection assembly is fluidly connected to the fluid distribution manifold, and a proximal end configured to be coupled to a syringe barrel having a bore defined therein, where the fluid pathway of the syringe connection assembly is fluidly connected to the bore of the syringe barrel.

[0007] The device may further include the following details, which details may be combined with each other in any combination unless they are clearly mutually exclusive.

[0008] (i) The syringe connection assembly may include a plenum coupled to and in fluid communication with a tubing connector. The tubing connector may have a distal portion coupled to a proximal surface of the plenum and a proximal portion configured to be fluidly connected to a bore of a syringe barrel. The plenum may be coupled to a proximal surface of a fluid distribution block and have a distal surface fluidly connected to a fluid distribution manifold.

[0009] (ii) the device may further include a first gasket disposed between and coupled to a distal end of the syringe connection assembly and a proximal face of the fluid distribution block, the first gasket may include an aperture fluidly connecting with the syringe connection assembly and a fluid pathway of the fluid distribution manifold.

[0010] (iii) The first gasket may have a proximal surface and a distal surface, the proximal surface and the distal surface having an adhesive layer disposed thereon and adapted to adhere a distal end of the syringe connection assembly to the proximal surface of the fluid distribution block.

[0011] (iv) The fluid distribution manifold may be configured to provide substantially equal flow rates of the fluid compositions to the outlet channels in each microneedle.

[0012] (v) the fluid distribution manifold may include a proximal inlet disposed in the proximal face of the fluid distribution block and in fluid communication with the distal end of the syringe connection assembly, a supply channel fluidly connected to the proximal inlet and configured to distribute the fluid composition to the plurality of resistance channels, a plurality of resistance channels fluidly connected to the supply channel and configured to provide a resistance to a flow of the fluid composition, and a plurality of outlet openings, each outlet opening fluidly connected to a resistance channel and a fluid outlet channel.

[0013] (vi) The fluid distribution block may include a proximal portion having a distal surface coupled to a proximal surface of the distal portion, and the supply channel and the resistance channel are disposed on the distal surface of the proximal portion and / or on the proximal surface of the distal portion.

[0014] (vii) The fluid distribution block may comprise a polymeric material, a glass material, and / or a silicon material, and the fluid distribution manifold may be formed therein by drilling, cutting, powder blasting, etching, or any combination thereof.

[0015] (viii) The proximal portion of the fluid distribution block and the distal portion of the fluid distribution block may be joined to one another.

[0016] (ix) The resistance channel may have a length of 400 μm to 1,000 μm; an axial depth of 10 μm to about 20 μm; and a lateral width of 15 μm to 70 μm.

[0017] (x) The plurality of microneedles may be 2 to 100 microneedles.

[0018] (xi) each of the resistance channels may include one or more inlet openings adapted to be fluidly connected to the supply channel. The resistance channels may include an inner resistance channel located proximal to a lateral center of the fluid distribution block and an outer resistance channel located distal to the lateral center of the fluid distribution block. The two or more inner resistance channels may be in fluid communication with one inlet opening and each outer resistance channel may be in fluid communication with one inlet opening.

[0019] (xii) The device may further include a protective cap coupled to a distal end of the syringe connection assembly and configured to protect the physical integrity and / or sterility of the microneedle fluid block assembly.

[0020] (xiii) The protective cap may be configured to be slidably coupled to the syringe connection assembly.

[0021] (xiv) The device may further include a syringe including a barrel, and the proximal end of the syringe connection assembly may be coupled to the syringe barrel and fluidly connected to the bore of the syringe barrel.

[0022] (xv) The syringe may further include a plunger slidably disposed within a longitudinal axis of the bore, the syringe adapted to expel a quantity of between 1 μl and 500 μl of the fluid composition disposed within the bore in response to an axial force applied to the plunger.

[0023] (xvi) The syringe may be adapted to expel a quantity of the fluid composition over a period of from 0.1 seconds to 300 seconds.

[0024] (xvii) The syringe may further include a fluid composition disposed within the bore.

[0025] (xviii) In response to an axial force applied to the plunger, the device may be adapted to deliver a fluid composition through the outlet channels of the multiple microneedles to a patient.

[0026] (xix) The device may be adapted to be manually operable by a user, the axial force being applied by the user's hand.

[0027] (xx) The microneedle further comprises nanotopography.

[0028] (xxi) The microneedle may have an axial length of about 50 μm to about 4000 μm, about 100 to about 3500 μm, about 150 μm to about 3000 μm, about 200 μm to about 3000 μm, about 250 μm to about 2000 μm, about 300 μm to about 1500 μm, or about 350 μm to about 1000 μm.

[0029] (xxii) The fluid composition may comprise a coronavirus vaccine.

[0030] (xxiii) The coronavirus vaccine may be an inactivated virus vaccine, a live virus vaccine, a recombinant protein vaccine, a vectored vaccine, an RNA vaccine or a DNA vaccine.

[0031] (xxiv) The coronavirus vaccine may be a SARS-CoV-2 vaccine.

[0032] (xxv) The SARS-CoV-2 vaccine may comprise a recombinant fusion protein comprising the coronavirus spike S1 protein or a fragment thereof linked to an immunoglobulin Fc region or a fragment thereof.

[0033] According to a second aspect, the present disclosure provides a method of delivering a fluid composition across a skin barrier of a patient, the method comprising inserting a plurality of microneedles of a device of the present disclosure across the skin barrier of a patient and delivering the fluid composition through fluid outlet channels of the plurality of microneedles to a location below the skin barrier.

[0034] The method may further include the following details, which details may be combined with each other in any combination unless they are clearly mutually exclusive.

[0035] (i) The plurality of microneedles may be 2 to 100 microneedles.

[0036] (ii) The total volume of the fluid composition delivered may be between 1 μL and 500 μL.

[0037] (iii) The fluid composition may be delivered to a patient at a rate of up to 20 μL, 19 μL, 18 μL, 17 μL, 16 μL, 15 μL, 14 μL, 13 μL, 12 μL, 11 μL, 10 μL, 9 μL, 8 μL, 7 μL, 6 μL, 5 μL, 4 μL, 3 μL, 2 μL, 1 μL, 0.5 μL, 0.1 μL, or 0.01 μL per second per microneedle.

[0038] (iv) The method may further include transporting the fluid composition to the patient's lymphatic system.

[0039] (v) The proximal end of the syringe connection assembly may be coupled to the syringe barrel and fluidly connected to a bore of the syringe barrel, the syringe may further include a plunger slidably disposed within a longitudinal axis of the bore, the syringe may be adapted to expel a quantity of between 1 μl and 500 μl of the fluid composition disposed within the bore in response to an axial force applied to the plunger, and the syringe may include the fluid composition disposed within the bore. The method may include placing a plurality of microneedles on the patient's skin proximate to a first location beneath the patient's skin, the first location being proximate to a lymphatic vessel and / or lymphatic capillary of the patient's lymphatic system; inserting the plurality of microneedles into the patient to a depth at least to which the epidermis is penetrated and at least one end of the microneedles is proximate to the first location; and delivering a quantity of a fluid composition from the device via the plurality of microneedles to the first location in response to applying an axial force to a plunger of a syringe.

[0040] (vi) The multiple microneedles may be inserted into the patient to a depth of about 50 μm to about 4000 μm, about 100 to about 3500 μm, about 150 μm to about 3000 μm, about 200 μm to about 3000 μm, about 250 μm to about 2000 μm, about 300 μm to about 1500 μm, or about 350 μm to about 1000 μm.

[0041] (vii) The fluid composition may be delivered to a lymph node, a lymphatic vessel, an organ that is part of the lymphatic system, or a combination thereof.

[0042] (viii) The lymph nodes may be selected from the group consisting of lymph nodes found in the hands, feet, thighs (femoral lymph nodes), arms, legs, armpits (axillary lymph nodes), groin (inguinal lymph nodes), neck (cervical lymph nodes), chest (pectoral lymph nodes), abdomen (iliac lymph nodes), popliteal lymph nodes, parasternal lymph nodes, lateral aortic lymph nodes, paraaortic lymph nodes, submental lymph nodes, parotid lymph nodes, submandibular lymph nodes, supraclavicular lymph nodes, intercostal lymph nodes, diaphragmatic lymph nodes, pancreatic lymph nodes, cisterna chyli, lumbar lymph nodes, sacral lymph nodes, obturator lymph nodes, mesenteric lymph nodes, mesocolic lymph nodes, mediastinal lymph nodes, gastric lymph nodes, hepatic lymph nodes, splenic lymph nodes, and any combination thereof.

[0043] (ix) The fluid composition may comprise a coronavirus vaccine.

[0044] (x) The coronavirus vaccine may be an inactivated virus vaccine, a live virus vaccine, a recombinant protein vaccine, a vectored vaccine, an RNA vaccine or a DNA vaccine.

[0045] (xi) The coronavirus vaccine may be a SARS-CoV-2 vaccine.

[0046] (xii) The SARS-CoV-2 vaccine may comprise a recombinant fusion protein comprising the coronavirus spike S1 protein or a fragment thereof linked to an immunoglobulin Fc region or a fragment thereof.

[0047] (xiii) The method may provide for delivery of approximately 10- to 40-fold higher concentrations of the coronavirus vaccine to a patient's lymph nodes compared to intravenous, subcutaneous, intramuscular, or intradermal administration routes.

[0048] (xiv) The method provides up to 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold increased levels of Th1 (e.g., CD4 + IFNγ +) T cells and Th2 (e.g., CD4 + IL-4 + ) T cells.

[0049] (xv) The method increases the ratio of Th1 to Th2 responses (e.g., CD4 + IFNγ + T Cells vs. CD4 + IL-4 + In some embodiments, the antibody may increase the ratio of T cells to total T cells by up to 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold.

[0050] (xvi) the method may provide an increase in Th1 T cells that is up to 1.5, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times greater than the increase in Th2 T cells.

[0051] (xvii) the method reduces or eliminates CD8+ expression in a patient compared to other routes of administration, such as intravenous, subcutaneous, intramuscular, or intradermal injection, of the same coronavirus vaccine given to a patient at the same dose. + (e.g., CD8 + IFNγ + ) T cells may be increased by up to 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold.

[0052] (xviii) The coronavirus vaccine may be in a concentration of up to 10 mg / mL, 9 mg / mL, 8 mg / mL, 7 mg / mL, 6 mg / mL, 5 mg / mL, 4 mg / mL, 3 mg / mL, 2 mg / mL or 1 mg / mL.

[0053] (xix) The device may be manually operated by a user and the axial force may be applied by the user's hand.

[0054] For a more complete understanding of the present disclosure and associated features and advantages, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, which are not to scale. [Brief description of the drawings]

[0055] [Figure 1A] FIG. 1A is a perspective exploded schematic view of an exemplary first set of components adapted to be combined to form a first exemplary microdosing device 10. FIG.

[0056] [Figure 1B] FIG. 1B is a perspective schematic diagram of the exemplary first set of components of FIG. 1A combined to form a first exemplary microdosing device 10. As shown in FIG.

[0057] [Figure 1C] FIG. 1C is a side view of the exemplary first set of components of FIG. 1B combined to form a first exemplary microdosing device 10. As shown in FIG.

[0058] [Figure 1D] FIG. 1D is a schematic diagram of a cross-sectional view of the first exemplary microdosing device 10 in plane BB of FIG. 1C.

[0059] [Figure 1E] FIG. 1E is a top-down schematic axial plan view of details of the first exemplary microdosing device 10. FIG.

[0060] [Figure 2A] FIG. 2A is a perspective schematic diagram of an exemplary microdosing device 10 including an attached protective cap 160 and syringe 20.

[0061] [Figure 2B] FIG. 2B is a perspective schematic view of an exemplary microdosing device 10 attached to a syringe 20, the microdosing device 10 including an attached protective cap 160.

[0062] [Figure 2C]FIG. 2C is a perspective schematic view of an exemplary microdosing device 10 with the protective cap 160 removed and attached to a syringe 20.

[0063] [Figure 2D] FIG. 2D is a schematic side view of an exemplary microdosing device 10 including a protective cap 160 attached to a syringe 20.

[0064] [Figure 2E] FIG. 2E is a schematic side view of an exemplary microdosing device 10 with the protective cap 160 removed and attached to the syringe 20.

[0065] [Figure 2F] FIG. 2F is a side schematic view of two exemplary distal ends 212 of a barrel 210 of a syringe 20 adapted to couple to a tubing connector 120 of a microdosing device 10.

[0066] [Figure 3A] FIG. 3A is a perspective schematic diagram of an exemplary microneedle fluid block assembly 150.

[0067] [Figure 3B] 3B is an exploded perspective schematic diagram of the exemplary microneedle fluid block assembly 150 of FIG. 3A, including a fluid distribution block 650 including a proximal layer 650a and a distal layer 650b, and a microneedle array 660.

[0068] [Figure 3C] FIG. 3C is a top-down schematic axial plan view of an exemplary microneedle fluid block assembly 150 showing a view of a plurality of microneedles 156 disposed on a base plate 300.

[0069] [Figure 3D] FIG. 3D is a side schematic view of an exemplary microneedle fluid block assembly 150.

[0070] [Figure 3E] FIG. 3E is detail A of FIG. 3D.

[0071] [Figure 3F] FIG. 3F is another schematic side view of an exemplary microneedle fluid block assembly 150.

[0072] [Figure 3G] FIG. 3G is a schematic axial plan view of an exemplary microneedle fluid block assembly 150 including an exemplary microneedle array 660 and exemplary proximal and distal layers 650 a and 650 b of an exemplary fluid distribution block 650 .

[0073] [Figure 3H] FIG. 3H is a schematic axial plan view of an exemplary distal layer 650b of the fluid distribution block 650 of the exemplary microneedle fluid block assembly 150.

[0074] [Figure 3I] FIG. 3I is detail B of FIG. 3H.

[0075] [Figure 3J] FIG. 3J is detail C of FIG. 3H.

[0076] [Figure 3K] FIG. 3K is a side schematic view of the proximal and distal layers 650 a and 650 b of an exemplary fluid distribution block 650 .

[0077] [Figure 3L] FIG. 3L is a schematic axial plan view of an exemplary proximal layer 650 a and a distal layer 650 b of an exemplary fluid distribution block 650 .

[0078] [Figure 3M]FIG. 3M is a table of exemplary parameters for an exemplary device design having the indicated combinations of resistance channel length, resistance channel depth, and resistance channel width, as well as the associated estimated fluid flow rate per microneedle at a pressure of 0.7 bar, and the estimated resistance ratio (R channel / R microneedle) based on a microneedle having an outlet channel with a length of 400 μm and a width of 40 μm.

[0079] [Figure 3N] FIG. 3N is a table of exemplary parameters for an exemplary device design having the indicated combinations of resistance channel length, resistance channel depth, and resistance channel width, as well as the associated estimated fluid flow rate per microneedle at a pressure of 1.0 bar, and the estimated resistance ratio (R channel / R microneedle) based on a microneedle having an outlet channel with a length of 400 μm and a width of 40 μm.

[0080] [Figure 4A] FIG. 4A is a perspective schematic diagram of an exemplary plenum 130.

[0081] [Figure 4B] FIG. 4B is a top-down axial plan view of the example plenum 130 of FIG. 4A.

[0082] [Figure 4C] FIG. 4C is an exemplary schematic diagram of a cross-sectional view in plane AA of FIG. 4B.

[0083] [Figure 4D] FIG. 4D is a schematic side view of the example plenum 130 of FIG. 4A.

[0084] [Figure 4E] FIG. 4E is a bottom-up schematic axial plan view of the example plenum 130 of FIG. 4A.

[0085] [Figure 5A]FIG. 5A is a top-down schematic axial plan view of an exemplary protective cap 160. FIG.

[0086] [Figure 5B] FIG. 5B is a schematic side view of an exemplary protective cap 160.

[0087] [Figure 5C] FIG. 5C is a bottom-up schematic axial plan view of an exemplary protective cap 160.

[0088] [Figure 5D] FIG. 5D is an exemplary schematic diagram of a cross-sectional view in plane AA of FIG. 5B.

[0089] [Figure 5E] FIG. 5E is detail B of FIG. 5D.

[0090] [Figure 6A] FIG. 6A is a perspective exploded schematic view of an exemplary second set of components adapted to combine to form the microdosing device 10.

[0091] [Figure 6B] FIG. 6B is a perspective schematic diagram of the exemplary second set of components of FIG. 6A combined to form an exemplary microdosing device 10.

[0092] [Figure 6C] FIG. 6C is a top-down schematic view of an exemplary microdosing device 10.

[0093] [Figure 6D] FIG. 6D is an exemplary schematic diagram of a cross-sectional view in plane AA of FIG. 6C.

[0094] [Figure 6E] FIG. 6E is detail B of FIG. 6D.

[0095] [Figure 7A] FIG. 7A is a perspective schematic diagram of a combination of proximal and distal layers 650 a and 650 b of an exemplary fluid distribution block 650 .

[0096] [Figure 7B] FIG. 7B is a schematic axial plan view of the combined proximal and distal layers 650a and 650b of the exemplary fluid distribution block 650 of FIG. 7A.

[0097] [Figure 7C] FIG. 7C is a detail B of FIG. 7B.

[0098] [Figure 7D] FIG. 7D is a schematic diagram of a cross-section in plane CC of FIG. 7C.

[0099] [Figure 7E] FIG. 7E is a detail D of FIG. 7D.

[0100] [Figure 7F] FIG. 7F is a side schematic view of the combined proximal and distal layers 650a and 650b of the exemplary fluid distribution block 650 of FIG. 7A.

[0101] [Figure 7G] FIG. 7G is detail A of FIG. 7F.

[0102] [Figure 8A] FIG. 8A is a perspective schematic diagram of an exemplary microneedle array 660.

[0103] [Figure 8B] FIG. 8B is a schematic axial plan view of the exemplary microneedle array 660 of FIG. 8A.

[0104] [Figure 8C] FIG. 8C is a detail B of FIG. 8B.

[0105] [Figure 8D] FIG. 8D is a schematic side view of the exemplary microneedle array 660 of FIG. 8A.

[0106] [Figure 8E] FIG. 8E is detail A of FIG. 8D.

[0107] [Figure 9A] FIG. 9A is a perspective schematic diagram of an exemplary draped microneedle array 900.

[0108] [Figure 9B] FIG. 9B is an exploded perspective schematic diagram of an exemplary microneedle array 660, a third gasket 1000 and a film 1100 adapted to be combined to form the exemplary draped microneedle array 900 of FIG. 9A.

[0109] [Figure 9C] FIG. 9C is a top-down schematic axial plan view of an exemplary draped microneedle array 900.

[0110] [Figure 9D] FIG. 9D is a side schematic view of an exemplary draped microneedle array 900.

[0111] [Figure 9E] FIG. 9E is detail A of FIG. 9D.

[0112] [Figure 10A] FIG. 10A is a perspective schematic diagram of a combination of proximal and distal layers 650a, 650b of an exemplary fluid distribution block 650. FIG.

[0113] [Figure 10B] FIG. 10B is a schematic axial plan view of the combined proximal and distal layers 650a and 650b of the exemplary fluid distribution block 650 of FIG. 10A.

[0114] [Figure 10C] FIG. 10C is detail A of FIG. 10B.

[0115] [Figure 10D] FIG. 10D is a schematic diagram of a cross-sectional view in plane BB of FIG. 10C.

[0116] [Figure 10E] FIG. 10E is detail C of FIG. 10D.

[0117] [Figure 10F] 10F is a detail view D of FIG. 10D.

[0118] [Figure 10G] FIG. 10G is a side schematic view of the combined proximal and distal layers 650a and 650b of the exemplary fluid distribution block 650 of FIG. 10A.

[0119] [Figure 10H] FIG. 10H is detail E of FIG. 10G.

[0120] [Figure 11] FIG. 11 is an exemplary near-infrared fluorescence (NIRF) image of indocyanine green (ICG) in the lymph of a mouse following injection of ICG using an exemplary microdosing device described herein coupled to a syringe described herein.

[0121] [Figure 12] FIG. 12 is a schematic diagram showing an exemplary time course of near-infrared fluorescence (NIRF) imaging of lymphatic delivery of ICG to the right brachial lymph node of a mouse.

[0122] [Figure 13A] FIG. 13A is a graph reporting an example of S1-specific serum IgG antibody optical density (OD, 450 nm) in mice following intramuscular injection of rS1-Fc vaccine.

[0123] [Figure 13B] FIG. 13B is a graph reporting an example of S1-specific serum IgG antibody optical density (OD, 450 nm) in mice following intradermal injection of rS1-Fc vaccine.

[0124] [Figure 13C] FIG. 13C is a graph reporting an example of S1-specific serum IgG antibody optical density (OD, 450 nm) in mice following SOFUSA® DoseConnect™ administration of rS1-Fc vaccine.

[0125] [Figure 14A] FIG. 14A is a graph showing box plots reporting examples of fold increase in T cell responses (Th1 and Th2) in mice following administration of SOFUSA® DoseConnect™ or rS1-Fc vaccine by intramuscular or intradermal injection.

[0126] [Figure 14B] FIG. 14B is a graph showing box plots reporting examples of fold increase in T cell responses (CD8+IFNγ+) in mice following administration of SOFUSA® DoseConnect™ or rS1-Fc vaccine by intramuscular or intradermal injection.

[0127] [Figure 14C] FIG. 14C is a graph reporting exemplary results of flow cytometry analysis of T cells from plasma of mice following administration of rS1-Fc vaccine with SOFUSA® DoseConnect™.

[0128] [Figure 14D] FIG. 14D is a graph showing box plots reporting an example of flow cytometric mean fluorescence intensity (MFI) quantification of CD4+IFNγ+ T cells, CD4+IL-4 T cells, and CD8+IFNγ+ T cells from mouse plasma following administration of rS1-Fc vaccine via SOFUSA® DoseConnect™.

[0129] [Figure 14E] FIG. 14E is a graph showing box plots reporting examples of fold increase in flow cytometric mean fluorescence intensity (MFI) quantification of CD4+IFNγ+ T cells, CD4+IL-4 T cells, and CD8+IFNγ+ T cells from plasma of mice following administration of rS1-Fc vaccine via SOFUSA® DoseConnect™ compared to flow cytometric MFI quantification of CD4+IFNγ+ T cells, CD4+IL-4 T cells, and CD8+IFNγ+ T cells from plasma of naive mice prior to administration of rS1-Fc vaccine via SOFUSA® DoseConnect™.

[0130] [Figure 15A-1] Figure 15A is a table listing SARS-CoV-2 candidate vaccines in preclinical trials (from the World Health Organization's Draft Landscape of COVID-19 Candidate Vaccines, accessed November 12, 2020). [Figure 15A-2] Same as above. [Figure 15A-3] Same as above. [Figure 15A-4] Same as above. [Figure 15A-5] Same as above. [Figure 15A-6] Same as above. [Figure 15A-7] Same as above. [Figure 15A-8] Same as above.

[0131] [Figure 15B-1] Figure 15B is a table listing SARS-CoV-2 candidate vaccines in clinical trials (from the World Health Organization's Draft Landscape of COVID-19 Candidate Vaccines, accessed November 12, 2020). [Figure 15B-2] Same as above. [Figure 15B-3] Same as above. [Figure 15B-4] Same as above. [Figure 15B-5] Same as above. [Figure 15B-6] Same as above. [Figure 15B-7] Same as above. [Figure 15B-8] Same as above. [Figure 15B-9] Same as above. [Figure 15B-10] Same as above.

[0132] [Figure 16] FIG. 16 is a schematic diagram of exemplary microneedle skin penetration depths for each microneedle of an exemplary 4×4 microneedle array (left image) and a graph reporting the frequency distribution of exemplary microneedle penetration results for the images shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0133] Unless otherwise indicated, the drawings provided herein are intended to depict features of embodiments of the present disclosure or the results of representative experiments illustrating some aspects of the subject matter disclosed herein. It is believed that these features and / or results are applicable to a wide variety of systems that include one or more embodiments of the present disclosure. Thus, the drawings are not intended to include all additional features known to those skilled in the art that are required to practice the embodiments, nor are they intended to limit the possible uses of the methods disclosed herein.

[0134] Detailed Description In the following description, details are set forth by way of example to facilitate discussion of the disclosed subject matter, however, it should be apparent to those skilled in the art that the disclosed embodiments and / or implementations are exemplary and do not encompass all possible embodiments and / or implementations.

[0135] The present disclosure relates generally to fluid delivery devices, and more specifically to devices configured for injection of microliter-scale doses of fluid (referred to herein as "microdosing devices"). The present disclosure also relates to methods of applying a microdosing device to a patient's skin to deliver a fluid composition across the patient's skin barrier, e.g., to the patient's lymphatic system. The present disclosure more particularly relates to a microdosing device adapted for microliter-scale injection of a coronavirus vaccine across a patient's skin barrier, e.g., the patient's lymphatic system. The present disclosure also relates to methods of administering a coronavirus vaccine across a patient's skin barrier, e.g., to the patient's lymphatic system.

[0136] As used herein, "skin barrier" refers to a portion of a subject's skin structure. The skin barrier may include one or more layers of skin (e.g., the stratum corneum, epidermis, and / or dermis). In some embodiments, the skin barrier includes the stratum corneum of a subject. In some embodiments, the skin barrier includes a portion of the epidermis of a subject. In some embodiments, the skin barrier includes the entire thickness of the epidermis of a subject. In some embodiments, the skin barrier includes at least a portion of the dermis of a subject.

[0137] As used herein, "lymphatic vasculature" includes any blood vessel or capillary that carries fluid to or from a lymph node. "In proximity to lymphatic vasculature" means sufficiently close to the lymphatic vasculature for materials from the fluid composition to be taken up by the lymphatic vasculature.

[0138] In some embodiments described herein, the microdosing device includes an array of microneedles and a fluid delivery system that can precisely control the flow from each microneedle. In use, the microneedles are adapted to penetrate the skin to a depth distributed between the epidermal and dermal skin layers in close proximity to lymphatic capillaries. This location of the microneedles can result in a primarily unidirectional transfer of fluid toward the lymphatic capillaries. In comparison, for example, conventional subcutaneous injections result in multidirectional transfer of fluid that diffuses by Brownian motion in all directions, reducing drug delivery to lymphatic capillaries. Furthermore, in some embodiments, a nanopatterned layer covering the microneedles can further enhance intralymphatic drug delivery by increasing paracellular and transcellular transport through the epidermal and dermal skin layers.

[0139] In various embodiments, the microdosing devices described herein provide for the delivery of microliter-scale amounts of a pharmaceutical composition, such as a coronavirus vaccine, across a patient's skin barrier and may induce a superior immune response compared to some existing devices. In some embodiments, a higher concentration of a pharmaceutical composition, such as a coronavirus vaccine, delivered to a patient's lymphatic system may effectively target dendritic cells beneath the surface of the patient's skin and induce a superior immune response compared to other delivery methods.

[0140] Further, the microdosing devices described herein advantageously provide a cost-effective solution for achieving lymphatic delivery of a pharmaceutical composition, such as a coronavirus vaccine. In addition to the relatively low cost of providing the microdosing device itself, small amounts of a pharmaceutical composition, such as a coronavirus vaccine, delivered to a patient provides a lower cost solution than using larger doses, and therefore provides a more efficient use of a limited supply of a pharmaceutical composition, such as a coronavirus vaccine. Advantageously, the microdosing devices, in some embodiments, can be used with existing syringes, including, but not limited to, use with syringes pre-filled with a pharmaceutical composition, such as a coronavirus vaccine. Further, in some embodiments, the microdosing devices described herein provide lymphatic delivery of a dose of a pharmaceutical composition, such as a coronavirus vaccine, in a shorter period of time than is typically achieved with existing devices. Furthermore, the microdosing devices described herein are simple to use and provide handheld, manual maneuverability for effective delivery of a pharmaceutical composition, such as a coronavirus vaccine, to a patient's lymphatic system, and are less painful than some existing delivery methods, such as intramuscular or intradermal injections.

[0141] For the purpose of promoting understanding of the principles of the present disclosure, reference will now be made to the embodiments and / or implementations shown in the drawings, and specific language will be used to describe them. Nevertheless, it will be understood that no limitation of the scope of the present disclosure is intended. Any modifications and further modifications to the described devices, methods, and any further applications of the principles of the present disclosure are fully contemplated as would normally occur to one skilled in the art to which the present disclosure pertains. In particular, it is fully contemplated that features, components, and / or steps described with respect to one embodiment and / or implementation may be combined with features, components, and / or steps described with respect to other embodiments and / or implementations of the present disclosure.

[0142] I. Microdosing Devices

[0143] In some embodiments, a device (herein referred to as a "microdosing device") configured to deliver a fluid composition across a skin barrier of a patient is described. The microdosing device includes a microneedle fluid block assembly including a microneedle array and a fluid distribution block. The microneedle array includes a plurality of microneedles disposed on a distal surface of a base plate. The microneedles have fluid outlet channels defined therein, and the microneedles are capable of penetrating the stratum corneum of the patient's skin and delivering the fluid composition to a depth below the surface of the patient's skin. The fluid distribution block has a distal surface coupled to a proximal surface of the base plate of the microneedle array. The fluid distribution block includes a fluid distribution manifold defined therein and in fluid communication with the fluid outlet channels of the microneedles and configured to controllably distribute the fluid composition to the plurality of microneedles through the fluid outlet channels. The microdosing device also has a syringe connection assembly having a fluid pathway defined therein. The syringe connection assembly includes a distal end coupled to a proximal face of the fluid distribution block, the fluid pathway of the syringe connection assembly being fluidly connected to the fluid distribution manifold. The syringe connection assembly also has a proximal end configured to be coupled to a syringe barrel having a bore defined therein, the fluid pathway of the syringe connection assembly being configured to be fluidly connected to the bore of the syringe barrel.

[0144] Certain illustrative embodiments of the microdosing device are shown in the drawings and described herein.

[0145] For example, Figures 1A-5E of the present disclosure show a first exemplary microdosing device 10 and its components. Figures 6A-8E of the present disclosure show a second exemplary microdosing device 10 and its components. Figures 9A-10H of the present disclosure show additional exemplary embodiments of the exemplary microdosing device 10 and its components.

[0146] 1A, 1B, 6A, and 6B, dashed line 110 indicates the longitudinal axis of the exemplary microdosing device 10 and components thereof described herein and shown in the drawings. Accordingly, it is to be understood that the schematic views of the drawings herein having an axial plan view are viewed along the longitudinal axis. It is also to be understood that the schematic views of the drawings herein having a side view are viewed at an angle substantially perpendicular to the longitudinal axis, and the term "lateral" refers to an orientation substantially perpendicular to the longitudinal axis of the microdosing device 10 or components thereof. The term "top-down" as used herein with respect to the drawings is understood to refer to an axial view from the distal end 101 of the microdosing device 10 or components thereof toward the proximal end 102 of the microdosing device 10 or components thereof. The term "bottom-up" as used herein with respect to the drawings is understood to refer to an axial view from the proximal end 102 of the microdosing device 10 or components thereof toward the distal end 101 of the microdosing device or components thereof. It should be understood that, in use, the fluid composition will generally flow in a proximal to distal direction as it is delivered from the microdosing device to a patient as described herein.

[0147] Referring to FIG. 1A, there is shown an oblique exploded schematic view of an exemplary first set of components adapted to be combined to form an exemplary microdosing device 10, as shown in FIG. 1B and described herein.

[0148] 1A includes a syringe connection assembly 11 that includes a tubing connector 120 and a plenum 130. The components of the exemplary microdosing device 10 shown in FIG. 1 also include a first gasket 140, a microneedle fluid block assembly 150, and a protective cap 160.

[0149] As can be seen from the exemplary drawings of Figures 1A and 1B, in some embodiments, a microdosing device of the present disclosure, such as the exemplary microdosing device 10 shown in Figure 1B, may be assembled from the exemplary components shown in Figure 1A described herein.

[0150] In some embodiments, the syringe connection assembly may be provided as a single component, for example formed in a single molded piece. In other embodiments, the syringe connection assembly may include one or more subcomponents configured to be fluidly connected to a bore of a syringe barrel to a fluid distribution manifold defined in the microneedle fluid block assembly. For example, as shown in the exemplary microdosing devices described herein, in some embodiments, the syringe connection assembly may include a plenum coupled and fluidly connected to the microneedle fluid block assembly, and may further include a tubing connector coupled and fluidly connected to the plenum and configured to be coupled and fluidly connected to the syringe barrel. With reference to the first exemplary microdosing device 10, as shown in FIGS. 1A and 1B, the exemplary syringe connection assembly 11 includes an exemplary tubing connector 120 and a plenum 130. A distal portion 121 of the tubing connector 120 is adapted to be coupled to a proximal surface 132 of the plenum 130. The distal portion 121 of the tubing connector 120 may be adapted to be slidably coupled to a proximal surface 132 of the plenum 130. As shown in more detail in FIG. 1D , the proximal portion 121 of the tubing connector 120 may be adapted to be slidably coupled within a proximal well 133 of the plenum 130. The distal portion 121 of the tubing connector 120 may contact a proximal seat 134 of the plenum 130 at a distal end of the proximal well 133. The tubing connector 120 defines a tube 123 therein adapted to allow fluid to flow therethrough. The distal portion 121 of the tubing connector 120 and the proximal surface 132 of the plenum 130 are adapted to be coupled to one another to allow fluid to flow from within the tube 123 of the tubing connector 120 to an orifice 135 disposed within the plenum 130. It should be understood that in the exemplary microdosing device 10 of FIG. 1A, the tube 123 of the tubing connector 120 and the orifice 135 of the plenum 130 are adapted to be fluidly connected to each other to form a fluid pathway of the syringe connection assembly 11.The proximal seat 134 of the plenum 130 and the distal portion 121 of the tubing connector 120 may be coupled together such that the fluid connection between the tube 123 and the orifice 135 is sealed, such that the coupling prevents leakage of fluid therethrough. In some embodiments, such as the example shown in FIGS. 1A-1E where the distal portion 121 of the tubing connector 120 is adapted to be slidably coupled to the proximal face 132 of the plenum 130, the inner wall 136 of the proximal well 133 of the plenum 130 (see, e.g., FIG. 4C ) and the distal portion 121 of the tubing connector 120 may be coupled together by a friction fit such that the fluid connection between the tube 123 and the orifice 135 prevents leakage of fluid therethrough.

[0151] In some embodiments, the distal portion 121 of the tubing connector 120 and the proximal surface 132 of the plenum 130 may be bonded to one another using an adhesive such as, for example, Loctite 3979, or other suitable adhesive identifiable by one of ordinary skill in the art. The bond between the distal portion 121 of the tubing connector 120 and the proximal surface 132 of the plenum 130 may provide a sealed fluid connection such that the bond between the distal portion 121 of the tubing connector 120 and the proximal surface 132 of the plenum 130 prevents leakage of fluid therethrough.

[0152] In some embodiments, the distal portion 121 of the tubing connector 120 may be adapted to be coupled to the proximal surface 132 of the plenum 130 by matching threads. In such embodiments, the distal portion 121 of the tubing connector 120 may have threads disposed thereon that mate with threads disposed on the proximal surface 132 of the plenum 130. Thus, in such embodiments, for example, the inner wall 136 of the proximal well 133 of the plenum 130 (see, e.g., FIG. 4C ) and the distal portion 121 of the tubing connector 120 may be adapted to form a sealed connection between the tube 123 and the orifice 135, which prevents leakage of fluid therethrough when coupled to one another via the respective threads disposed thereon.

[0153] In some embodiments, the plenum 130 and the tubing connector 120 may be coupled to one another by adhesive bonding, a welded joint (e.g., spin welding, ultrasonic welding, laser welding, or heat staking), etc. In some embodiments, the plenum 130 and the tubing connector 120 may be coupled to one another using any connection technique that allows for the formation of the syringe connection assembly 11.

[0154] In some embodiments, the plenum 130 and the tubing connector 120 may be formed from any suitable material, such as a plastic material or other polymer, such as a cyclic olefin copolymer, among others.

[0155] In some embodiments, tubing connector 120 may be a commercially available component, such as a female luer adapter available from Qosina Corp (Ronkonkoma, NY; Part No. 11203).

[0156] In some embodiments, when the tubing connector 120 is connected to the plenum 130 to form the syringe connection assembly 11, the axial length from the proximal end 122 of the tubing connector 120 to the distal face 131 of the plenum 130 may be approximately 17 mm.

[0157] In some embodiments, the microdosing device 10 may include a first gasket 140 disposed between and coupled to the syringe connection assembly 11 and the microneedle fluid block assembly 150. In some embodiments, such as shown in FIG. 1A, for example, the first gasket 140 is adapted to be coupled to the distal surface 131 of the plenum 130. The proximal surface 142 of the first gasket 140 may be coupled to the plenum 130 in a distal seat 137 disposed in the distal surface 131 of the plenum 130. The first gasket 140 may be sized such that the side edge 141 of the first gasket 140 is adapted to be coupled to an inner wall 138 (see, for example, FIG. 4A) surrounding the distal seat 137 disposed in the distal surface 131 of the plenum 130. The proximal surface 142 of the first gasket 140 may be adapted to adhere to the distal surface 131 of the plenum 130. The first gasket 140 may be a pressure sensitive adhesive (PSA) gasket. The first gasket 140 may have an adhesive disposed on a proximal surface 142 of the first gasket 140 and / or a distal surface 143 of the first gasket 140. The first gasket 140 has holes 144 adapted to allow fluid to flow through the first gasket 140 from the proximal surface 142 of the first gasket 140 to the distal surface 143 of the first gasket 140. When the first gasket 140 is coupled to the plenum 130, the holes 144 of the first gasket 140 may be fluidly connected to the orifices 135 of the plenum 130. In some embodiments, the device may not include a first gasket 140 disposed between and coupled to the syringe connection assembly 11 and the microneedle fluid block assembly 150. In some embodiments, a distal portion of the syringe connection assembly 11, e.g., the distal surface of the plenum 130, may be coupled to the microneedle fluid block assembly 150, for example, by overmolding a distal portion of the syringe connection assembly 11, e.g., the distal surface of the plenum 130, around a portion of the microneedle fluid block assembly 150.In some embodiments, an overmolding of a distal portion of the syringe connection assembly 11, such as the distal face of the plenum 130, may provide a leak-proof fluid connection between the syringe connection assembly 11 and the microneedle fluid block assembly 150.

[0158] In some embodiments, the lateral diameter of the distal surface 131 of the plenum 130 may be about 10.33 mm (see, e.g., "(A)" shown in FIG. 4C). In some embodiments, the lateral diameter of the distal seat 137 of the plenum 130 may be about 5.71 mm (see, e.g., "(B)" shown in FIG. 4C). In some embodiments, the axial depth of the proximal well 133 of the plenum 130 may be about 2.12 mm (see, e.g., "(C)" shown in FIG. 4C). In some embodiments, the lateral inner diameter within the inner wall 136 of the proximal well 133 of the plenum 130 may be about 5.45 mm (see, e.g., "(D)" shown in FIG. 4C and "(A)" shown in FIG. 4E). In some embodiments, the axial depth of the distal seat 137 of the plenum 130 may be about 0.88 mm (see, e.g., "(E)" shown in FIG. 4C).

[0159] In some embodiments, the lateral diameter of the orifice 135 of the plenum 130 may be about 1.23 mm. (See, for example, "(B)" shown in FIG. 4B.) In some embodiments, the diameter of the hole 144 of the first gasket 140 may be about 1.23 mm.

[0160] In some embodiments, the axial length between the proximal face 132 of the plenum 130 and the distal face 131 of the plenum 130 may be about 4.00 mm (see, for example, "(A)" shown in FIG. 4D). In some embodiments, the lateral outer diameter of the outer wall 139 of the proximal well 133 of the plenum 130 may be about 7.61 mm (see, for example, "(B)" shown in FIG. 4D).

[0161] 3A-3J, the microneedle fluid block assembly 150 of the first exemplary microdosing device 10 includes a microneedle array 660 including a plurality of microneedles 156 disposed on a distal surface 152 of a base plate 300, which also has a proximal surface 96 (see, e.g., FIGS. 1A and 3A-3J). Each of the microneedles 156 has a base 158 coupled to the distal surface 152 of the base plate 300 and extending distally away from the base plate 300 to a distal end including a tip 159. The tip 159 may have a puncture or needle-like shape, such as a cone or pyramid shape, or a cylinder that transitions to a cone or pyramid shape.

[0162] The tip 159 of each microneedle 156 is disposed furthest from the base plate 300 and may define a minimum dimension (e.g., diameter or cross-sectional width) of each microneedle 156. Further, each microneedle 156 may generally define any suitable axial length between its base 158 and its tip 159 sufficient for the microneedle 156 to penetrate the stratum corneum of a patient. In some embodiments, it may be desirable to limit the length of the microneedle 156 so that it does not penetrate the inner surface of the epidermis and enter the dermis, which may advantageously help minimize pain to a patient receiving the fluid.

[0163] In some embodiments, each microneedle 156 may have an axial length of about 50 μm to about 4000 μm, about 100 to about 3500 μm, about 150 μm to about 3000 μm, about 200 μm to about 3000 μm, about 250 μm to about 2000 μm, about 300 μm to about 1500 μm, or about 350 μm to about 1000 μm. In some embodiments, each microneedle 156 may have an axial length of less than about 1000 micrometers (μm), such as less than about 800 μm, or about 750 μm or less, or about 500 μm or less (e.g., lengths in the range of about 200 μm to about 400 μm), or any other subrange therebetween. In one example, the microneedle 156 can have an axial length from base 158 to tip 159 of about 400 μm (eg, as shown by "(A)" in FIG. 3E).

[0164] The length of the microneedles 156 may vary depending on the intended location in which the microdosing device 10 will be used on a patient. For example, the length of the microneedles 156 of a microdosing device 10 used on a patient's leg may be substantially different than the length of the microneedles 156 of a microdosing device 10 used on a patient's arm. Each microneedle 156 may generally define any suitable aspect ratio (i.e., the axial length across the cross-sectional lateral width dimension of each microneedle 156). The aspect ratio may be greater than 2, such as greater than 3, or even 4 or more. Where the cross-sectional width dimension (e.g., diameter) varies across the length of each microneedle 156, the aspect ratio may be determined based on the average cross-sectional width dimension.

[0165] As used herein, "aspect ratio" refers to the ratio of the axial length of a microneedle to a cross-sectional transverse dimension perpendicular to the length (e.g., width or diameter) of the microneedle. When the cross-sectional dimension (e.g., the diameter of a cone-shaped projection) varies over the length, the aspect ratio is determined based on the average cross-sectional transverse dimension, unless otherwise indicated.

[0166] In some embodiments, the plurality of microneedles 156 are adapted to penetrate the patient's skin and deliver a fluid, such as a liquid pharmaceutical composition, to the patient's lymphatic system.

[0167] Examples of microneedle arrays include those described in International Publication No. WO 2012 / 020332, International Publication No. WO 20111070457, International Publication No. WO 2011 / 135532, U.S. Patent Application Publication No. 2011 / 0270221, U.S. Patent Application Publication No. 2013 / 0165861, U.S. Patent Application Publication No. 2019 / 90143090, and U.S. Provisional Patent Application No. 61 / 996,148 and U.S. Provisional Patent Application Publication No. 62 / 942,971, each of which is incorporated by reference herein in its entirety.

[0168] In general, the microneedle fluid block assembly 150 may have any suitable configuration known in the art for delivering fluid through the patient's skin to the patient's lymphatic system. The fluid distribution block 650, base plate 300 and microneedles 156 may generally be constructed from rigid, semi-rigid or flexible sheets of material, such as metallic, ceramic, polymeric (e.g., plastic) materials and / or any other suitable material. For example, the fluid distribution block 650, base plate 300 and microneedles 156 may be formed from silicon by reactive ion etching or in any other suitable manner.

[0169] 1A , the proximal surface 151 of the microneedle fluid block assembly 150 is adapted to be coupled to the distal surface 143 of the first gasket 140. The proximal surface 151 of the microneedle fluid block assembly 150 may be adapted to be coupled to the distal surface 143 of the first gasket 140, for example, by bonding the proximal surface 151 of the microneedle fluid block assembly 150 to the distal surface 143 of the first gasket 140.

[0170] In some embodiments, the plenum 130 is adapted to be slidably coupled to the microneedle fluid block assembly 150 and configured to hold the microneedle fluid block assembly 150. For example, as shown in FIG. 1E, the base plate 300 of the microneedle fluid block assembly 150 may be sized such that a side edge 663 of the base plate 300 is adapted to be coupled to an inner wall 138 of a distal seat 137 disposed on the distal surface 131 of the plenum 130. The side edge 663 of the base plate 300 may be glued to the inner wall 138 of the distal seat 137 disposed on the distal surface 131 of the plenum 130 using an adhesive such as, for example, Loctite 3979, or other suitable adhesive identifiable by one of skill in the art. An adhesive may be applied between the side edge 663 of the base plate 300 and the inner wall 138 of the distal seat 137 disposed on the distal surface 131 of the plenum 130, for example, in a continuous bead (see, for example, adhesive 90 in FIG. 1E).

[0171] In some embodiments, the plenum 130 and the microneedle fluid block assembly 150 may be coupled to one another via, for example, but not limited to, an adhesive bond, a welded joint (e.g., spin welding, ultrasonic welding, laser welding, or heat staking), or the like.

[0172] In some embodiments, the microneedle fluid block assembly 150 includes a fluid distribution block 650 including a fluid distribution manifold extending therethrough. The fluid distribution manifold is configured to provide a substantially uniform supply, e.g., substantially equal flow rates, of the fluid composition to the outlet channels 155c in each microneedle 156. A distal surface 97 of the fluid distribution block 650 may be bonded to a proximal surface 96 of the base plate 300, e.g., by an adhesive. The fluid distribution manifold may be configured to supply the fluid composition to the fluid outlet channels 155c in one or more microneedles 156, e.g., as shown in FIG. 3B.

[0173] In some embodiments, the fluid distribution manifold includes a proximal inlet 154 that forms an opening in a proximal face 151 of the fluid distribution block 650 (see, e.g., FIG. 3B). In some embodiments, the proximal inlet 154, if present, is adapted to allow fluid to flow from the holes 144 of the first gasket 140 to the supply channels 155a and resistance channels 155b (see below) of the fluid distribution manifold disposed within the fluid distribution block 650.

[0174] In some embodiments, the first gasket 140 may not be present, such that the proximal surface 151 of the fluid distribution block 650 may be coupled to a distal end of the syringe connection assembly, e.g., the distal surface 131 of the plenum 130, and the proximal inlet 154 of the fluid distribution block 650 is fluidly connected to the fluid path of the syringe connection assembly 11. In some embodiments, for example, the proximal surface 151 of the fluid distribution block 650 and the distal surface 131 of the plenum 130 may be bonded to one another using an adhesive, e.g., Loctite 3979 or other suitable adhesive. The bonding of the proximal surface 151 of the fluid distribution block 650 to the distal surface 131 of the plenum 130 may further provide a sealed connection between the proximal surface 151 of the fluid distribution block 650 and the distal surface 131 of the plenum 130 adapted to prevent leakage of fluid as the fluid enters the proximal inlet 154 of the fluid distribution block 650 from the fluid path of the syringe connection assembly 11.

[0175] The fluid distribution manifold is adapted to receive fluid through the proximal inlet 154 of the microneedle fluid block 150 and distribute the fluid to fluid outlet channels 155c in one or more microneedles 156 (see, e.g., Figures 3A-3F).

[0176] In some embodiments, for example as shown in FIG. 1D , when the microneedle fluid block assembly 150 is positioned within the distal seat 137 of the distal surface 131 of the plenum 130, the axial distance between the tip 159 of the microneedle 156 and the distal surface 131 of the plenum 130 (e.g., as shown by “(A)” in FIG. 1D ) may be about 0.45 mm.

[0177] In some embodiments, the fluid distribution block 650 may be formed by joining a proximal layer 650a, including a proximal inlet 154 formed therethrough, to a distal layer 650b, including an outlet opening 302 formed therethrough. The supply channels 155a and / or resistance channels 155b may be formed in the distal surface 99 of the proximal layer 650a and / or the proximal surface 98 of the distal layer 650b.

[0178] In some embodiments, the proximal layer 650a and the distal layer 650b of the fluid distribution block 650 may comprise a glass material. In some embodiments, the proximal layer 650a and the distal layer 650b of the fluid distribution block 650 may comprise silicon. The proximal layer 650a and the distal layer 650b may be fabricated from different materials in any combination that enables the fluid distribution block 650 to function as described herein. In some embodiments, the proximal layer 650a may comprise glass and the distal layer 650b may comprise silicon.

[0179] The inlets 154 may be formed in the proximal layer 650a by drilling, cutting, etching, and / or powder blasting, or any other manufacturing technique for forming channels or openings through the proximal layer 650a. In some embodiments, the feed channels 155a and resistor channels 155b are formed in the distal surface 99 of the proximal layer 650a and / or the proximal surface 98 of the distal layer 650b using etching techniques. For example, in some embodiments, wet etching or hydrofluoric acid etching is used to form the feed channels 155a and resistor channels 155b. In another suitable embodiment, deep reactive ion etching (DRIE or plasma etching) may be used to create deep, high density, high aspect ratio feed channels 155a and resistor channels 155b in the distal surface 99 of the proximal layer 650a and / or the proximal surface 98 of the distal layer 650b. Alternatively, the supply channels 155a and resistor channels 155b can be formed in the distal surface 99 of the proximal layer 650a and / or the proximal surface 98 of the distal layer 650b using any manufacturing process that enables the fluid distribution block 650 to function as described herein. The outlet openings 302 may be formed through the distal layer 650b by drilling, cutting, etching, and / or powder blasting, or any other manufacturing technique for forming channels or openings through the distal layer 650b. Suitable commercially available etching and lithography processes that may be used in manufacturing the channels, microneedles, etc. of the microdosing devices described herein are available, for example, from Micronit Micro Technologies BV (Enschede, The Netherlands).

[0180] In some embodiments, the proximal layer 650a and the distal layer 650b may be bonded together in face-to-face contact to seal the edges of the supply channels 155a and the resistor channels 155b of the fluid distribution manifold to provide a leak-proof fluid connection between the supply channels 155a and the resistor channels 155b of the proximal layer 650a and the distal layer 650b. In some embodiments, direct bonding or direct aligned bonding may be used by creating a pre-bond between the proximal layer 650a and the distal layer 650b. The pre-bond may include applying a bonding agent to the distal surface 99 of the proximal layer 650a and / or the proximal surface 98 of the distal layer 650b before directly contacting the proximal layer 650a and the distal layer 650b. The proximal layer 650a and the distal layer 650b may be aligned, brought into face-to-face contact, and annealed at high temperature. In some embodiments, anodic bonding may be used to bond the proximal layer 650a and the distal layer 650b together. For example, an electric field may be applied across the bond interface at the distal surface 99 of the proximal layer 650a and / or the proximal surface 98 of the distal layer 650b while the proximal layer 650a and / or the distal layer 650b are heated. In an alternative embodiment, the proximal layer 650a and the distal layer 650b may be bonded together using a laser assisted bonding process that includes applying localized heat to the distal surface 99 of the proximal layer 650a and / or the proximal surface 98 of the distal layer 650b to bond them together.

[0181] In some embodiments, for example as shown in Figures 3A-3F, the fluid distribution block 650 can include a proximal layer 650a that includes the supply channels 155a of the fluid distribution manifold and a distal layer 650b that includes the resistance channels 155b of the fluid distribution manifold.

[0182] In various embodiments, the fluid distribution manifold includes a plurality of channels and / or openings extending between the proximal surface 151 and the distal surface 97 of the fluid distribution block 650. In some embodiments, each of the supply channels 155a is fluidly coupled to a plurality of resistance channels 155b. In some embodiments, the resistance channels 155b extend away from the supply channels 155a and are configured to promote an increase in the resistance of the fluid distribution manifold to the flow of fluid. Each resistance channel 155b may be fluidly coupled to an outlet opening 302. Each outlet opening 302 may be aligned with an outlet channel 155c of a microneedle 156 to distribute fluid through the outlet channel 155c. In some embodiments, the resistance channels 155b may be formed in any configuration that enables the fluid distribution block 650 to function as described herein.

[0183] In some embodiments, the resistance channels 155b can have an inner axial and / or lateral diameter that is smaller than an inner axial and / or lateral diameter of the supply channels 155a. Additionally, the resistance channels 155b can be formed to form a tortuous flow path for the fluid, thereby facilitating an increase in the fluid distribution manifold's resistance to fluid flow.

[0184] Each microneedle 156 may define one or more outlet channels 155c in fluid communication with a fluid distribution manifold defined in the fluid distribution block 650. In general, the outlet channels 155c may be defined at any suitable location within each microneedle 156. For example, the outlet channels 155c may be defined along an outer surface of each microneedle 156. Alternatively and / or additionally, the outlet channels 155c may be defined through an interior of the microneedle 156 such that each microneedle 156 forms a hollow shaft. The supply channels 155a, the resistance channels 155b, and the fluid outlet channels 155c may be configured to define any suitable cross-sectional shape. For example, each supply channel 155a, the resistance channel 155b, and / or the fluid outlet channel 155c may define a semicircular or circular shape, or a non-circular shape, such as a "v" shape or any other suitable cross-sectional shape. In some embodiments, the exit channel 155c of the microneedle 156 may terminate in an exit hole 157.

[0185] In some embodiments, for example as shown in Figures 3G-3J, each of the resistor channels 155b may include one or more inlet openings 301 adapted to be coupled and fluidly connected to the supply channel 155a. Each of the resistor channels 155b may also include one or more outlet openings 302 adapted to be coupled and fluidly connected to the outlet channel 155c. Each outlet channel 155c may extend through the base plate 300 as well as through the microneedle 156 (see, for example, Figure 3F).

[0186] In some embodiments, for example as shown in FIG. 3B, the distal surface 99 of the proximal layer 650a is adapted to be coupled to the proximal surface 98 of the distal layer 650b, and the distal surface 97 of the proximal layer 650b is adapted to be coupled to the proximal surface 96 of the base plate 300 such that the proximal inlets 154 of the microneedle fluid block 150 are in fluid communication with the outlet channels 155c of the microneedles 156 via the fluid distribution manifold. The proximal layer 650a, the distal layer 650b and the base plate 300 are adapted to form a sealed, leak-proof fluid connection when coupled together. The proximal layer 650a and the distal layer 650b may be bonded together with an adhesive and / or the distal layer 650b and the base plate 300 may be bonded together with an adhesive or other bonding methods described herein.

[0187] In some embodiments, for example as shown in FIG. 3A , when the proximal layer 650a, the distal layer 650b and the base plate 300 of the microneedle fluid block assembly 150 are coupled to one another, the supply channel 155a, the resistor channel 155b and the outlet channel 155c are adapted to fluidly connect and are configured to allow fluid to flow through the microneedle fluid block assembly 150.

[0188] In some embodiments, the arrangement and dimensions of the supply channels 155a, resistance channels 155b and / or outlet channels 155c of the microneedle fluid block assembly 150 are configured to provide suitable resistance to movement of fluid such that the flow of fluid through each microneedle 156 is substantially the same, thereby substantially equally distributing the distal flow of fluid from the proximal inlet 154 to each of the microneedles 156 and providing a suitable fluid flow rate through each of the microneedles 156.

[0189] In some embodiments, for example, as shown in FIG. 3K, the proximal layer 650a may have an axial thickness of about 0.7 mm (see, for example, "(H)" in FIG. 3K). In some embodiments, for example, as shown in FIG. 3K, the distal layer 650b may have an axial thickness of about 0.5 mm (see, for example, "(I)" in FIG. 3K).

[0190] 3K, in some embodiments, the proximal inlet 154 of the fluid distribution block 650 may have an axially tapered or funnel-like shape. For example, in some embodiments, the proximal inlet 154 may have a transverse diameter of about 0.6 mm to 0.4 mm, e.g., about 0.50 mm, at the proximal surface 151 of the proximal layer 650a of the fluid distribution block 650 (see, e.g., FIG. 3K, "B") and a transverse diameter of about 0.15 mm to 0.35 mm, e.g., about 0.25 mm, at the distal surface 99 of the proximal layer 650a of the fluid distribution block 650 (see, e.g., FIG. 3K, "C"). For example, in some embodiments, the outlet opening 302 may have a lateral diameter of about 0.09 mm to 0.23 mm, e.g., about 0.16 mm, at the proximal surface 98 of the distal layer 650b of the fluid distribution block 650 (see, e.g., “(D)” in FIG. 3K), and may have a lateral diameter of about 0.23 mm to 0.37 mm, e.g., about 0.3 mm, at the distal surface 97 of the distal layer 650b of the fluid distribution block 650 (see, e.g., “(E)” in FIG. 3K).

[0191] In some embodiments, the supply channel may have an axial depth of about 40 μm (see, e.g., FIG. 3K, “(G)”) and a lateral width of about 200 μm (see, e.g., FIG. 3L, “(A)”).

[0192] In particular, in some embodiments, the dimensions of the resistance channel 155b may be varied to provide a range of fluid flow rates. It should be understood that one or more of the length, axial depth, and / or lateral width of the resistance channel 155b may be varied in any combination. The distance along the resistance channel from the inlet opening 301 to the outlet opening 302 may define the length of the resistance channel 155b (see, e.g., FIG. 3L). The depth of an exemplary resistance channel 155b is shown diagrammatically in FIG. 3K (see "(F)" in FIG. 3K). The width of an exemplary resistance channel 155b is shown diagrammatically in FIG. 3I and FIG. 3J (see "(X)" in FIG. 3I and FIG. 3J).

[0193] For example, in some embodiments, the length of the resistance channel 156 may be about 400 μm to about 1,000 μm, such as about 400 μm, 450 μm, 500 μm, 550 μm, 600 μm, 650 μm, 700 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950 μm, or 1,000 μm. In some embodiments, the axial depth of the resistance channel 156 may be about 10 μm to about 20 μm, such as about 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, or 20 μm. In some embodiments, the lateral width of the resistive channel 156 may be from about 15 μm to about 70 μm, such as about 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, or 70 μm. Various values ​​of length, depth, and width of the resistive channel may be used in any combination.

[0194] For example, the tables of Figures 3K and 3L show various exemplary combinations of resistance channel length, depth and width used in the exemplary fluid distribution block, as shown, for example, in microdosing device designs D01-D15. For each exemplary design, an associated estimated fluid flow rate per microneedle is shown in response to forcing fluid into the device using a syringe as described herein. For each of the exemplary designs, the pressure of the fluid flowing through the microdosing device is 0.7 bar (Figure 3M) or 1.0 bar (Figure 3N), and an estimated resistance ratio (R channel / R microneedle) is shown based on a microneedle having an outlet channel with a length of 400 μm and a width of 40 μm. It should be understood that the fluid flow rate per microneedle is multiplied by the number of microneedles per microdosing device to provide the total fluid flow rate of the microdosing device. For example, for a device with 16 microneedles, the estimated flow rate per microneedle shown in the tables of Figures 3M and 3N is multiplied by 16. For example, in response to an axial fluid delivery force resulting in a pressure of 1.0 bar, a device having 16 microneedles and exemplary dimensions such as design D07 shown in the table in FIG. 3N provides a microdose device flow rate of 18,735 μL / hr per microneedle × 16 microneedles = 299,760 μL / hr, which corresponds to a total microdose flow rate of 83.27 μL per second for the exemplary D07 design microdose device with 16 microneedles.

[0195] In some embodiments, the outlet opening 302 may have a diameter of 0.04 mm (see, e.g., "(Y)" in Figures 3I and 3J), as shown in Figures 3I and 3J. In the exemplary resistor channel 155b shown in Figures 3I and 3J, the outlet opening 302 is configured to couple to the outlet channel 155c of the exemplary microneedle fluid block assembly 150, as shown in Figures 3B and 3C, and is spaced apart, e.g., a distance of 0.9 mm.

[0196] In some embodiments, the dimensions of the outlet channels 155c may be selected to induce capillary flow of the fluid delivered by the microdosing device. Without being limited by theory, in some embodiments, the capillary pressure in the outlet channels 155c is inversely proportional to the cross-sectional dimension of the outlet channels 155c, directly proportional to the surface energy of the fluid of interest, multiplied by the cosine of the contact angle of the liquid at the interface defined between the liquid and the external channel. Thus, to promote capillary flow of the fluid through the microneedle fluid block assembly 150, the cross-sectional width dimension of the outlet channels 155c (e.g., the diameter of the outlet channels 155c) may be selectively controlled, with smaller dimensions generally resulting in higher capillary pressure. For example, the cross-sectional width dimension of the outlet channels 155c may be selected such that, with respect to the width of each outlet channel 155c, the cross-sectional area of ​​each outlet channel 155c is approximately 1,000 square microns (μm 2 ) ~ approx. 125,000μm 2 , for example, about 1,250 μm 2 ~about 60,000μm 2 , or about 6,000 μm 2 ~about 20,000μm 2 , or any other subrange therebetween.

[0197] Further details of an exemplary embodiment of the microneedle fluid block assembly 150 are shown in Figures 3C-3J. In some embodiments, as shown in the example microneedle fluid block assembly 150 of Figure 3C, the plurality of microneedles 156 may include an array of 16 microneedles 156 arranged on the distal surface 152 of the base plate 300 in a square 4 x 4 arrangement. It should be understood that other numbers of microneedles and / or other arrangements of microneedles are contemplated, as described further herein.

[0198] The plurality of microneedles 156 may generally include any suitable number of microneedles 156 disposed on the base plate 300. For example, the number of microneedles 156 may be about 10 microneedles per square centimeter (cm 2 ) ~ approx. 1,500 microneedles / cm2 , for example about 50 microneedles / cm 2 ~Approximately 1250 microneedles / cm 2 , or about 100 microneedles / cm 2 ~About 500 microneedles / cm 2 , or any other subrange therebetween.

[0199] For example, in some embodiments, the plurality of microneedles may be between 2 and 100 microneedles, e.g., between 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, It may comprise 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 microneedles.

[0200] The microneedles of the microneedles described herein need not be identical to one another: the microneedles may have different lengths, outer diameters, inner diameters, cross-sectional shapes, nanotopography surfaces, and / or spacing.

[0201] The microneedles may be uniformly or non-uniformly or randomly spaced apart on the distal surface 152 of the base plate 300, or may be arranged thereon in other arrangements, such as circles, triangles, crosses, or other patterns. The microneedles 156 may generally be arranged on the base plate 300 in a variety of different patterns, and such patterns may be designed for any particular use. For example, in some embodiments, the microneedles 156 may be spaced apart in a uniform manner, such as a rectangular or square grid or concentric circles. In such embodiments, the spacing of the microneedles 156 may generally depend on a number of factors, including, but not limited to, the length and width of the microneedles 156, and the amount and type of fluid intended to be delivered through or along the microneedles 156.

[0202] In some embodiments, the spacing between each microneedle may be about 1 μm to about 1500 μm, including each integer within the specified range. In some aspects, the spacing between each microneedle may be about 200 μm, about 300 μm, about 400 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm, about 1000 μm, about 1100 μm, about 1200 μm, about 1300 μm, about 1400 μm, or about 1500 μm. When used in this context, "about" means ±50 μm.

[0203] In the example shown in FIG. 3C, the microneedles 156 are uniformly spaced in a 4×4 square array of four microneedles 156 in each of four parallel rows, each row spaced 0.9 mm apart (see FIG. 3C “A”), each microneedle 156 is spaced 0.9 mm apart from the nearest microneedle 156 in the same row, for example (see FIG. 3C “A”), and the total length of each row is 2.7 mm (see FIG. 3C “B” and “C”)). In some embodiments, the microneedle density referred to herein may be calculated by dividing the total number of microneedles by the total area of ​​the base plate on which the microneedles are disposed. For example, the total area of ​​the exemplary microneedle array in FIG. 3C is 2.7 mm×2.7 mm=7.29 square mm. Thus, such an exemplary microneedle array having a total of 16 microneedles arranged in an area of ​​7.29 mm squared provides a microneedle density of about 2.2 microneedles per mm squared. It should be understood that in some embodiments, the microneedles 156 may be spaced closely together or may be spaced further apart. In some embodiments, the microneedles 156 may be arranged on the base plate 300 at a density of about 0.01 to 7 microneedles per mm squared. For example, in some embodiments, the microneedles 156 may be arranged on the base plate 4.5 at a density of about 0.01, 0.1, 0.5, 1, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 300, 5.0, 5.5, 6.0, 6.5, or 7.0 microneedles per mm squared. In some embodiments, the device may include one or more microneedles 156 arranged on the base plate 300. The exemplary base plate 300 of FIG. 3C has a square shape with a side length of 5.4 mm (see "(C)" in FIG. 3C). It should be understood that in some embodiments, the base plate 300 may have different shapes and / or dimensions.

[0204] In some embodiments, such as shown in the exemplary microneedle fluid block assembly 150 of FIG. 3D, the distance between the proximal surface 151 of the fluid distribution block 650 and the distal surface 152 of the base plate 300 may be approximately 0.50 mm (see, for example, "(B)" in FIG. 3D).

[0205] In some embodiments, such as FIG. 3E showing detailed view A of the exemplary microneedle fluid block assembly 150 of FIG. 3D, the axial distance between the base 158 of each microneedle 156 coupled to the distal surface 152 of the base plate 300 and the tip 159 of each microneedle 156 may be about 0.4 mm.

[0206] FIG. 3F is a side schematic diagram of an exemplary microneedle fluid block assembly 150, showing a side view of the proximal layer 650a, the distal layer 650b, and the base plate 300 combined with the plurality of microneedles 156. In FIG. 3F, the supply channel 155a, as well as the resistance channel 155b and the outlet channel 155c, are fluidly connected and are shown in dashed lines. FIG. 3G is an axial plan schematic diagram through the composite proximal layer 650a, the distal layer 650b, the base plate 300, and the plurality of microneedles 156 of the microneedle fluid block assembly 150. FIG. 3H is an axial plan schematic diagram of the distal layer 650b of the fluid distribution block 650, showing the resistance channel 155b.

[0207] In some embodiments, for example, as shown in FIG. 3H, the resistance channels 155b may include an inner resistance channel 155b located near the lateral center of the fluid distribution block 650 (see, e.g., the circle labeled "C" in FIGS. 3H-3J) and an outer resistance channel 155b located further away from the lateral center of the fluid distribution block 650 (see, e.g., the circle labeled "B" in FIGS. 3H-3J). In some embodiments, each outlet channel 155c may be in fluid communication with one resistance channel 155b. In some embodiments, two or more inner resistance channels 155b may be in fluid communication with one inlet opening 301 (see, e.g., FIGS. 3H-3J). In some embodiments, each outer resistance channel 155 may be in fluid communication with one inlet opening 301 (see, e.g., FIGS. 3H-3J).

[0208] In some embodiments, devices comprising an array of microneedles that are adaptable for use in the microdosing devices herein will be identifiable by one of skill in the art upon reading this disclosure.Certain exemplary structures and devices are described in WO 2014 / 188343, WO 2014 / 132239, WO 2014 / 132240, WO 2013 / 061208, WO 2012 / 046149, WO 2011 / 135531, WO 2011 / 135530, WO 2011 / 135533, WO 2014 / 132240, WO 2015 / 16821, and in International Application PCT / US2015 / 028154 (WO 2015 / 168214 No. 2015 / 168215), PCT / US2015 / 028150 (published as WO 2015 / 168210), PCT / US2015 / 028158 (published as WO 2015 / 168215), PCT / US2015 / 028162 (published as WO 2015 / 168217), PCT / US2015 / 028164 (published as WO 2015 / 168219), PCT / US2015 / 038231 (published as WO 2016 / 003856), PCT / US2015 / 038232 (published as WO 2016 / 003857), PCT / US2015 / 038233 (published as WO 2016 / 003859), PCT / US2015 / 038234 (published as WO 2016 / 003859), PCT / US2015 / 038235 (published as WO 2016 / 003859), PCT / US2015 / 038236 (published as WO 2016 / 003859), PCT / US2015 / 038237 (published as WO 2016 / 003859), PCT / US2015 / 038238 (published as WO 2016 / 003859), PCT / US2015 / 038239 ... No. 2016 / 003857), PCT / US2016 / 043623 (published as WO 2017 / 019526), ​​PCT / US2016 / 043656 (published as WO 2017 / 019535), PCT / US2017 / 027879 (published as WO 2017 / 189258), PCT / US2017 / 027891 (published as WO 2017 / 189259), PCT / US2017 / 064604 (published as WO 2018 / 111607), PCT / US201 No. 7 / 064609 (published as WO 2018 / 111609), PCT / US2017 / 064614 (published as WO 2018 / 111611), PCT / US2017 / 064642 (published as WO 2018 / 111616), PCT / US2017 / 064657 (published as WO 2018 / 111620) and PCT / US2017 / 064668 (published as WO 2018 / 111621), all of which are incorporated by reference in their entireties.

[0209] Such devices include the SOFUSA® drug delivery platform (Sorrento Therapeutics, Inc., San Diego). For example, such devices include the SOFUSA® DoseConnect™ device (Sorrento Therapeutics, Inc., San Diego).

[0210] The disclosures of the specifications, claims and drawings of the following patent applications and patents related to devices, including lymphatic delivery devices, methods of providing same, and methods of using same for lymphatic administration, are incorporated by reference in their entirety: U.S. Patent Nos. 9,962,536 and 9,550,053, U.S. Patent Application Nos. 15 / 305,193, 15 / 305,206, 15 / 305,201, 15 / 744,346, and 14 / 354,223, as well as International Application Nos. PCT / US2017 / 027879, PCT / US2017 / 027891, PCT / US2017 / 027892, PCT / US2017 / 027893, PCT / US2017 / 027894, PCT / US2017 / 027895, PCT / US2017 / 027896, PCT / US2017 / 027897, PCT / US2017 / 027899, PCT / US2017 / 027898, PCT / US2017 / 02789 ... Nos. 2016 / 043656, PCT / US2017 / 064604, PCT / US2017 / 064609, PCT / US2017 / 064642, PCT / US2017 / 064614, PCT / US2017 / 064657, PCT / US2017 / 064668, U.S. Provisional Patent Application No. 62 / 678,601, filed May 31, 2018, U.S. Provisional Patent Application No. 62 / 678,592, filed May 31, 2018, and U.S. Provisional Patent Application No. 62 / 678,584, filed May 31, 2018, and International Application No. PCT / US2019 / 034736.

[0211] Thus, in some embodiments of the microdosing device 10, as shown, for example, in Figures 1A and 1B, the tubing connector 120, the plenum 130, the first gasket 140, and the microneedle fluid block assembly 150 are generally adapted to be connected to one another to allow fluid to flow from within the tube 123 of the tubing connector 120 in a proximal-to-distal direction, through the microdosing device 10, through the orifice 135 of the plenum 130, through the hole 144 of the first gasket 140, through the inlet 154 of the microneedle fluid block assembly 150, through the supply channel 155a, the resistor channel 155b and the outlet opening 302 of the fluid distribution manifold, and the outlet channel 155c of the microneedle 156.

[0212] In some embodiments, the microdosing device 10 may include a protective cap 160, for example as shown in FIGS. 1A and 1B. The protective cap may be configured to provide a cover adapted to protect the physical integrity and / or sterility of the microdosing device, particularly the physical integrity and / or sterility of the microneedle fluid block assembly 150 and / or other components of the microdosing device, until use. For example, the microdosing device may be sterilized using methods known in the art, such as irradiation or chemical sterilization methods. The protective cap may be adapted to be coupled to a syringe. In some embodiments, the protective cap 160 is adapted to be slidably coupled to the plenum 130 until the microdosing device is used to administer a fluid composition to a patient. In some embodiments, for example, as shown in FIG. 1D, the protective cap 160 may have one or more ridges 161 (e.g., four ridges 161 as shown in FIG. 5C) disposed on an inner surface 162 of the protective cap 160, the ridges adapted to engage the plenum 130, the ridges providing a friction fit adapted to provide resistance to unintentional disengagement of the protective cap 160 from the plenum 130, the ridges 161 allowing the protective cap 160 to remain covering the plurality of microneedles 156 until the protective cap 160 is intentionally removed by a user. Typically, a proximal portion 163 of the protective cap 160 may include a cover 164 slidably coupled to the plenum 130. The protective cap 160 may have a tab 165 thereon, for example, disposed on a distal end 166 of the protective cap 160, the tab 165 adapted to be grasped by a user.A user may slidably attach the protective cap 160 to the plenum 130 by applying an axial force in a proximal direction until the ridges 161 of the protective cap 160 engage via a friction fit with the plenum 130, and when the user wishes to use the microdosing device 10 to administer fluid from the microdosing device 10 to a patient, the protective cap 160 may be slidably removed from the plenum 130 by applying an axial force in a distal direction to disengage the ridges 161 from the plenum 130.

[0213] In some embodiments, the axial length of the protective cap 160 (from the proximal end 163 to the distal end 166) may be about 22 mm (see, for example, "(B)" shown in FIG. 5B). In some embodiments, the lateral diameter of the cover 164 of the protective cap 160 may be about 12.5 mm (see, for example, "(C)" shown in FIG. 5B).

[0214] In some embodiments, the tabs 165 may have a lateral thickness of about 1.3 mm (see, for example, "(C)" shown in FIG. 5D). In some embodiments, the cover 164 may have an axial depth of about 7.1 mm (see, for example, "(D)" shown in FIG. 5D). In some embodiments, the tabs 165 may have an axial length of about 15 mm (see, for example, "(E)" shown in FIG. 5D). In some embodiments, the cover 164 may have an inner diameter of about 10.4 mm (see, for example, "(F)" shown in FIG. 5D). In some embodiments, each of the ridges 161 may extend laterally about 0.6 mm into the inner space of the cover 164, so that when two ridges 161 are disposed on either side of the inner surface 162 of the cover 164, the diameter between the two ridges may be about 9.8 mm (see, for example, "(G)" shown in FIG. 5D). In some embodiments, the ridge 161 may have an axial thickness of about 0.6 mm (see, e.g., "(A)" shown in FIG. 5E). In some embodiments, the ridge 161 may be disposed on the inner surface 162 of the cover 164 at a distance of about 1.9 mm from the distal end 163 of the protective cap 160 (see, e.g., "(B)" shown in FIG. 5E). In some embodiments, the wall 169 of the cover 164 may have a thickness of about 1 mm (see, e.g., "(C)" shown in FIG. 5E). The protective cap 160 may be formed from any suitable material, such as a plastic material or other polymer, such as a cyclic olefin copolymer, among others, and has suitable flexibility to allow the cover 164 to flex sufficiently to allow the ridge 161 to engage or disengage with the plenum 130 upon application of a user force, as described above.

[0215] In some embodiments, the microdosing device of the present disclosure configured to deliver a fluid composition across a patient's skin barrier is adapted to be used with a syringe. For example, FIGS. 2A-2E show a diagram of an exemplary microdosing device 10 and an exemplary syringe 20, such as a 1 mL syringe. The syringe 20 has a barrel 210 having a bore defined therein and a plunger 220 slidably coupled within the bore 213 of the syringe barrel 210. The barrel 210 has a proximal end 211 and a distal end 212. In response to an axial force applied to the plunger 220 in a distal direction, the plunger 220 moves axially within the bore 213 of the syringe barrel 210 toward the distal end 212 of the barrel 210, causing fluid within the bore 213 to flow out of the distal end 212 of the syringe barrel 210. A proximal portion 122 of the syringe connection assembly 11, e.g., the proximal portion 122 of the exemplary tubing connector 120, is adapted to be coupled to a distal end 212 of the syringe barrel 210 such that a bore 213 of the syringe barrel 210 and a fluid pathway defined within the syringe connection assembly 11, e.g., the tube 123 of the exemplary tubing connector 120, are fluidly connected. The proximal portion 122 of the exemplary tubing connector 120 and the distal end 212 of the syringe barrel 210 may be adapted to form a sealed, leak-proof fluid connection when coupled to one another. The proximal portion 122 of the tubing connector 120 and the distal end 212 of the syringe barrel 210 may be adapted to maintain a sealed, leak-proof fluid connection as fluid travels from the bore 213 of the syringe barrel 210 to a fluid pathway defined within the syringe connection assembly 11, e.g., the tube 123 of the tubing connector 120.

[0216] Any suitable syringe 20 adapted to be coupled to the proximal portion 122 of the tubing connector 120 and having a distal end 212 of its barrel 210 capable of controllably discharging a fluid composition in an amount between 1 μl and 500 μl may be used in combination with the microdosing devices of the present disclosure, for example, syringes having a fluid volume capacity of the bore 213 of 1-10 μl, 10-50 μl, 50-100 μl, 100-500 μl, 500-1000 μl, 1.0-1.5 ml, or up to 2 ml, 5 ml, or 10 ml.

[0217] In some embodiments, the syringe may be adapted to controllably eject volumes of the fluid composition from 1 μl to 500 μl over a period of about 0.1 seconds to about 5 minutes, such as up to 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 seconds, or up to 90, 120, 180, 210, 240, 270, or 300 seconds. The rate of ejection of the fluid from the syringe may be constant or variable, such as an increasing rate, or a decreasing rate, or a pulsatile rate, or any combination thereof.

[0218] In some embodiments, the syringe 20 may further include a fluid, such as any of the fluids described herein, in the bore 213. The syringe coupled to the microdosing device may be provided to the user with the syringe bore pre-filled with fluid, or the user may fill the syringe with fluid and attach the syringe to the microdosing device.

[0219] Thus, in some embodiments, when the microdosing device 10 of the present disclosure is coupled to the syringe barrel 210 of the syringe 20, in response to an axial force applied distally to the plunger 220, fluid within the bore 213 of the barrel 210 of the syringe 20 flows out of the syringe 20 and the microdosing device is configured such that fluid flows through the microdosing device 10 and exits the fluid outlet channels 155c of the multiple microneedles 156 of the microdosing device 10.

[0220] In some embodiments, the proximal portion 122 of the syringe connection assembly 11, e.g., the proximal portion 122 of the exemplary tubing connector 120, and the distal end 212 of the syringe barrel 210 may be adapted to be slidably coupled to one another. In some embodiments, the proximal portion 122 of the syringe connection assembly 11, e.g., the proximal portion 122 of the tubing connector 120, may be adapted to be coupled to the distal end 212 of the syringe barrel 210 by a matching thread. In such embodiments, the proximal portion 122 of the syringe connection assembly 11, e.g., the proximal portion 122 of the tubing connector 120, may have threads disposed thereon (e.g., see the exemplary threads 124 in FIGS. 1A and 1C ) that mate with threads disposed on the distal end 212 of the syringe barrel 210.

[0221] In some embodiments, suitable syringes include, but are not limited to, BD Luer slip-tip or BD Luer-Lok® (Becton, Dickinson And Company Corporation, New Jersey) syringes. For example, BD Luer slip-tip syringes and other similar syringes have a distal end 212 adapted for a friction fit connection 218 that allows the proximal portion 122 of the tubing connector 120 to be slidably coupled to the distal end 212 of the syringe barrel 210. In another example, BD Luer-Lok® syringes and other similar syringes have threads 219 disposed on the distal end 212 of the syringe barrel 210 (see, for example, FIG. 2F). In some embodiments, the microdosing device is adapted to be attached to an existing syringe, such as a standard 0.5 mL or 1.0 mL capacity syringe, e.g., a 0.5 mL or 1.0 mL BD Luer, BD Luer-Lok® syringe.

[0222] Suitable syringes are commercially available from suppliers such as Becton, Dickinson and Company, or Hamilton, among others identifiable by one of skill in the art upon reading this disclosure. Suitable syringes may be sterile packaged or may be sterilized using an autoclave or using chemical sterilization methods or other methods known in the art.

[0223] In use, in some embodiments, the microdosing device coupled to the syringe may be configured to be handheld and / or coupled to a syringe pump device adapted to controllably advance the plunger through the barrel. Such syringe pump devices include, but are not limited to, commercially available syringe pumps such as those from Harvard Apparatus, among others, identifiable by those of skill in the art upon reading this disclosure.

[0224] In some embodiments, as used herein, a desired fluid delivery rate may be initiated by applying pressure or other driving means to drive the fluid compositions described herein, including the use of pumps, elastomeric membranes, gas pressure, piezoelectric, electric, electromagnetic, peristaltic or osmotic pumping, or rate controlling membranes, or combinations thereof.

[0225] In some embodiments, the microdosing device described herein can be coupled to a syringe described herein and configured to be held in a user's hand and used in a simple and straightforward manner to manually administer a bolus injection of a fluid composition (e.g., but not limited to, having a total volume of up to 500 μL, e.g., 100 μL) across a patient's skin barrier for a short period of time (e.g., but not limited to, up to 300 seconds, e.g., 10 seconds). In contrast, existing devices such as the SOFUSA® DoseConnect™ device (Sorrento Therapeutics, Inc., San Diego) are typically configured to deliver an infusion of a fluid composition across a patient's skin barrier over a longer period of time. Further, in some embodiments, administration of a fluid composition using a microdosing device described herein may be performed without the aid of one or more additional components, such as one or more of a collet assembly, a controller assembly, an applicator, or a mounting band, such as those described for use with the SOFUSA® DoseConnect™ device (Sorrento Therapeutics, Inc., San Diego), as described, for example, in U.S. Provisional Application No. 62 / 942,971. For example, as described in U.S. Provisional Application No. 62 / 942,971, the collet assembly is configured to contact a surface of the patient's skin sufficient to cause the multiple microneedles to penetrate the surface of the patient's skin and penetrate across a skin barrier, the controller assembly is configured to control the flow of the fluid composition during delivery of the fluid composition through the multiple microneedles, the applicator is configured to facilitate transition of the microdosing device from a non-actuated configuration to an actuated configuration, and the mounting band assembly is configured to facilitate contact with a surface of the subject's skin sufficient to cause the multiple protrusions to penetrate the surface of the subject's skin and penetrate across a skin barrier.For example, as evidenced by the exemplary results described in Example 5 and Example 1 of the present disclosure, in use, the microdosing device described herein can be configured to be held in a user's hand and operable in a simple and straightforward manner, e.g., without the aid of one or more of a collet assembly, a controller assembly, an applicator, or an attachment band, to achieve penetration of the multiple protrusions into the surface of a subject's skin and across the skin barrier to deliver a fluid composition across the patient's skin barrier, e.g., to the patient's lymphatic system.

[0226] In some embodiments, the microdosing device is adapted to have a leak-proof fluid connection between the bore of the syringe and the outlet channel of the microneedle such that, during use, when an axial force is applied to the plunger of the syringe, fluid flows through the microdosing device and exits the outlet channel of the microneedle without leakage or loss of fluid from any of the connections between the components of the microdosing device or between the microdosing device and the syringe. As described in Example 4, the microdosing devices of the present disclosure are adapted to perform in a leak-proof manner when used in the methods described herein.

[0227] 6A-8E of the present disclosure illustrate a second exemplary microdosing device and its components.

[0228] 6A shows a perspective exploded schematic view of an exemplary second set of components adapted to be combined to form a microdosing device 10 of the present disclosure as shown in FIG. 6B. The components shown in FIG. 6A include a syringe connection assembly 11 including a tubing connector 120 and a plenum 130. The components of the exemplary microdosing device 10 shown in FIG. 1 also include a first gasket 140, a microneedle fluid block 150 including a fluid block 650, a second gasket 640, and a microneedle array 660. The components of the exemplary microdosing device 10 shown in FIG. 6A also include a protective cap 160.

[0229] As can be seen from the exemplary drawings of Figures 6A and 6B, in some embodiments, a microdosing device of the present disclosure, such as the exemplary microdosing device 10 shown in Figure 6B, may be assembled from the exemplary components shown in Figure 6A described herein.

[0230] The second exemplary microdosing device 10 shown in Figures 6A-10F differs from the first exemplary microdosing device 10 shown in Figures 1A-5E, for example, in that the microneedle fluid block 150 of the second exemplary microdosing device 10 includes a second gasket 640 disposed between the fluid block 650 and the microneedle array 660. The configuration and assembly of the other components of the second exemplary microdosing device 10 shown in Figures 6A-10F, including the tubing connector 120, the plenum 130, the first gasket 140, and the protective cap 160, are similar to those described herein for the first exemplary microdosing device shown in Figures 1A-5E.

[0231] 6A , the fluid distribution block 650 has a proximal surface 151 and a distal surface 97. In the second exemplary microdosing device 10 shown in FIG. 6A , the distal surface 97 of the fluid distribution block 650 is adapted to be coupled to the proximal surface 641 of the second gasket 640. The distal surface 642 of the second gasket 640 is adapted to be coupled to the proximal surface 96 of the base plate 300 of the microneedle array 660.

[0232] 6A, 6D, and 6E, the fluid distribution block 650 (including the proximal layer 650a and the distal layer 650b of the fluid distribution block 650; see, e.g., FIG. 7A) may be sized such that a side edge 653 of the fluid distribution block 650 is adapted to be coupled to an inner wall 138 of a distal seat 137 disposed on the distal surface 131 of the plenum 130. Additionally, the base plate 300 of the microneedle array 660 may be sized such that a side edge 663 of the base plate 300 of the microneedle array 660 is also adapted to be coupled to an inner wall 138 of a distal seat 137 disposed on the distal surface 131 of the plenum 130.

[0233] The side edge 653 of the fluid distribution block 650 and / or the side edge 663 of the base plate 300 of the microneedle array 660 may be adhered to the inner wall 138 of the distal seat 137 disposed on the distal surface 131 of the plenum 130 using an adhesive such as, for example, Loctite 3979, or other suitable adhesive identifiable by one of skill in the art. An adhesive may be applied, for example, in a continuous bead, between the inner wall 138 of the distal seat 137 disposed on the distal surface 131 of the plenum 130 and the side edge 653 of the fluid distribution block 650 and / or the side edge 663 of the base plate 300 of the microneedle array 660 (see, for example, adhesive 90 in FIG. 6E ).

[0234] An exemplary fluid distribution block 650 is shown in greater detail in Figures 6E and 7A-7G.

[0235] The fluid distribution block 650 has a proximal inlet 154 forming an opening in a proximal face 151 of the fluid distribution block 650 (see, e.g., FIG. 6E). In some embodiments, the proximal inlet 154 is adapted to allow fluid to flow from the holes 144 of the first gasket 140 into a fluid distribution manifold that includes supply channels 155a, resistance channels 155b, and outlet openings 302 disposed within the fluid block 650.

[0236] In some embodiments, as shown, for example, in Figures 7A-7G, the fluid distribution block 650 may include a proximal layer 650a including the supply channels 155a of the fluid distribution manifold and a distal layer 650b including the resistance channels 155b of the fluid distribution manifold and a plurality of outlet openings 302, each of which extends axially through the distal layer 650b to a distal surface 97 of the fluid distribution block 650. Alternatively, in some embodiments, the fluid distribution block 650 may include a proximal layer 650a including the resistance channels 155b and a distal layer 650b including the supply channels 155a and a plurality of outlet openings 302, each of which extends axially through the distal layer 650b to a distal surface 97 of the fluid distribution block 650.

[0237] The distal surface 99 of the proximal layer 650a may be coupled, e.g., bonded, to the proximal surface 98 of the distal layer 650b, such that the proximal inlet 154, the supply channel 155a, the resistance channel 155b and the outlet opening 302 are adapted to be fluidly connected and configured to allow fluid to flow through the fluid distribution manifold of the fluid distribution block 650.

[0238] It should be understood that any suitable configuration of fluid distribution manifold may be used in the fluid blocks described herein, with the proximal inlet 154, supply channel 155a, resistance channel 155b, and outlet opening 302 adapted to fluidly connect and configured to allow fluid to flow through the fluid distribution block.

[0239] The proximal layer 650a and the distal layer 650b are adapted to form a sealed, leak-proof fluid connection when coupled together. The proximal layer 650a and the distal layer 650b may be bonded to each other using an adhesive.

[0240] In some embodiments, for example as shown in FIGS. 7A-7C, each of the resistance channels 155b can include one or more inlet openings 301 adapted to be coupled and fluidly connected to the supply channel 155a.

[0241] The exemplary fluid block 650 in FIG. 7B has a square shape with a side length of 5.4 mm (see "(C)" in FIG. 7B). It should be understood that in some embodiments, the fluid block 650 may have different shapes and / or dimensions.

[0242] In the exemplary resistance channel 155b shown in Figures 7B and 7C, the outlet openings 302 may be spaced apart, for example, by a distance of 0.9 mm, so as to be configured to be coupled and fluidly connected to the outlet channel 155c (see, for example, as shown in "(A)" in Figure 7C).

[0243] In some embodiments, as shown, for example, in Figure 7E, the inlet opening 301 of the resistance channel 155b may have an axial depth having dimensions described herein, such as in Figures 3M and 3N (see, for example, "(X)" in Figure 7E), and may have a lateral width having dimensions described herein, such as in Figures 3M and 3N (see, for example, "(Y)" in Figure 7E). In some embodiments, as shown, for example, in Figure 7E, the supply channel 155a may have an axial depth having dimensions described herein, such as in Figures 3M and 3N (see, for example, "(Z)" in Figure 7E), and may have a lateral width having dimensions described herein (see, for example, "(A)" in Figure 7E).

[0244] In some embodiments, as shown, for example, in FIG. 7F, the fluid distribution block 650 may have an axial thickness of about 1.2 mm (see, for example, FIG. 7F, "(B)"). In some embodiments, as shown, for example, in FIG. 7F, the proximal layer 650a may have an axial thickness of about 0.5 mm (see, for example, FIG. 7F, "(C)"). In some embodiments, as shown, for example, in FIG. 7F, the distal layer 650b may have an axial thickness of about 0.7 mm (see, for example, FIG. 7F, "(D)").

[0245] As shown, for example, in some embodiments, the proximal inlet 154 of the fluid distribution block 650 may have an axially tapered or funnel-shaped shape. For example, in some embodiments, the proximal inlet 154 may have a transverse diameter at the proximal surface 151 of the proximal layer 650a of the fluid distribution block 650 having dimensions described herein (see, e.g., "(B)" of FIG. 7G) and may have a transverse diameter at the distal surface 99 of the proximal layer 650a of the fluid distribution block 650 having dimensions described herein (see, e.g., "(C)" of FIG. 7G). In some embodiments, the outlet opening 302 may have a transverse diameter at the proximal surface 98 of the distal layer 650b of the fluid distribution block 650 having dimensions described herein (see, e.g., "(D)" of FIG. 7G) and may have a transverse diameter at the distal surface 97 of the distal layer 650b of the fluid distribution block 650 having dimensions described herein (see, e.g., "(E)" of FIG. 7G).

[0246] Further details of an exemplary microneedle array 660 are shown in Figures 8A-8E. The microneedle array 660 includes a base plate 300 having a proximal surface 96 and a distal surface 152. The microneedle array 660 also includes a plurality of microneedles 156 disposed on the distal surface 152 of the base plate 300. Each of the microneedles 156 has a base 158 coupled to the distal surface 152 of the base plate 300 and extending distally away from the base plate 300 to a distal end including a tip 159. The tip 159 may have a puncture or needle-like shape, such as a cone or pyramid shape, or a cylindrical shape transitioning to a cone or pyramid shape. In some embodiments, the exit channel 155 of the microneedle 156 may terminate in an exit hole 157.

[0247] Similar to the first exemplary microdosing device 10 (see, e.g., FIG. 3C), in the second exemplary microdosing device 10, the exemplary microneedle array 660 shown in FIG. 8B has an array of 16 microneedles 156 arranged on the distal surface 152 of the base plate 300 in a square 4×4 arrangement. It should be understood that other numbers of microneedles and / or other arrangements of microneedles are contemplated. In the example shown in FIG. 8B, the microneedles 156 are uniformly spaced in a 4×4 square array of four microneedles 156 in each of four parallel rows, each row spaced 0.9 mm apart (see FIG. 8B “C”), each microneedle 156 spaced 0.9 mm apart from the nearest microneedle 156 in the same row (see FIG. 8B “C”), and the microneedle 156 nearest the side edge 663 of the microneedle array 660 is spaced approximately 1.35 mm apart from the side edge 663 (see FIG. 8B “D”). It should be understood that in some embodiments, the microneedles 156 may be spaced closer together or further apart. The exemplary base plate 300 of FIG. 8B has a square shape with a side length of 5.4 mm (see FIG. 8B “E”). It should be understood that in some embodiments, the base plate 300 may have different shapes and / or dimensions.

[0248] Further details of the exemplary microneedle array 660 of FIG. 8B are shown in FIGS. 8C-8E. In some embodiments, such as FIG. 8C, the exit hole 157 may be located within the tip 159 of the microneedle 156 such that it is off-center. For example, in FIG. 8C, the lateral center of the diameter of the exit hole 159 is located approximately 0.025 mm from the lateral center of the diameter of the microneedle 156 (see, e.g., FIG. 8C, "(C)"). In some embodiments, the lateral diameter of the exit hole 157 may be approximately 0.035 mm (see, e.g., FIG. 8C, "(D)"). In some embodiments, as shown, for example, in the example microneedle 156 of FIG. 8C, the microneedle base 158 (shown in dashed lines) has a smaller lateral diameter than the widest portion of the tip 159 of the microneedle, shown as a solid circle around the dashed circle of the base 158 (see also FIG. 8E).

[0249] In some embodiments, the outlet opening 302 of the fluid distribution block 650 is configured to fluidly connect with the outlet hole 157 of the microneedle 156 via the outlet channel 155c extending from the proximal surface 96 of the base plate 300 of the microneedle array 660 to the outlet hole 157, as shown, for example, in FIG. 8D. In some embodiments, for example, as shown in FIG. 8D, the axial thickness of the base plate 300 may be about 0.325 mm (see, for example, "(B)" shown in FIG. 8D). As shown in more detail in FIG. 8E, in some embodiments, the axial distance from the distal end of the tip 159a to the proximal end of the outlet hole 157 may be about 0.079 mm (see, for example, "(B)" in FIG. 8E). In some embodiments, the base 158 of the microneedle may have a smaller lateral diameter than the widest portion of the tip 159b of the microneedle. For example, the base 158 of the microneedle may have a lateral diameter of about 0.08 mm (see, e.g., "(C)" in FIG. 8E) and the widest portion of the tip 159b of the microneedle may have a lateral diameter of about 0.14 mm (see, e.g., "(D)" in FIG. 8E). In some embodiments, the microneedle 156 may have an axial length of about 0.39 mm (see, e.g., "(E)" in FIG. 8E).

[0250] In some embodiments, the fluid distribution block 650 and / or the microneedle array 660 may be formed from any suitable material, such as, for example, a suitable polymer or plastic material, such as, but not limited to, polymethylmethacrylate, or a silica or glass material, such as, but not limited to, borosilicate glass (e.g., MEMpax®, Schott, Germany), among others.

[0251] In some embodiments, the proximal surface 96 of the base plate 300 of the microneedle array 660 may be connected to the distal surface 642 of the second gasket 640, and the distal surface 97 of the fluid distribution block 650 may be connected to the proximal surface 641 of the second gasket 640.

[0252] The second gasket 640 may be a pressure sensitive adhesive (PSA) gasket. The second gasket 640 may have an adhesive disposed on a proximal surface 641 of the second gasket 640 and / or a distal surface 642 of the second gasket 640. The second gasket 640 has a plurality of holes 646 adapted to allow fluid to flow through the second gasket 640 from the proximal surface 641 of the second gasket 640 to the distal surface 642 of the second gasket 640. When the second gasket 640 is coupled to the base plate 300 and the fluid distribution block 650 of the microneedle array 660, the holes 646 are adapted to allow fluid to flow from the plurality of outlet openings 302 through the holes 646 of the second gasket 640 and into the outlet channel 155c of the microneedle array 660.

[0253] Thus, in some embodiments, when the microdosing device 10 of the present disclosure is coupled to a syringe 20, in response to an axial force applied to the plunger 220 in a distal direction, fluid within the bore 213 of the barrel 210 of the syringe 20 flows out of the syringe 20 and the microdosing device is configured such that the fluid flows through the microdosing device 10 and out of the outlet channels 155c of the multiple microneedles 156 of the microneedle array 660.

[0254] In some embodiments, the microneedle array may be a draped microneedle array. An exemplary draped microneedle array 900 is shown in Figures 9A-9E. For example, as shown in Figures 9A-9B, in some embodiments, the draped microneedle array 900 may include a microneedle array 660, a third gasket 1000, and a film 1100. The film 1100 may have a nanopatterned layer disposed thereon, such that the draped microneedle array includes a nanopatterned layer, also referred to herein as nanotopography, and the film is at least partially draped over the plurality of microneedles 156 and, optionally, at least partially draped over the base plate 300 of the microneedle array 660.

[0255] In some embodiments, for example, as shown in FIG. 9B , the distal surface 152 of the base plate 300 of the microneedle array 660 is adapted to be coupled to the proximal surface 1001 of the third gasket 1000, and the distal surface 1002 of the third gasket 1000 is adapted to be coupled to the proximal surface 1101 of the film 1100.

[0256] The third gasket 1000 may be a pressure sensitive adhesive (PSA) gasket. In some embodiments, the third gasket 1000 may include a PSA layer disposed between the nanopatterned layer and the surface of the plurality of microneedles to provide support. The PSA layer may be formed from an adhesive material (e.g., ARcare® 93445).

[0257] The third gasket 1000 may have an adhesive disposed on a proximal surface 1001 of the third gasket 1000 and / or a distal surface 1002 of the third gasket 1000. The third gasket 1000 has a plurality of holes 1046 adapted to allow the plurality of microneedles 156 of the microneedle array 660 to be disposed through the plurality of holes 1046 when the distal surface 152 of the base plate 300 of the microneedle array 660 is coupled to the proximal surface 1001 of the third gasket 1000.

[0258] 9A-9D and 9E, when the distal surface 152 of the base plate 300 of the microneedle array 660 is coupled to the proximal surface 1001 of the third gasket 1000, the film 1100 may be coupled to the distal surface 152 of the base plate 300 of the microneedle array 660 and the distal surface 1002 of the third gasket 1000 such that the film 1100 forms a drape over the plurality of microneedles 156. The film 1100 may include film exit holes 1103 configured to fluidly connect with the exit holes 157 of the microneedles 156 and allow fluid to flow therethrough, such that the draped microneedle array 900 is adapted to allow fluid to flow from the exit channels 155c of the microneedle array 660, through the exit holes 157 of the microneedles 156 and through the film exit holes 1103.

[0259] In some embodiments, the nanopatterned layer may include a plurality of nanostructures covering a surface of the plurality of microneedles 156. In some embodiments, the nanostructures include a height and a cross-sectional dimension. In some embodiments, at least a portion of the nanostructures have a center-to-center distance of about 50 nanometers to about 1 micrometer. In some embodiments, at least a portion of the nanostructures have a height of about 10 nanometers to about 20 micrometers. In some embodiments, at least a portion of the nanostructures have an aspect ratio of height to cross-sectional dimension of about 0.15 to about 30. In some embodiments, the nanostructures comprise a nanopattern having a fractal dimension of greater than about 1. In some embodiments, at least a portion of the nanostructures have a surface including a plurality of nanostructures having an average surface roughness in the range of about 10 nm to about 200 nm. In some embodiments, at least a portion of the nanostructures have an effective compressive modulus in the range of about 4 MPa to about 320 MPa. In some embodiments, the microneedle array 660 includes a nanopatterned layer including nanostructures having one or more of the above characteristics.

[0260] In some embodiments, the nanopatterned layer further comprises a plurality of additional nanostructures having cross-sectional dimensions smaller than the cross-sectional dimensions of the nanostructure.

[0261] In some embodiments, the nanopatterned layer may be fabricated from a polymer film or the like and coupled to the fluid distribution assembly using an additional adhesive layer, in other embodiments, the film may comprise an embossed or nanoimprinted polymer (e.g., plastic) film, or any other suitable material, such as a polyetheretherketone (PEEK) film, or a polypropylene film.

[0262] A further example of a fluid distribution block 650 of the present disclosure is shown in Figures 10A-10H.

[0263] The exemplary fluid distribution block 650 shown in Figures 10A-10H has an alternative configuration of supply channels 155a and resistance channels 155b compared to the exemplary fluid block 650 shown in Figures 7A-7G, in which in the exemplary fluid distribution block 650 shown in Figures 10A-10H, the proximal layer 650a includes the resistance channels 155b and the distal layer 650b includes the supply channels 155a.

[0264] The exemplary fluid distribution block 650 of FIG. 10B has a square shape with a side length of 5.4 mm (see "(C)" in FIG. 10B). It should be understood that in some embodiments, the fluid block 650 may have different shapes and / or dimensions.

[0265] In the exemplary resistance channel 155b shown in Figures 10B and 10C, the outlet openings 302 may be spaced apart, for example, by a distance of 0.9 mm, so as to be coupled to and configured to be fluidly connected with the outlet channel 155c, as shown in Figures 10A-10C (see, for example, as shown in "(C)" in Figure 10C).

[0266] 10E and 10F, the inlet opening 301 may have an axial diameter of about 0.0037 mm (see, e.g., "(X)" in FIG. 10F) and a lateral diameter of about 0.0284 mm (see, e.g., "(Y)" in FIG. 10F). In some embodiments, as shown, e.g., in FIG. 10E, the feed channel 155a may have an axial depth having dimensions described herein (see, e.g., "(Z)" in FIG. 10E) and a lateral width having dimensions described herein (see, e.g., "(A)" in FIG. 10E).

[0267] In some embodiments, as shown, for example, in FIG. 10G, the fluid distribution block 650 may have an axial thickness of about 1.2 mm (see, for example, FIG. 10G, "(B)"). In some embodiments, as shown, for example, in FIG. 10G, the proximal layer 650a may have an axial thickness of about 0.7 mm (see, for example, FIG. 10G, "(C)"). In some embodiments, as shown, for example, in FIG. 10G, the distal layer 650b may have an axial thickness of about 0.5 mm (see, for example, FIG. 10G, "(D)").

[0268] 10H, in some embodiments, the proximal inlet 154 of the fluid block 650 may have an axially tapered or funnel-like shape. For example, in some embodiments, the proximal inlet 154 may have a transverse diameter at the proximal face 151 of the proximal layer 650a of the fluid distribution block 650 having dimensions described herein (see, e.g., "(B)" in FIG. 10H) and may have a transverse diameter at the distal face 99 of the proximal layer 650a of the fluid distribution block 650 having dimensions described herein (see, e.g., "(C)" in FIG. 10H). In some embodiments, the outlet opening 302 may have a transverse diameter at the proximal surface 98 of the distal layer 650b of the fluid distribution block 650 having the dimensions described herein (see, for example, "(D)" in FIG. 10H ), and may have a transverse diameter at the distal surface 97 of the distal layer 650b of the fluid distribution block 650 having the dimensions described herein (see, for example, "(E)" in FIG. 10H ).

[0269] II. How to Use a Microdosing Device

[0270] In some embodiments, methods are provided for using a fluid delivery device ("microdosing device") described herein. In some embodiments, methods are provided for delivering a fluid composition across a skin barrier of a patient. In some embodiments, the method includes inserting a plurality of microneedles of a microdosing device described herein across the skin barrier of a patient and transporting the fluid composition through fluid outlet channels of the plurality of microneedles to a location below the skin barrier.

[0271] In some embodiments, a method is provided for delivering a fluid composition across a skin barrier of a patient, the method comprising penetrating the skin barrier with a plurality of microneedles of a microdosing device described herein, the microneedles optionally comprising a nanopatterned layer comprising nanostructures overlaid thereon, and transporting the fluid composition through a fluid outlet channel of the plurality of microneedles to a location below the skin barrier, the number of microneedles in the plurality of microneedles being between 2 and 100 microneedles, e.g., up to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115 6, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 microneedles. In some embodiments, the microdosing device may have one or more microneedles.

[0272] In some embodiments, the total amount of fluid delivered from the microdosing device to the patient may be up to 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 μL. In some embodiments, the total amount of fluid delivered from the microdosing device to the patient may be over a period of up to 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 seconds, or up to 90, 120, 180, 210, 240, 270, or 300 seconds.

[0273] In some embodiments, fluid volumes of 1 μL to 500 μL may be delivered to a patient over a period of about 0.1 seconds to about 5 minutes, for example up to 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 seconds, or up to 90, 120, 180, 210, 240, 270, or 300 seconds. In some embodiments, the fluid delivery rate per second per microneedle may be up to about 20 μL, 19 μL, 18 μL, 17 μL, 16 μL, 15 μL, 14 μL, 13 μL, 12 μL, 11 μL, 10 μL, 9 μL, 8 μL, 7 μL, 6 μL, 5 μL, 4 μL, 3 μL, 2 μL, 1 μL, 0.5 μL, 0.1 μL, or 0.01 μL, for example, at pressures of up to about 10 bar, 9 bar, 8 bar, 7 bar, 6 bar, 5 bar, 4 bar, 3 bar, 2 bar, 1 bar, 0.8 bar, 0.7 bar, 0.6 bar, 0.5 bar, 0.4 bar, 0.3 bar, 0.2 bar, or 0.1 bar. In some embodiments, the rate of delivery of fluid from the microdosing device to the patient may be constant or variable, such as an increasing rate, a decreasing rate, a pulsatile rate, or any combination thereof.

[0274] In some embodiments, up to 1 μL, 5 μL, 10 μL, 20 μL, 30 μL, 40 μL, 50 μL, 60 μL, 70 μL, 80 μL, 90 μL, 100 μL, 110 μL, 120 μL, 130 μL, 140 μL, 150 μL, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950 A fluid volume of 50, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, or 500 μL may be delivered to the patient over a period of less than 5 minutes, such as up to 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 seconds, or up to 90, 120, 180, 210, 240, 270, or 300 seconds.

[0275] In some embodiments, when the microdosing device 10 of the present disclosure is coupled to a syringe barrel 210, in response to an axial force applied to the plunger 220 in a distal direction following penetration of the patient's skin barrier by the multiple microneedles, fluid within the bore 213 of the barrel 210 of the syringe 20 flows from the syringe 20 through the microdosing device 10 and exits the fluid outlet channels 155c of the multiple microneedles 156 of the microdosing device 10, thereby transporting the fluid composition through the fluid outlet channels of the multiple microneedles to a location below the patient's skin barrier.

[0276] In some embodiments, the methods are performed by a medical professional, such as a doctor or nurse.

[0277] In some embodiments, the method further comprises delivering the fluid composition to the patient's lymphatic system, hi some embodiments, the method further comprises delivering the fluid composition to the patient's blood circulatory system.

[0278] In use, when the microdosing device of the present disclosure is coupled to a syringe for administering a fluid to a patient, in some embodiments, the multiple microneedles may be positioned on the patient's skin proximate to a first location below the patient's skin, the first location being proximate to a lymphatic vessel and / or lymphatic capillary of the patient's lymphatic system. The multiple microneedles may then be inserted into the patient at least to a depth that penetrates the epidermis and at least one end of the microneedle is proximate to the first location. Then, in response to applying an axial force to the plunger of the syringe, a volume of fluid may be delivered from the microdosing device through the multiple microneedles to the first location.

[0279] In some embodiments, the method includes contacting the microdosing device directly with the patient's skin. In some embodiments, an intervening layer or structure may be placed between the patient's skin and the microdosing device. For example, surgical tape or gauze may be used to reduce possible skin irritation between the microdosing device and the patient's skin. In some embodiments of the method, the microneedles penetrate the epidermis or dermis of the patient to deliver the pharmaceutical agent to the patient. Delivery of the fluid composition may be to the blood circulation system, lymphatic system, interstitial, subcutaneous, intramuscular, intradermal, or a combination thereof. In some embodiments, the fluid composition is delivered directly to the patient's lymphatic system. In some embodiments, the fluid composition is delivered to superficial blood vessels of the lymphatic system.

[0280] In some embodiments, the method includes placing a microdosing device in an area of ​​the patient's skin where a dense network of lymphatic and / or blood capillaries exists. Multiple microdosing devices may be placed in one or more locations in the area, or the same microdosing device may be placed sequentially in one or more locations in the area. In some embodiments, the method may include placing one or more, for example 1, 2, 3, 4, 5, or more, microdosing devices on the subject's skin. These microdosing devices may be placed spatially separated or adjacent or juxtaposed to each other. The one or more microdosing devices may be the same device placed sequentially on the skin at the same or different locations, or different microdosing devices placed on the skin at the same or different locations.

[0281] In some embodiments, at least a portion or all of the fluid composition may be delivered or administered directly to an initial depth of the skin, including the nonviable epidermis and / or viable epidermis. In some embodiments, a portion of the fluid composition may be delivered directly to the viable dermis in addition to the epidermis. The range of delivery depths depends on the medical condition being treated and the skin physiology of a given subject. This initial delivery depth may be defined as the location within the skin where the therapeutic agent first comes into contact as described herein. Without being bound by any theory, it is believed that the administered agent may migrate (e.g., diffuse) from the initial delivery site (e.g., nonviable epidermis, viable epidermis, viable dermis, or stroma) to a deeper location within the viable skin. For example, some or all of the administered agent may be delivered to the nonviable epidermis and then continue to migrate (e.g., diffuse) into the viable epidermis, passing through the basal layer of the viable epidermis, and entering the viable dermis. Alternatively, some or all of the administered agent may be delivered to the viable epidermis (i.e., just below the stratum corneum), then continue to move (e.g., diffuse) beyond the basal layer of the viable epidermis and enter the viable dermis. Finally, some or all of the administered agent may be delivered to the viable dermis. The movement of one or more active agents across the skin is multifactorial and depends, for example, on the liquid carrier composition (e.g., its viscosity), the administration rate, the delivery structure, etc. This movement through the epidermis into the dermis is further defined as a transport phenomenon and can be quantified by mass transfer rate(s) and / or fluid dynamics (e.g., mass flow rate(s)).

[0282] Thus, in some embodiments described herein, an agent may be delivered deep in the epidermis, where the agent migrates beyond the basal layer of the viable epidermis into the viable dermis, in some embodiments, the agent is then absorbed by one or more susceptible lymphatic capillary plexuses and then delivered to one or more lymph nodes and / or lymphatic vessels.

[0283] Since skin thickness can vary from patient to patient based on many factors, including but not limited to medical condition, diet, sex, age, body mass index, and body part, the depth below the skin surface to deliver the fluid composition can vary. In some embodiments, the delivery depth is about 50 μm to about 4000 μm, about 100 to about 3500 μm, about 150 μm to about 3000 μm, about 200 μm to about 3000 μm, about 250 μm to about 2000 μm, about 300 μm to about 1500 μm, or about 350 μm to about 1000 μm. In some embodiments, the delivery depth is about 50 μm, about 100 μm, about 150 μm, about 200 μm, about 250 μm, about 300 μm, about 350 μm, about 400 μm, about 450 μm, about 500 μm, about 600 μm, about 700 μm, about 800 μm, about 900 μm, or about 1000 μm. As used in this context, "about" means ±50 μm.

[0284] In some embodiments described herein, therapeutic agents are delivered to viable skin, and the depth distribution within the viable skin for delivery of the agents is directly through the stratum corneum of the epidermis but above the subcutaneous tissue, resulting in uptake of the agents by the patient's lymphatic vasculature. In some aspects, the depth of the viable skin for delivery of one or more agents ranges from about 1 μm to about 4,500 μm beyond the stratum corneum, but still within the viable skin above the subcutaneous tissue.

[0285] Non-limiting tests for assessing the initial delivery depth in the skin may be invasive (e.g., biopsy) or non-invasive (e.g., imaging). Conventional non-invasive optical methodologies, including remittance spectroscopy, fluorescence spectroscopy, photothermal spectroscopy, or optical coherence tomography (OCT), may be used to assess the delivery depth of the agent into the skin. Imaging using the method may be performed in real time to assess the initial delivery depth. Alternatively, an invasive skin biopsy may be taken immediately after administration of the agent, followed by standard histological and staining methods to determine the delivery depth of the agent. For examples of optical imaging methods useful for determining the skin penetration depth of an administered drug, see Sennhenn et al., Skin Pharmacol. 6(2) 152-160 (1993), Gotter et al., Skin Pharmacol. Physiol. 21 156-165 (2008), or Mogensen et al., Semin. Cutan. Med. Surg 28 196-202 (2009), each of which is incorporated herein by reference for its teachings.

[0286] In some embodiments, the fluid composition is delivered to the patient's interstitium, e.g., the space between the skin and one or more internal structures, e.g., an organ, muscle, or blood vessel (artery, vein, or lymphatic vessel), or any other space within or between portions of a tissue or organ. In some embodiments, the fluid composition is delivered to both the interstitium and the lymphatic system.

[0287] In some embodiments, the method further comprises increasing the permeability of lymphatic vasculature, wherein the nanostructures are in contact with or in close proximity to epithelial cells of the subject, thereby opening intercellular junctions between the epithelial cells and facilitating the flow of the fluid composition during transport to a location below the skin barrier.

[0288] In some embodiments described herein, the microdosing device described herein may function as a permeability enhancer and increase the delivery of a fluid composition through the epidermis. This delivery may occur by modulating transcellular transport mechanisms (e.g., active or passive mechanisms) or by paracellular permeation. Without being bound by any theory, the nanostructures of the nanopatterned layer may increase the permeability of one or more layers of the viable epidermis, including the epidermal basement membrane (e.g., transcellular transport), by modifying cell / cell tight junctions that allow for paracellular transport pathways or by modifying cell active transport pathways, allowing an administered agent to diffuse or migrate and / or be actively transported through the viable epidermis to the underlying viable dermis. This effect may be due to modulation of gene expression of cell / cell tight junction proteins. As previously mentioned, tight junctions are found in viable skin, particularly in the viable epidermis. Opening of tight junctions may provide a paracellular pathway for improved delivery of any agent, such as those previously blocked from delivery through the skin.

[0289] Interaction between individual cells and nanotopography structures can increase the permeability of epithelial tissues (e.g., epidermis), induce the passage of drugs through barrier cells, and promote transcellular transport. For example, interaction with viable epidermal keratinocytes can promote drug distribution (e.g., transcellular transport) to the keratinocytes, followed by diffusion through the cells and back through the lipid bilayer. Furthermore, interaction of nanotopography structures with keratinocytes of the stratum corneum can induce changes in barrier lipids or corneodesmosomes, resulting in diffusion of drugs through the stratum corneum to the underlying viable epidermal layers. Drugs can pass through the barrier by paracellular and transcellular routes, but the primary transport route can differ depending on the nature of the drug.

[0290] In some embodiments, the microdosing device may interact with one or more components of epithelial tissue to increase the porosity of the tissue and make it more susceptible to paracellular and / or transcellular transport mechanisms. Epithelial tissue is one of the major tissue types of the body. Epithelial tissue that may be made more porous may include both simple and stratified epithelium, including both cornified and transitional epithelium. Furthermore, epithelial tissue encompassed herein may include any cell type of the epithelial layer, including but not limited to keratinocytes, endothelial cells, lymphatic endothelial cells, squamous epithelial cells, columnar cells, cuboidal cells, and pseudostratified cells. Any method for measuring porosity may be used, including but not limited to any epithelial permeability assay. For example, whole mount permeability assays may be used to measure the porosity or barrier function of epithelia (e.g., skin) in vivo, see, for example, Indra and Leid., Methods Mol Biol. (763) 73-81, the teachings of which are incorporated herein by reference.

[0291] In some embodiments, the structural changes induced by the presence of the nanotopography (a nanopatterned layer having a plurality of nanostructures) on the barrier cells are temporary and reversible, including a reversible increase in the porosity of the epithelial tissue by altering the stability and dynamics of the junctions, and may result in a temporary increase in paracellular and transcellular transport of the administered agent through the epidermis to the viable dermis, without being bound by any theory. Thus, in some aspects, the increase in permeability of the epidermis or epithelial tissue induced by the nanotopography, such as the promotion of paracellular or transcellular diffusion or the movement of one or more agents, returns to the normal physiological state that existed before contacting the epithelial tissue with the nanotopography after removal of the nanotopography. In this way, the normal barrier function of the barrier cell(s) (e.g., epidermal cell(s)) is restored, and no further diffusion or movement of molecules occurs beyond the normal physiological diffusion or movement of molecules in the patient's tissue.

[0292] These reversible structural changes induced by nanotopography may function to limit secondary skin infections, absorption of harmful toxins, and limit dermal irritation. Also, the gradual reversal of epidermal permeability from the top to the basal layers of the epidermis may facilitate downward movement of one or more agents through the epidermis into the dermis and prevent reflux or back diffusion of one or more agents back into the epidermis.

[0293] In some embodiments, a method is provided for administering a fluid composition to the lymphatic system of a patient, the method comprising applying a microdosing device as described herein to deliver the fluid composition to the lymphatic system, including, for example, delivery to a target in the lymphatic system or delivery via the lymphatic system to the systemic circulation or to a non-lymphatic target, which may include, for example, but is not limited to, circulating cells, organs, tissues, etc.

[0294] The fluid composition may include one or more agents to be delivered to a therapeutic target. In some embodiments, the therapeutic target is a lymph node, a lymphatic vessel, an organ that is part of the lymphatic system, or a combination thereof. In some embodiments, the therapeutic target is a lymph node. In some embodiments, the therapeutic target is a specific lymph node as described elsewhere herein.

[0295] In some embodiments, delivery of a therapeutic agent to the lymphatic system is to a blood vessel of the lymphatic vasculature, a lymph node as described elsewhere herein, or both. In some embodiments, delivery is to a superficial lymphatic vessel. In yet another aspect, delivery is to one or more lymph nodes.

[0296] Because lymph nodes often exist in groups as opposed to as single, isolated lymph nodes, the term "lymph node" as used herein may be singular or plural and refers to either a single, isolated lymph node or a group of lymph nodes in a small physical location. For example, reference to an inguinal lymph node or multiple inguinal lymph nodes refers to a group of lymph nodes recognized by those skilled in the art as a group of lymph nodes located in the hip / groin or femoral triangle in a patient. Also, unless otherwise specified, refers to both superficial and deep lymph nodes.

[0297] In some embodiments, the lymph nodes are selected from the group consisting of lymph nodes found in the hands, feet, thighs (femoral lymph nodes), arms, legs, armpits (axillary lymph nodes), groin (inguinal lymph nodes), neck (cervical lymph nodes), chest (pectoral lymph nodes), abdomen (iliac lymph nodes), popliteal lymph nodes, parasternal lymph nodes, lateral aortic lymph nodes, paraaortic lymph nodes, submental lymph nodes, parotid lymph nodes, submandibular lymph nodes, supraclavicular lymph nodes, intercostal lymph nodes, diaphragmatic lymph nodes, pancreatic lymph nodes, cisterna chyli, lumbar lymph nodes, sacral lymph nodes, obturator lymph nodes, mesenteric lymph nodes, mesocolic lymph nodes, mediastinal lymph nodes, gastric lymph nodes, hepatic lymph nodes, and splenic lymph nodes, and combinations thereof.

[0298] In some embodiments, two or more different lymph nodes are selected. In some embodiments, three or more different lymph nodes are selected. The lymph nodes may be on both sides of the patient's body. In yet another embodiment, the lymph nodes are inguinal lymph nodes. The inguinal lymph nodes may be right inguinal lymph nodes, left inguinal lymph nodes, or both. In yet another embodiment, the lymph nodes are axillary lymph nodes. The axillary lymph nodes may be right axillary lymph nodes, left axillary lymph nodes, or both.

[0299] In some embodiments, two or more different lymph nodes are selected. In some embodiments, three or more different lymph nodes are selected. The lymph nodes may be on both sides of the patient's body. In yet another embodiment, the lymph nodes are inguinal lymph nodes. The inguinal lymph nodes may be right inguinal lymph nodes, left inguinal lymph nodes, or both. In yet another embodiment, the lymph nodes are axillary lymph nodes. The axillary lymph nodes may be right axillary lymph nodes, left axillary lymph nodes, or both.

[0300] In some embodiments, the pharmaceutical agent is delivered to the patient's interstitium, e.g., the space between the skin and one or more internal structures, e.g., an organ, muscle, or blood vessel (artery, vein, or lymphatic vessel), or any other space within or between portions of a tissue or organ. In yet other embodiments, the pharmaceutical agent is delivered to both the interstitium and the lymphatic system. In embodiments in which a therapeutic agent is delivered to the patient's interstitium, it may not be necessary to locate the patient's lymph nodes or lymphatic vasculature prior to administering the therapeutic agent.

[0301] In some embodiments, a method for administering a therapeutic agent to a patient's lymphatic system is disclosed herein. The method generally includes: placing a microdosing device comprising a plurality of microneedles as described herein on a patient's skin at a first location adjacent to a first location under the patient's skin, the first location being adjacent to a lymphatic vessel and / or lymphatic capillary, and optionally the microneedles of the microdosing device having a surface comprising nanotopography; inserting the microneedles of the microdosing device into the patient to a depth at least penetrating the epidermis and at least one end of the protrusion being adjacent to the first location; and administering a dose of a therapeutic agent through the microneedles of the microdosing device to the first location.

[0302] In some embodiments, the dose of the therapeutic agent may be a therapeutically effective amount. In some embodiments, a single dose of the therapeutic agent may not be a therapeutically effective amount, and therefore more than two doses may be administered to the patient. In some embodiments, the total amount of doses is therapeutically effective. In some embodiments, at least two doses may be administered to the patient. The at least two doses may be administered sequentially or simultaneously.

[0303] The therapeutically effective dose or doses may be less than the therapeutically effective dose when the agent is administered by a different route (e.g., intravenous, subcutaneous, intramuscular, intradermal or parenteral delivery route, etc.).

[0304] In some embodiments, disclosed herein is a method for increasing the bioavailability of a therapeutic agent in a patient, the method comprising placing at least one microdosing device described herein on a skin surface of a subject, and administering a therapeutic agent to the subject together with the at least one microdosing device.

[0305] In some embodiments, the methods of delivering a therapeutic agent to a patient described herein may result in comparable serum absorption rates of the therapeutic agent compared to intravenous, subcutaneous, intramuscular, intradermal or parenteral delivery routes while maintaining the relatively high lymphatic delivery rates described herein. Without being bound by any theory, the increased delivery rate and bioavailability may be due to lymphatic circulation of one or more agents that enter the blood circulation through the thoracic duct or right lymphatic duct. Standard highly accurate and precise methods for measuring serum concentrations at desired time points and therapeutic monitoring, such as radioimmunoassay, high performance liquid chromatography (HPLC), fluorescence polarization immunoassay (FPIA), enzyme immunoassay (EMIT) or enzyme-linked immunosorbent assay (ELISA), well known in the art, may be used. To calculate the absorption rate using the above methods, the serum concentration is measured starting immediately after administration and then C max Drug concentrations may be measured at several incremental time points until a value is established and the associated absorption rate calculated.

[0306] The terms "pharmaceutical product", "medicine", "medicine", "therapeutic agent" and "drug" are used interchangeably herein to describe a pharmaceutical composition or product intended for the treatment of a medical condition having at least one symptom. The pharmaceutical composition or product has a physiological effect on the patient when introduced into the patient's body. The pharmaceutical composition may be in any suitable formulation, unless a specific formulation type is required or disclosed. In some instances, the pharmaceutical product is approved by the U.S. FDA, while in other instances, it may be experimental (e.g., in clinical trials or preclinical trials) or approved for use in countries other than the United States (e.g., approved for use in China or Europe). When these terms are used, it is understood that they refer to both the singular and plural cases. In some embodiments herein, two or more pharmaceutical products may be used in the form of combination therapy. In all cases, the selection of the appropriate pharmaceutical product(s) is based on the evaluation of the patient's medical condition and the medical professional managing, supervising and / or directing the treatment of the patient. Combination therapy may be more effective than a single agent and is used for many different medical conditions. It is understood that combination therapy is encompassed herein and contemplated with the disclosed subject matter.

[0307] An "effective amount" or "therapeutically effective dose" of a pharmaceutical is an amount sufficient to treat, ameliorate or reduce the intensity of at least one symptom associated with a medical condition. In some aspects of the present disclosure, an effective amount of a pharmaceutical is an amount sufficient to produce a beneficial or desired clinical result, including alleviation or mitigation of one or more symptoms of a medical condition. In some embodiments, an effective amount of a pharmaceutical is an amount sufficient to alleviate all symptoms of a medical condition. In some aspects, a dose of a therapeutic agent is administered that is not therapeutically effective alone. In these aspects, multiple doses may be administered to a patient, either sequentially or simultaneously (using the same microdosing device or different microdosing devices), such that the combination of the individual doses is therapeutically effective. Additional medical microdosing devices including multiple prongs or entirely different routes of administration may be used for simultaneous administration.

[0308] As used herein, the term "patient" refers to a warm-blooded animal, such as a mammal, that is the subject of medical treatment for a medical condition causing at least one symptom. At least humans, dogs, cats and horses are understood to be within the meaning of this term. In some embodiments, the patient is a human.

[0309] As used herein, the term "treat" or "treatment" or derivatives thereof contemplate partial or complete improvement of at least one symptom associated with a patient's medical condition, including, but not limited to, slowing or stopping the worsening of symptoms that occur in the absence of treatment. "Preventing" the occurrence of a symptom or medical condition is considered to be a form of treatment. "Reducing" the incidence of a symptom or medical condition is considered to be a form of treatment.

[0310] As used herein, "bioavailability" means the total amount of a given dose of an administered drug that reaches the blood compartment, measured as the ratio of (AUC / dose) for a given route of administration / (AUC / dose) for intravenous administration, and has the area under the curve (AUC) in a plot of concentration versus time.

[0311] C max refers to the maximum concentration that a drug achieves in a patient's plasma or tissues after it is administered, and C t refers to the concentration achieved by a pharmaceutical agent at a particular time (t) after administration. Unless otherwise stated, all discussions herein refer to pharmacokinetic parameters in plasma.

[0312] AUC t refers to the area under the plasma concentration-time curve from time 0 to time t after administration of a pharmaceutical agent.

[0313] AUC ∞ refers to the area under the plasma concentration time curve from time 0 to infinity (infinity means that the plasma concentration of the drug is below detectable levels).

[0314] T max is the time required for the concentration of a drug to reach its maximum plasma concentration in a patient after administration. Some dosage forms of drugs have a T max slowly reach the T max is reached almost immediately (e.g., subcutaneous and intravenous administration).

[0315] "Steady state" refers to a situation in which the overall uptake of a drug is in near dynamic equilibrium with its elimination.

[0316] A discussion of various pharmacokinetic parameters and how to measure and calculate them can be found in Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, M. Rowland and TN Tozer, (Lippincott, Williams & Wilkins, 2010), the teachings of which are incorporated by reference.

[0317] The lymphatic system plays a vital role in transporting fluids and particulate matter throughout the body. The lymphatic system includes several lymphatic organs (e.g., the spleen and thymus) in addition to lymph nodes, lymphatic vessels, and lymphatic capillaries. Blood vessels transport lymph unidirectionally around the body in either superficial or deep vessels (i.e., lymphatic vasculature). Drainage begins with blind ducts that gradually develop into blood vessels. These vessels then travel through several lymph nodes. Lymph nodes contain both T and B lymphocytes, in addition to other cells associated with the immune system. Antigens and other foreign particles are filtered out in the lymph nodes. The lymphatic vessels eventually end in either the right lymphatic duct, which drains into the right internal jugular vein, or the thoracic duct, which drains into the subclavian vein. It is a one-way system in which lymph (also called lymph) is eventually returned to the patient's circulatory system.

[0318] In some embodiments described herein, the therapeutic agent may be delivered in a liquid carrier solution. In one aspect, the tonicity of the liquid carrier may be hypertonic with respect to the fluid in blood capillaries or lymphatic capillaries. In another aspect, the tonicity of the liquid carrier solution may be hypotonic with respect to the fluid in blood capillaries or lymphatic capillaries. In another aspect, the isotonicity of the liquid carrier solution may be isotonic with respect to the fluid in blood capillaries or lymphatic capillaries. The liquid carrier solution may further comprise at least one or more pharma- ceutically acceptable excipients, diluents, cosolvents, particulates, or colloids. Pharmaceutically acceptable excipients for use in liquid carrier solutions are known, see, for example, Pharmaceutics: Basic Principles and Application to Pharmacy Practice (Alekha Dash et al. eds., 1st ed. 2013), the teachings of which are incorporated herein by reference.

[0319] In some embodiments described herein, the therapeutic agent is present in the liquid carrier as a substantially dissolved solution, a suspension, or a colloidal suspension. Any suitable liquid carrier solution meeting at least the specifications of the United States Pharmacopeia (USP) may be utilized, and the isotonicity of such solutions may be modified as known (see, e.g., Remington: The Science and Practice of Pharmacy (Lloyd V. Allen Jr. ed., 22nd ed. 2012). Exemplary non-limiting liquid carrier solutions may be aqueous, semi-aqueous, or non-aqueous, depending on the bioactive agent(s) to be administered. For example, aqueous liquid carriers may include any one or combination of water and water-miscible vehicles, ethyl alcohol, liquid (low molecular weight) polyethylene glycols, and the like. Non-aqueous carriers may include fixed oils such as corn oil, cottonseed oil, peanut oil, or sesame oil. Suitable liquid carrier solutions may further include any one of preservatives, antioxidants, complexation enhancers, buffers, acidifiers, saline, electrolytes, viscosity enhancers, viscosity reducers, alkalizing agents, antibacterial agents, antifungal agents, solubility enhancers, or combinations thereof.

[0320] III. Methods of Administering Coronavirus Vaccines

[0321] In some embodiments, the fluid composition may comprise a coronavirus vaccine. In particular, in some embodiments, the fluid composition comprises a SARS-CoV-2 vaccine.

[0322] More than 180 vaccine candidates based on several different platforms are currently in development against SARS-CoV-2 (for review see, e.g., Krammer, F. SARS-CoV-2 vaccines in development. Nature 586, 516-527 (2020). https: / / doi.org / 10.1038 / s41586-020-2798-3).

[0323] The World Health Organization (WHO) maintains a working document containing most of the vaccines in development and available at https: / / www.who.int / publications / m / item / draft-landscape-of-covid-19-candidate-vaccines. The document is currently titled Draft Landscape of COVID-19 Candidate Vaccines.https: / / www.who.int / publications / m / item / draft-landscape-of-covid-19-candidate-vaccines (WHO, accessed November 12, 2020) (also referred to herein as the "Draft Landscape of COVID-19 Candidate Vaccines").

[0324] Vaccine platforms can be divided into 'traditional' approaches (inactivated or live viral vaccines), recombinant protein and vectored vaccines, and nucleic acid (RNA and DNA) vaccines.

[0325] Inactivated vaccines are typically produced by growing SARS-CoV-2 in cell culture, for example on Vero cells, followed by chemical inactivation of the virus.

[0326] Live attenuated vaccines are typically produced by generating genetically attenuated versions of viruses that replicate to a limited extent, do not cause disease, but induce an immune response similar to that induced by natural infection. Attenuation can be achieved, for example, by adapting the virus to unfavorable conditions (e.g., growth at low temperatures, growth in non-human cells) or by rational genetic modification of the virus (e.g., by codon deoptimization or by deleting genes involved in counteracting natural immune recognition).

[0327] Recombinant protein vaccines can be divided into recombinant spike protein-based vaccines, recombinant RBD-based vaccines, and virus-like particle (VLP)-based vaccines. These recombinant proteins can be expressed in different expression systems, including insect cells, mammalian cells, yeast, bacteria, and plants. The yield, as well as the type and extent of post-translational modifications, vary depending on the expression system. Especially for recombinant spike protein-based vaccines, modifications such as deletion of polybasic cleavage sites, inclusion of stabilizing mutations, and inclusion of trimerization domains, as well as purification modes (soluble protein vs. membrane extraction) can vary.

[0328] Replication-deficient vector vaccines are typically based on another virus that has been engineered to express the spike protein and whose replication in vivo has been abolished by deletion of parts of its genome. Most of these approaches are based on adenovirus (AdV) vectors, but modified vaccinia virus (MVA), human parainfluenza virus vectors, influenza virus, adeno-associated virus and Sendai virus are also used.

[0329] Replication-competent vectors are typically derived from attenuated or vaccine strains of viruses that are engineered to express transgenes, such as spike proteins.For example, genetically engineered influenza viruses, measles viruses, vesicular stomatitis viruses (VSV), horsepox and Newcastle disease viruses (NDV) can be used.In some cases, animal viruses that do not replicate efficiently and do not cause disease in humans are used.

[0330] Some SARS-CoV-2 vaccine candidates currently in development use viral vectors that display the spike protein on their surface and are then inactivated before use. Examples of inactivated viral vectors include NDV-based vaccines that display the spike protein on their surface (which can be produced in a similar manner to influenza virus vaccines) as well as rabies vectors.

[0331] DNA vaccines are typically based on plasmid DNA that can be produced on a large scale in bacteria. These plasmids typically contain a mammalian expression promoter and a gene encoding the spike protein, which is expressed in the patient upon delivery.

[0332] RNA vaccines are a relatively recent development. Similar to DNA vaccines, the genetic information for the antigen is delivered and then the antigen is expressed in the patient's cells. Either mRNA or self-replicating RNA can be used.

[0333] In some embodiments, the coronavirus vaccines of the present disclosure include, but are not limited to, any of the vaccine candidates referenced in the draft landscape of COVID-19 candidate vaccines or otherwise identifiable by one of skill in the art upon reading this disclosure.

[0334] For example, coronavirus vaccines of the present disclosure include, but are not limited to, vaccine candidates currently in clinical evaluation listed in the table of FIG. 15A, or vaccine candidates currently in preclinical evaluation listed in the table of FIG. 15B (both tables are from the WHO draft landscape of COVID-19 candidate vaccines, accessed on November 12, 2020). Details listed in the table of FIG. 15A include the vaccine developer / manufacturer, vaccine platform, type of candidate vaccine, number of doses given to patients in the clinical trial, timing of dosing in the clinical trial, route of administration used in the clinical trial, and clinical phase (phase 1, 1 / 2, 2, or 3, clinical trial identifier provided). Listed in the table of FIG. 15B are the vaccine platform, type of candidate vaccine, developer, and coronavirus target.

[0335] In some embodiments, the coronavirus vaccine includes, but is not limited to, a recombinant fusion protein comprising a coronavirus spike S1 protein or a fragment thereof linked to an immunoglobulin Fc region or a fragment thereof (also referred to herein as "rS1-Fc"), and a nucleic acid (DNA or mRNA) encoding the rS1-Fc fusion protein, and an expression vector comprising the nucleic acid, and any composition thereof, such as those described in U.S. Provisional Application No. 62 / 993,527 filed March 23, 2020 and U.S. Provisional Application No. 63 / 045,685 filed June 29, 2020, and in Herrmann A, Maruyama J, Yue C, et al. A Targeted Vaccine against COVID-19: S1-Fc Vaccine Targeting the Antigen-Presenting Cell Compartment Elicits Protection against SARS-CoV-2 Also described in Infection.bioRxiv;2020.DOI:10.1101 / 2020.06.29.178616, the disclosure of which is incorporated herein in its entirety.

[0336] In some embodiments, the coronavirus spike S1 protein or fragment thereof may be derived from SARS-CoV-2. In some embodiments, for example, as described in U.S. Provisional Application Nos. 62 / 993,527 and 63 / 045,685, the rS1-Fc vaccine described therein is expected to induce a post-immune response against SARS-CoV-2 in patients administered the rS1-Fc vaccine. In some embodiments, MHC class I / II antigen presentation by the patient's dendritic cells (e.g., presentation of the SARS-CoV-2 spike S1 protein fragment of the rS1-Fc fusion protein) generates both a cytotoxic CD8+ Tc cell response and a helper Th CD4+ response. As a result, the CD4+ T cells are expected to activate B cells to produce neutralizing antibodies against the SARS-CoV-2 spike S1 protein, and the CD8+ cytotoxic T cells kill cells infected with SARS-CoV-2.

[0337] In some embodiments, rS1-Fc immunization induces early seroconversion and promotes anti-S1-specific IgG production that protects against live SARS-CoV-2 challenge. For example, as described in U.S. Provisional Patent Application No. 63 / 045,685, mice immunized intramuscularly with linearized dsDNA encoding S1-Fc showed significant and robust CD4+ upregulation in vivo in a dose-dependent manner. + IFNγ + In addition, S1 antigen-specific CD8 + T cells accumulated with increasing doses upon immunization. Furthermore, high-dose immunization increased the number of CD8 + IFNγ +It dose-dependently promoted the in vivo education of effector T cells. Thus, the dose-dependent adaptive immune response upon administration of S1-Fc dsDNA indicates that a rather high dose of S1-Fc dsDNA, which is expected to continuously produce and release S1 antigen systemically, is necessary to induce the desired adaptive T cell immune response. Complete seroconversion was detectable on day 10 of initial immunization with both 50 μg and 20 μg administered S1-Fc dsDNA, and initiated similar levels of S1-specific serum IgG antibodies. Furthermore, mice immunized by intramuscular injection of recombinant rS1-Fc protein promoted accelerated seroconversion detectable on day 7, and considerably increased levels of S1-specific serum IgG antibodies over time. Mouse sera seropositive for anti-S1 IgG significantly reduced the interaction of the viral S1 domain with the host receptor ACE2. Collected sera seropositive for anti-S1 IgG induced protection against live SARS-CoV-2 infection in a stringent experimental virus stimulation assay. Routing rS1-Fc administration by intravenous injection produced similar protective effects.

[0338] The immunogenicity of coronavirus vaccines can be evaluated in preclinical studies, for example in mice, such as C57BL / 6 and Balb / c mice. Th1, Th2, Th17, and T-reg cytokine patterns can be evaluated, for example, using ELISA, flow cytometry, and other methods known in the art, to observe whether coronavirus vaccines induce more effective Th1 immune responses (e.g., IFN-γ and IL-12), with no, low, or very low increases in IL-17 and IL-4, and no, low, or very low increases in TGF-β.

[0339] In some embodiments, a coronavirus vaccine (e.g., an rS1-Fc vaccine, or some other vaccines described herein) can enable selective uptake into APCs, induce cross-presentation of a coronavirus antigen protein (e.g., spike S1 protein) or fragments thereof, and elicit a robust anti-SARS-CoV-2 response in the context of Th1 / Th2 and Th17 / T-reg balance, which can enable an immune response in a patient to provide for effective vaccination of the patient, treatment of coronavirus infection in the patient, and minimization or prevention of adverse immune-related effects in the patient.

[0340] In previous studies, efforts to develop respiratory viral vaccines to protect against respiratory syncytial virus (RSV) and SARS-related diseases have demonstrated the potential clinical benefits of eliciting Th1 adaptive immune responses over the disease-exacerbating effects of Th2-polarized responses. Immunization studies in mice with four candidate SARS vaccines (VLP, whole virus, and rDNA-produced spike protein) resulted in pulmonary immunopathology upon antigenic stimulation with SARS virus, an effect demonstrated by Th2 polarization in mice immunized with each candidate vaccine. Other previous studies have shown that the use of APC-attracting antigens in the development of tumor vaccines, such as fusing the ectodomain of the XCL1 ligand with the XCR1 receptor on the surface of DCs, engages dendritic cells in the periphery of immunized mice and elicits a predominantly Th1-polarized response. Direct attraction of DCs in this manner results in cross-presentation of tumor antigens, expression of inflammatory cytokines including IL-12 and IFNγ, recruitment of NK cells, and emergence of Th1 cytotoxic T cell responses.

[0341] It is expected that in some embodiments, administration of the rS1-Fc vaccine described herein may result in an increase in Th1 polarized responses and a decrease or absence of mixed Th1 / Th2 or predominantly Th2 responses.

[0342] In some embodiments, it is expected that the rS1-Fc vaccine described herein may enhance APC-specific targeting, enhance Th1 immunity, and prevent tolerance induction.

[0343] In some embodiments, administering a coronavirus vaccine, such as the rS1-Fc vaccine or other coronavirus vaccines described herein, to a patient delivered using the microdosing devices and methods described herein may provide one or more therapeutic advantages compared to delivering the coronavirus vaccine to a patient using other routes of administration, such as intramuscular, intravenous, or intradermal delivery.

[0344] Without being limited by theory, in some embodiments, the microdosing devices and methods of the present disclosure are configured to deliver a fluid composition containing a therapeutic agent (e.g., a coronavirus vaccine) just above the skin ridge / dermal papilla to access the apical dermis, which contains dendritic cells that are 10 times more abundant than the total blood volume of an average individual (XN Wang et al., A Three-Dimensional Atlas of Human Dermal Leukocytes, Lymphatics, and Blood Vessels. Investigative Society of Investigative Dermatology, 2014. Volume 134, Issue 4, Pages 965-974. doi.org / 10.1038 / jid.2013.481). Without being limited by theory, the dermal dendritic cells (but not macrophages) migrate to lymphatic vessels where they are expected to improve immunity.

[0345] In some embodiments, the microdosing devices of the present disclosure may deliver about 10-40 fold higher (e.g., about 15 fold higher) concentrations of a therapeutic agent (e.g., a coronavirus vaccine) to lymph nodes compared to other routes of administration, such as intravenous, subcutaneous, intramuscular, or intradermal injection.

[0346] In some embodiments, it is expected that lymphatic delivery of a therapeutic agent (e.g., a coronavirus vaccine) using a microdosing device of the present disclosure may provide improved immunity to coronavirus infection, including increased coronavirus antigen-specific IgG levels and / or T cell responses, as compared to other routes of administration, such as intravenous, subcutaneous, intramuscular, or intradermal injection. Because the microdosing devices described herein are adapted to deliver a fluid composition to the lymphatic system of a patient (see, e.g., Example 1), a similar improvement in immunity to coronavirus infection in a patient is expected following delivery of a coronavirus vaccine using a microdosing device as observed following delivery of a coronavirus vaccine using a SOFUSA® DoseConnect™ device described in Example 3 of the present disclosure.

[0347] In some embodiments, lymphatic delivery of a coronavirus vaccine using the microdosing devices and methods described herein may improve Th1 (e.g., CD4 + IFNγ + ) T cells and Th2 (e.g., CD4 + IL-4 + For example, in Example 3 of the present disclosure, lymphatic delivery of rS1-Fc using the SOFUSA® DoseConnect™ device resulted in significantly higher levels of Th1 (CD4 + IFNγ + ) and Th2 (CD4 + IL-4 +) T cells. Moreover, in some embodiments, lymphatic delivery of coronavirus vaccines using the microdosing devices and methods described herein can provide an increase in the ratio of Th1 to Th2 responses. For example, in Example 3 of the present disclosure, lymphatic delivery of rS1-Fc using the SOFUSA® DoseConnect™ device resulted in a significant increase in Th1 responses compared to Th2 responses, but there was no significant difference between the increase in Th1 and Th2 responses following intramuscular or intradermal injection of the rS1-Fc vaccine.

[0348] In some embodiments, lymphatic delivery of a coronavirus vaccine (e.g., rS1-Fc vaccine) using the microdosing devices and methods described herein enhances Th1 (e.g., CD4+) proliferation in patients compared to other routes of administration, such as intravenous, subcutaneous, intramuscular, or intradermal injection of the same coronavirus vaccine given to a patient at the same dose. + IFNγ + ) T cells and / or Th2 (e.g., CD4 + IL-4 + ) T cells may be increased by up to 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold.

[0349] In some embodiments, lymphatic delivery of a coronavirus vaccine (e.g., rS1-Fc vaccine) using the microdosing devices and methods described herein results in an increase in the ratio of Th1 to Th2 responses in a patient (e.g., CD4 + IFNγ + T Cells vs. CD4 + IL-4 +For example, in some embodiments, lymphatic delivery of a coronavirus vaccine can result in an increase in Th1 T cells that is up to 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold greater than the increase in Th2 T cells.

[0350] In some embodiments, lymphatic delivery of a coronavirus vaccine using the microdosing devices and methods described herein reduces CD8+ counts in patients compared to other routes of administration, such as intravenous, subcutaneous, intramuscular, or intradermal injection of the same coronavirus vaccine given to a patient at the same dose. + (e.g., CD8 + IFNγ + For example, in Example 3 of the present disclosure, lymphatic delivery of rS1-Fc using the SOFUSA® DoseConnect™ device resulted in significantly higher levels of CD8 T cells than after intramuscular or intradermal injection of the rS1-Fc vaccine. + IFNγ + T cells were generated.

[0351] In some embodiments, lymphatic delivery of a coronavirus vaccine (e.g., rS1-Fc vaccine) using the microdosing devices and methods described herein increases CD8+ expression in patients compared to other routes of administration, such as intravenous, subcutaneous, intramuscular, or intradermal injection of the same coronavirus vaccine given to a patient at the same dose. + IFNγ + It may provide up to a 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold increase in T cells.

[0352] In some embodiments, the therapeutic agent (e.g., coronavirus vaccine) may be delivered to a patient at a concentration of up to 10 mg / mL, such as up to 10 mg / mL, 9 mg / mL, 8 mg / mL, 7 mg / mL, 6 mg / mL, 5 mg / mL, 4 mg / mL, 3 mg / mL, 2 mg / mL, 1 mg / mL, 0.9 mg / mL, 0.8 mg / mL, 0.7 mg / mL, 0.6 mg / mL, 0.5 mg / mL, 0.4 mg / mL, 0.3 mg / mL, 0.2 mg / mL, 0.1 mg / mL, 0.05 mg / mL, or 0.01 mg / mL. In some embodiments, the therapeutic agent (e.g., coronavirus vaccine) may be delivered to a patient at a dose of up to 5 mg in a volume of a fluid composition of up to 500 μL. In some embodiments, the microdosing devices and methods described herein may be used to deliver a fluid composition having a dose of up to 5 mg of therapeutic agent in a volume of a fluid composition of up to 500 μL. In some embodiments, the microdosing devices and methods described herein may be used to deliver doses of coronavirus vaccine up to 5 mg to a patient in a volume of fluid composition up to 500 μL.

[0353] In some embodiments, the coronavirus vaccine is one disclosed in any of the following publications: WO 2014 / 188343, WO 2014 / 132239, WO 2014 / 132240, WO 2013 / 061208, WO 2012 / 046149, WO 2011 / 135531, WO 2011 / 135530, WO 2011 / 135533, WO 2014 / 132240, WO 2015 / 16821, International Application PCT / US2015 / 028154 (published as WO 2015 / 168214), , PCT / US2015 / 028150 (published as WO 2015 / 168210), PCT / US2015 / 028158 (published as WO 2015 / 168215), PCT / US2015 / 028162 (published as WO 2015 / 168217), PCT / US2015 / 028164 (published as WO 2015 / 168219), PCT / US2015 / 038231 (published as WO 2016 / 003856), PCT / US2015 / 038232 (published as WO 2016 / 003857) (published as WO 2017 / 019526), ​​PCT / US2016 / 043656 (published as WO 2017 / 019535), PCT / US2017 / 027879 (published as WO 2017 / 189258), PCT / US2017 / 027891 (published as WO 2017 / 189259), PCT / US2017 / 064604 (published as WO 2018 / 111607), PCT / US2017 / 064609 (published as WO 2018 / 111609) Nos. 9,962,536 and 9,550,053; U.S. Patent Application Nos. 15 / 305,193, 15 / 305,206, 15 / 305,210, 15 / 305,307, 15 / 305,404, 15 / 305,509, 15 / 305,606, 15 / 305,704, 15 / 305,806, 15 / 305,906, 15 / 305,Nos. 201, 15 / 744,346, and 14 / 354,223, and international applications PCT / US2017 / 027879, PCT / US2017 / 027891, PCT / US2016 / 043656, PCT / US2017 / 064604, PCT / US2017 / 064609, PCT / US2017 / 064642, PCT / US2017 / 064614, PCT / US2017 / 064657, PCT / US2017 / 064668, and and may be administered to a patient using any of the devices or methods described in U.S. Provisional Patent Application No. 62 / 678,601, filed May 31, 2018, U.S. Provisional Patent Application No. 62 / 678,592, filed May 31, 2018, U.S. Provisional Patent Application No. 62 / 678,584, filed May 31, 2018, and International Application No. PCT / US2019 / 034736, all of which are incorporated herein by reference in their entireties. Such devices include the SOFUSA® drug delivery platform (Sorrento Therapeutics, Inc., San Diego). For example, such devices include the SOFUSA® DoseConnect™ device (Sorrento Therapeutics, Inc., San Diego). EXAMPLES

[0354] The devices and methods disclosed herein are further illustrated in the following examples, which are offered by way of illustration and are not intended to be limiting.

[0355] Example 1. Lymphatic delivery of indocyanine green (ICG)

[0356] This example describes an experiment to verify the delivery of a fluid composition using a microdosing device described herein coupled to a syringe. The exemplary microdosing device used in this example has a 4 x 4 microneedle array.

[0357] C57BL / 6 mice were anesthetized with isoflurane, and the dorsal area was shaved and covered with depilatory cream (Nair Sensitive) for 8 minutes, after which the cream was wiped off with warm, damp paper towels followed by an alcohol wipe.

[0358] The syringe was filled with 0.5 mg / ml indocyanine green (ICG) and the syringe was connected to a microdosing device described herein via the syringe connection assembly of the microdosing device described herein.

[0359] While the user held the microdosing device connected to the syringe freely in their hand, the microdosing device was placed on the skin of anesthetized mice so that the microneedle penetrated the surface of the skin. With the microneedle below the surface of the mouse's skin, 50 μL of IGC was injected over approximately 2 minutes by manually depressing the syringe plunger.

[0360] Lymphatic imaging was performed using non-invasive near-infrared fluorescence (NIRF) imaging as described in Sevick-Muraca EM, Kwon S, Rasmussen JC. Emerging lymphatic imaging technologies for mouse and man. J Clin Invest. 2014;124:905-14.

[0361] Fluorescent imaging of IGCs in lymph nodes was observed approximately 20 seconds after injection, as shown in FIG.

[0362] Example 2. Validation of lymphatic delivery of indocyanine green (ICG) prior to lymphatic administration of rS1-Fc vaccine using the SOFUSA® DoseConnect™ device.

[0363] This example describes an experiment to verify lymph node delivery with ICG prior to rS1-Fc vaccine injection in C57BL / 6 mice (average body weight 26 g).

[0364] Before switching to the rS1-Fc vaccine, ICG was administered first to verify delivery to the right brachial lymph node (see Example 3).

[0365] In this example, a SOFUSA® DoseConnect™ device equipped with a 10×10 microneedle array was used.

[0366] 24 hours prior to SOFUSA® DoseConnect™ administration, mice were anesthetized with isoflurane, and the dorsal area was shaved and covered with depilatory cream (Nair Sensitive) for 8 minutes. The cream was then wiped off with a warm, damp paper towel, followed by an alcohol wipe. SOFUSA® DoseConnect™ was then applied to the dorsal area using a plastic shell containing skin adhesive. A handheld applicator was then placed on the plastic shell and the microneedle was inserted into the skin. The operation of the device was as follows: The applicator strikes the microneedle with a post that moves at a speed of 6 m / s. 66 mm 2 A total of 100 microneedles are present over an area of ​​100 mm. With the microneedles inserted into the skin, the syringe pump was started to deliver indocyanine green (ICG).

[0367] Isoflurane-anesthetized healthy mice were infused with 0.5 mg / ml ICG at a rate of 75 μl / h into the right dorsolateral side. Lymphatic imaging was performed using non-invasive near-infrared fluorescence (NIRF) imaging as described in Sevick-Muraca EM, Kwon S, Rasmussen JC. Emerging lymphatic imaging technologies for mouse and man. J Clin Invest. 2014; 124: 905-14.

[0368] As shown in FIG. 12, lymph node delivery was verified and observed as early as 16 seconds after the start of administration of ICG via SOFUSA® DoseConnect™.

[0369] Example 3. IgG and T cell responses following intralymphatic, intramuscular or intradermal administration of rS1-Fc vaccine.

[0370] This example describes experiments that provide preclinical data in mice following lymphatic delivery of a 100 μg dose of an exemplary coronavirus vaccine, rS1-Fc vaccine (Sorrento Therapeutics, Inc.), using a SOFUSA® DoseConnect™ device equipped with a 10 x 10 microneedle array.

[0371] After validation of lymphatic delivery using ICG (see Example 2), the same SOFUSA® DoseConnect™ device was left in place in the skin of the mice at the location of the microneedle insertion and used to administer 100 μg of rS1-Fc vaccine (2 mg / mL in sterile water) at 75 μL / hour over 40 minutes.

[0372] Data are compared with results obtained after injecting mice with 100 μg of rS1-Fc vaccine intramuscularly or intradermally using multiple Mantoux injections of 5–10 doses proximal to the brachial lymph node.

[0373] Mice were administered 100 μg of rS1-Fc vaccine via SOFUSA® DoseConnect™ on days 0 (first immunization) and 21 (second immunization), and sera were collected 3 days before and 3, 7, 10, 14, 21, 28, 35 and 42 days after the first immunization.

[0374] Mice were administered 100 μg of rS1-Fc vaccine by intramuscular injection on days 0 (first immunization) and 21 (second immunization), and sera were collected 3 days before and 3, 7, 10, 14, 17, 24, 28, 31, 35, and 47 days after the first immunization.

[0375] Mice were administered 100 μg of rS1-Fc vaccine by intradermal injection on days 0 (first immunization) and 21 (second immunization), and sera were collected 3 days before and 3, 4, 7, 11, 14, 18, 25, 28, 32, 35, 39, and 41 days after the first immunization.

[0376] S1-specific serum IgG antibody optical density (OD, 450 nm) was determined at each of the serum collection time points. The results of the IgG response following administration of 100 μg of rS1-Fc vaccine via SOFUSA® DoseConnect™ or intramuscular or intradermal injection are shown in Figures 13A-C. Similar levels of S1-specific serum IgG antibodies were detected by approximately 28 days after the first immunization with SOFUSA® DoseConnect™ or via intramuscular or intradermal injection.

[0377] FIG. 14A is a graph showing box plots reporting the fold increase in T cell responses (Th1 and Th2) in mice following lymphatic administration of rS1-Fc vaccine via SOFUSA® DoseConnect™, or intramuscular or intradermal injection. Administration of rS1-Fc vaccine via SOFUSA® DoseConnect™ increased Th1 (CD4 + IFNγ + ) T cells and Th2 (CD4 + IL-4 +) T cells, resulting in a mean increase of 45.3-fold and a mean increase of 15.86-fold, respectively, and also resulting in a significant increase in Th1 responses compared to Th2 responses (p=00002). In comparison, intramuscular or intradermal injection of rS1-Fc vaccine resulted in a less than 10-fold increase in both Th1 and Th2 responses, and there was no significant difference between the increases in Th1 and Th2 responses following intramuscular or intradermal injection of rS1-Fc vaccine.

[0378] FIG. 14B shows T cell responses (CD8 + IFNγ + 1 is a graph showing box plots reporting examples of fold increases in CD8 + IFNγ + The largest increase in CD8 T cells was observed after intramuscular injection of the rS1-Fc vaccine, with an average increase of approximately 13-fold. + IFNγ + This was significantly greater than the approximately 7-fold increase in T cells (p=0.001) and CD8 + IFNγ + This was significantly greater than the approximately two-fold increase in T cells (p=0.000007).

[0379] FIG. 14C is a graph reporting exemplary results of flow cytometry analysis of T cells from plasma of mice following administration of rS1-Fc vaccine with SOFUSA® DoseConnect™. The average number of live cells in the samples was 86%. The graph on the left shows Th1 (CD4 + IFNγ + The graph in the center shows an example of the flow cytometry results for quantifying Th2 (CD4 + IL-4 + ) An example of flow cytometry results for quantification of T cells. The graph on the right shows CD8 + IFNγ+ An example of flow cytometry results quantifying T cells is shown. In serum from naive mice before administration of rS1-Fc vaccine with SOFUSA® DoseConnect™, CD4 + IFNγ + The proportion of T cells was 0.31%, and the CD4 + IL-4 + The proportion of T cells was 0.81%, and CD8 + IFNγ + The proportion of T cells was 1.34%.

[0380] FIG. 14D shows CD4+ / -100% from plasma of mice following administration of rS1-Fc vaccine via SOFUSA® DoseConnect™. + IFNγ + T cells, CD4 + IL-4 T cells and CD8 + IFNγ + Graphs reporting examples of mean fluorescence intensity (MFI) quantification by flow cytometry of T cells. Figure 14E shows CD4+ T cells from plasma of naive mice before administration of rS1-Fc vaccine via SOFUSA® DoseConnect™. + IFNγ + T cells, CD4 + IL-4 T cells and CD8 + IFNγ + CD4 counts from plasma of mice following administration of rS1-Fc vaccine via SOFUSA® DoseConnect™ compared to mean fluorescence intensity (MFI) quantification by flow cytometry of T cells + IFNγ + T cells, CD4 + IL-4 T cells and CD8 + IFNγ + FIG. 13 is a graph showing box plots reporting examples of fold increases in mean fluorescence intensity (MFI) quantification by flow cytometry of T cells.

[0381] Example 4. Leakage testing of microdosing devices

[0382] This example describes the results of testing fluid delivery using a microdosing device over a range of fluid flow rates and assessing whether leakage was present using a fluorescent dye present in the fluid.

[0383] An exemplary microdosing device having a 4x4 microneedle array with a total of 16 microneedles was connected to a syringe and the syringe was attached to a syringe pump set to inject fluid from the syringe through the microdosing device at the flow rates shown in Table 1 (the total flow rate and flow rate through each of the 16 microneedles of the exemplary microdosing device are also shown). At each flow rate, a force transducer measured the pressure of the fluid flowing through the microdosing device. The microdosing device was also visually inspected for leaks.

[0384] [Table 1]

[0385] Exemplary microdosing devices were capable of withstanding at least 82 psi without leakage while delivering fluid at a rate of at least 2000 μL / hr, which equates to delivering fluid at a rate of at least approximately 33 μL / min.

[0386] Example 5. Microneedle skin penetration test

[0387] This example describes an experiment to evaluate microneedle penetration into skin using handheld manual insertion with an exemplary microdosing device. Pig cadaver skin was used to quantify the depth of microneedle insertion into skin. Manual insertion was performed using an exemplary microdosing device with a 4x4 microneedle array (a microneedle array with a total of 16 microneedles). Analysis of microneedle insertion depth was performed by visual evaluation of microneedle insertion on methylene blue-stained skin, and the skin was shaved at 10 μm intervals and visual evaluation was performed at each depth.

[0388] Tests were performed using microdosing devices with three different configurations of proudness of the distal surface of the microneedle array baseplate, which protruded axially from the distal surface of the plenum by 0.56 μm, 1.06 μm, or 1.21 μm. Representative results are shown in Table 2.

[0389] [Table 2]

[0390] Figure 16 shows an exemplary schematic diagram of an exemplary microneedle skin penetration depth for each microneedle of a 4x4 microneedle array (left image), and a graph reporting the frequency distribution of exemplary microneedle penetration results for the images shown. For the exemplary results shown in Figure 16, the maximum microneedle skin penetration depth is 190 μm and the minimum microneedle skin penetration depth is 80 μm, with an average of 157.5 μm and a standard deviation of 29.26 μm.

[0391] The results of these examples are consistent with those observed for SOFUSA® DoseConnect™ devices with, for example, 10×10 or 18×18 microneedle arrays (having 100 or 324 microneedles, respectively) with skin penetration using an applicator. The results in this example demonstrated that manual handheld insertion of an exemplary microdosing device of the present disclosure with a 4×4 microneedle array provides adequate microneedle skin penetration for lymphatic delivery of a fluid composition in a patient.

[0392] Unless otherwise required by context herein, singular terms shall include the plural and plural terms shall include the singular. The singular forms "a," "an," and "the," as well as the singular use of any word, include plural referents unless expressly and clearly limited to one referent.

[0393] The use of the alternative (eg, "or") herein is understood to mean either one or both of the alternatives or any combination thereof.

[0394] The term "and / or" as used herein should be interpreted to mean specific disclosure of each of the specified features or components, whether or not the other is present. For example, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (single), and "B" (single). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to include each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (single); B (single); and C (single).

[0395] As used herein, the terms "comprising," "including," "having," and "containing," as well as grammatical variations thereof, are intended to be open-ended, such that one or more items in a list do not exclude other items that may be substituted for or added to the recited items. Whenever an embodiment is described herein with the term "comprising," it is understood that other similar embodiments described with the term "consisting of" and / or "consisting essentially of" are also provided.

[0396] As used herein, the term "about" refers to a value or composition that is within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which depends in part on how the value or composition is measured or determined, i.e., on the limitations of the measurement system. For example, "about" or "approximately" can mean within one or more standard deviations per practice in the art. Alternatively, "about" or "approximately" can mean a range of up to 10% (i.e., ±10%) or more, depending on the limitations of the measurement system. For example, about 5 mg can include any number between 4.5 mg and 5.5 mg. When a particular value or composition is provided in this disclosure, unless otherwise specified, the meaning of "about" or "approximately" should be assumed to be within an acceptable error range for that particular value or composition.

[0397] The terms "administer", "administered" and grammatical variations refer to the physical introduction of an agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In one embodiment, the formulation is administered via a route that is not parenteral, for example orally. Other parenteral routes include topical, epidermal or mucosal routes of administration, for example, intranasal, intravaginal, rectal, sublingual or topical. Administration can be, for example, once, multiple times, and / or over one or more extended periods of time.

[0398] Throughout this application, various publications, patents, and / or patent applications are referenced. The disclosures of the publications, patents, and / or patent applications are hereby incorporated by reference in their entireties into this application in order to more fully describe the state of the art to which this disclosure pertains.

[0399] The subject matter disclosed above should be considered as illustrative rather than limiting, and the appended claims are intended to cover all such modifications, enhancements, and other embodiments that fall within the true spirit and scope of the present disclosure. Accordingly, to the maximum extent permitted by law, the scope of the present disclosure should be determined by the broadest permissible interpretation of the following claims and their equivalents, and should not be restricted or limited by the foregoing detailed description.

Claims

1. 1. A device for delivering a fluid composition across a skin barrier of a patient, the device comprising:

1. A microneedle fluid block assembly comprising: a microneedle fluid block assembly including a microneedle array including a plurality of microneedles disposed on a distal surface of a base plate, the plurality of microneedles having a plurality of fluid outlet channels defined therein, the plurality of microneedles capable of penetrating a stratum corneum of a patient's skin and delivering a fluid composition to a depth below a surface of the patient's skin; a fluid distribution block having a distal surface coupled to a proximal surface of the base plate of the microneedle array, the fluid distribution block including a fluid distribution manifold defined therein and in fluid communication with the plurality of fluid outlet channels of the plurality of microneedles and configured to controllably distribute the fluid composition through the plurality of fluid outlet channels to the plurality of microneedles; 1. A syringe connection assembly having a fluid pathway defined therein, comprising: a distal end coupled to a proximal face of the fluid distribution block, the fluid pathway of the syringe connection assembly fluidly connected to the fluid distribution manifold; and a syringe connection assembly including a proximal end configured to be coupled to a syringe barrel having a bore defined therein, the fluid pathway of the syringe connection assembly configured to be fluidly connected to the bore of the syringe barrel; device.

2. the syringe connection assembly including a plenum coupled to and in fluid communication with the tubing connector; The tubing connector comprises: a distal portion coupled to a proximal surface of the plenum; a proximal portion configured to be fluidly connected to the bore of the syringe barrel; The plenum: a distal surface coupled to the proximal surface of the fluid distribution block and fluidly connected to the fluid distribution manifold; The device of claim 1 .

3. a first gasket disposed between the distal end of the syringe connection assembly and the proximal surface of the fluid distribution block and coupled to the distal end of the syringe connection assembly and the proximal surface of the fluid distribution block; The device of claim 1 , wherein the first gasket has holes that fluidly connect with the syringe connection assembly and the fluid pathway of the fluid distribution manifold.

4. 4. The device of claim 3, wherein the first gasket has a proximal surface and a distal surface, the proximal surface and the distal surface having an adhesive layer disposed thereon and adapted to adhere the distal end of the syringe connection assembly to the proximal surface of the fluid distribution block.

5. 10. The device of claim 1, wherein the fluid distribution manifold is configured to provide substantially equal flow rates of the fluid composition to the multiple fluid outlet channels of the multiple microneedles.

6. the fluid distribution manifold comprising: a proximal inlet disposed in the proximal face of the fluid distribution block and in fluid communication with the distal end of the syringe connection assembly; a supply channel fluidly connected to the proximal inlet and configured to distribute the fluid composition to a plurality of resistance channels, a supply channel, the plurality of resistance channels being fluidly connected to the supply channel and configured to provide a resistance to a flow of the fluid composition; 2. The device of claim 1, comprising: a plurality of outlet openings, each outlet opening of the plurality of outlet openings fluidly connected to a resistance channel of the plurality of resistance channels and a fluid outlet channel of the plurality of fluid outlet channels.

7. The device of claim 6, wherein the fluid distribution block includes a proximal portion having a distal surface connected to a proximal surface of a distal portion, and the supply channel and the resistance channel are disposed on the distal surface of the proximal portion and / or the proximal surface of the distal portion.

8. 10. The device of claim 1, wherein the fluid distribution block comprises a polymeric, glass and / or silicon material and the fluid distribution manifold is formed therein by drilling, cutting, powder blasting and / or etching.

9. The device of claim 7 , wherein the proximal and distal portions are joined to one another.

10. each resistor channel of the plurality of resistor channels: A length of 400 μm to 1,000 μm, an axial depth of 10 μm to about 20 μm; and having a width of 15 μm to 70 μm; The device of claim 6.

11. The device of claim 1 , wherein the plurality of microneedles is between 2 and 100 microneedles.

12. The method of claim 11, wherein each of the resistance channels of the plurality of resistance channels includes one or more inlet openings adapted to be fluidly connected to a supply channel of the plurality of supply channels; the resistance channels include an inner resistance channel located proximal to a lateral center of the fluid distribution block and an outer resistance channel located distal to the lateral center of the fluid distribution block; two or more of the inner resistance channels are in fluid communication with an inlet opening of the one or more inlet openings; each outer resistance channel of the outer resistance channels is in fluid communication with one inlet opening of the one or more inlet openings; The device of claim 6.

13. 10. The device of claim 1, further comprising a protective cap coupled to the distal end of the syringe connection assembly and configured to protect the physical integrity and / or sterility of the microneedle fluid block assembly.

14. The device of claim 13 , wherein the protective cap is configured to be slidably coupled to the syringe connection assembly.

15. The device of claim 1, further comprising a syringe including the syringe barrel, wherein the proximal end of the syringe connection assembly is coupled to the syringe barrel and fluidly connected to the bore of the syringe barrel.

16. The device of claim 15, wherein the fluid composition is disposed within the bore, the bore having a longitudinal axis, and the syringe further comprises a plunger slidably disposed within the longitudinal axis of the bore, and the syringe is adapted to expel a quantity of 1 μl to 500 μl of the fluid composition disposed within the bore in response to an axial force applied to the plunger.

17. The device of claim 16, wherein the syringe is adapted to expel the amount of the fluid composition over a period of from 0.1 seconds to 300 seconds.

18. 17. The device of claim 16, wherein in response to an axial force applied to the plunger, the device is adapted to deliver the fluid composition to a patient through the plurality of fluid outlet channels of the plurality of microneedles.

19. 20. The device of claim 18, wherein the device is adapted to be manually operable by a user, and the axial force is applied by the user's hand.

20. The device described in claim 1, wherein the plurality of microneedles further comprise nanotopography.

21. 10. The device of claim 1, wherein each microneedle of the plurality of microneedles has an axial length of about 50 μm to about 4000 μm, about 100 to about 3500 μm, about 150 μm to about 3000 μm, about 200 μm to about 3000 μm, about 250 μm to about 2000 μm, about 300 μm to about 1500 μm, or about 350 μm to about 1000 μm.

22. The device of claim 1 , wherein the fluid composition comprises a coronavirus vaccine.

23. 23. The device of claim 22, wherein the coronavirus vaccine is an inactivated virus vaccine, a live virus vaccine, a recombinant protein vaccine, a vectored vaccine, an RNA vaccine, or a DNA vaccine.

24. The device of claim 22, wherein the coronavirus vaccine is a SARS-CoV-2 vaccine.

25. 25. The device of claim 24, wherein the SARS-CoV-2 vaccine comprises a recombinant fusion protein comprising a coronavirus spike S1 protein or a fragment thereof linked to an immunoglobulin Fc region or a fragment thereof.

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