Needle-free delivery device

Abstract

The present invention relates to a needle-free delivery solution for delivering drugs and vaccines applied in the field of human clinical care and animal health care, including a needle-free delivery device and components thereof, a system, and a related drug-instrument combination product. By means of the arrangement of multiple pores and the control of the flow rate of the jet flow of drugs and vaccines, the dispersion degree of drugs and vaccines in vivo, the number of pores, the pore size, and the distribution of the pores, the present invention can significantly improve the single-dose delivery amount of drugs and vaccines without damaging the skin, has a delivery efficiency far higher than that of existing needle-free injections, and can be applied to a wider range of application scenarios. The present invention can also accurately deliver drugs and vaccines to one or more target sites at different depths in the intracutaneous tissues, subcutaneous tissues, muscles, or human organs and enhance the dispersion effect at the target sites. The present invention can also precisely control the three-dimensional dispersion degree of drugs and vaccines at the target sites, and particularly, control and regulate the dispersion volume, the dispersion range, and the dispersion center position of drugs and vaccines at the target sites, thereby greatly improving the contact effect of drugs and vaccines with the in-vivo tissues and the bioavailability of drugs and vaccines. The needle-free delivery solution of the present invention exhibits a significantly improved drug absorption effect, effectiveness, and a significantly enhanced vaccine response effect in drug-instrument combination use with a feline triple vaccine, a human hepatitis B vaccine, a human pneumonia vaccine, a human tumor vaccine, and semaglutide, and especially after the vaccine is injected at an amount of 60% of a standard dose, the average antibody titer of the vaccine is 1.1 or more times that of a needle injection at a 100% standard dose, and 60 days after the second dose of the vaccine is injected, the average antibody titer can reach up to 6.3 or more times that of the average antibody titer of the needle injection. Therefore, a novel needle-free delivery solution featuring high efficiency, precision, and excellent bioavailability is provided for drug and vaccine delivery. This invention relates to a needle-free jet technology for the delivery of drugs and vaccines in the field of human and animal health,including needle-free delivery devices and their components,systems,and related drug-device combination products.By changing nozzle settings such as the number of pores,the size of pores,and the distribution of pores,the invention controls the jet rate and the dispersion of drugs and vaccines in the body,therefore achieves better efficiency compared to the traditional needle-based delivery method,and significantly increases quantities deliverable in a single dose without damaging the skin.The invention can accurately deliver drugs and vaccines to target depths in the skin,subcutis,muscle,or organs with enhanced dispersion of drugs and vaccines at the target depth.The invention can also accurately control the three-dimensional dispersion of drugs and vaccines at the target position.Through controlling and regulating the dispersion volume,dispersion area,and dispersion epicenter,the invention greatly improves the bioavailability of drugs and vaccines in the body.The needle-free jet delivery solution of this invention has been used in delivering multivalent cat vaccines,GLP-1 drugs,human hepatitis B vaccines,and human cancer vaccines in animal models.The drug-device combination of a polypeptide vaccine with the device shows significantly improved drug absorption and immunogenicity.For the commercially available polyvalent cat vaccine from Zoetis,60％of the standard dose was combined with the needle-free jet device,generating 1.1 times the average antibody titer of the standard dose using traditional needle-based injections.When a standard dose was combined with the needle-free jet device,the average antibody titer 60 days after the second dose of the vaccine reached up to 6.3 times the average antibody titer for the standard dose using traditional needle-based injection.The invention provides a new needle-free jet delivery solution with high efficacy,accuracy,and bioavailability for drugs and vaccines.

Description

Needle-free delivery device

[0001] This application claims priority to Chinese patent application No. 202311787890.0 filed on December 22, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of medical devices, and in particular to a needle-free delivery device and a drug-device combination product. Background Art

[0003] Needle-free injection technology offers numerous advantages over traditional needle-assisted injection. Despite the availability of a variety of needle-free injection devices on the market, its widespread clinical application in both human and animal healthcare settings remains largely unexplored. This is primarily due to insufficient scientific research on the penetration and delivery performance of needle-free injection, particularly regarding the impact of jet velocity, drug chemical properties, needle-free injection aperture design, and the effects of media such as the epidermis, subcutaneous tissue, and muscle on drug penetration and delivery in humans and animals. Existing needle-free injectors typically utilize a single-aperture jet, while research and application of truly effective multi-aperture jet technology remains limited. In the vaccine delivery field, needle-free injection has been clinically studied for inactivated, attenuated, recombinant protein, nucleic acid (mRNA), and DNA vaccines. However, due to unreliable efficacy, it has not been widely adopted in practice. In practice, needle-free delivery devices require high skin adhesion, are prone to leakage due to hair, and face difficulties in precisely controlling the injection location, depth, and diffusion of the drug solution. Because high-pressure jets can be destructive, the jet apertures of current needle-free injection devices on the market are typically smaller than 0.15mm. This limits current needle-free injection technology when larger doses of drugs are required. Furthermore, drug metabolism and vaccine immunogenicity require high-quality three-dimensional diffusion and precise targeting of drugs and vaccines within the body, a challenge currently faced by needle-free injection technology in this area.

[0004] The content of this background technology description is only for facilitating understanding of the relevant technology in this field and is not regarded as an admission of the prior art.

[0005] Summary of the Invention

[0006] Therefore, in response to the above-mentioned shortcomings of current needle-free injection, embodiments of the present invention intend to provide a needle-free delivery device that at least partially addresses the problems existing in existing needle-free injection. Embodiments of the present invention also provide related drug-device combination products and needle-free syringes for use in needle-free delivery devices.

[0007] An embodiment of the present invention provides a needle-free delivery device, comprising:

[0008] a tube for containing a fluid, the tube having a first end and a second end, the second end having a plurality of holes disposed therein for distributing the fluid within the tube; and

[0009] A power mechanism includes a piston disposed in the first end of the tube and capable of pushing the fluid, or the power mechanism is operatively connected to the piston to apply delivery pressure to the piston pushing the fluid.

[0010] Other optional features and technical effects of the embodiments of the present invention are partially described below, and partially can be understood by reading this document. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. The elements shown are not limited to the scale shown in the drawings. The same or similar reference numerals in the drawings represent the same or similar elements, wherein:

[0012] FIG1 shows a schematic structural diagram of a needle-free delivery device according to an embodiment of the present invention;

[0013] FIG2 shows a schematic structural diagram of a needle-free delivery device according to an embodiment of the present invention;

[0014] FIG3 shows a schematic diagram of a multi-hole arrangement of a needle-free delivery device according to an embodiment of the present invention;

[0015] FIG4 shows a schematic diagram of a multi-hole arrangement of a needle-free delivery device according to an embodiment of the present invention;

[0016] FIG5 shows a schematic diagram of a multi-hole arrangement of a needle-free delivery device according to an embodiment of the present invention;

[0017] FIG6 shows a schematic diagram of a multi-hole arrangement of a needle-free delivery device according to an embodiment of the present invention;

[0018] FIG7 shows a schematic diagram of a linear arrangement of multiple holes in a needle-free delivery device according to an embodiment of the present invention;

[0019] FIG8 shows a schematic diagram of a linear arrangement of multiple holes in a needle-free delivery device according to an embodiment of the present invention;

[0020] FIG9 shows a schematic diagram of a linear arrangement of multiple holes in a needle-free delivery device according to an embodiment of the present invention;

[0021] FIG10 shows a schematic diagram of a linear arrangement of multiple holes in a needle-free delivery device according to an embodiment of the present invention;

[0022] FIG11 shows a schematic diagram of a porous array arrangement of a needle-free delivery device according to an embodiment of the present invention;

[0023] FIG12 is a schematic diagram showing a multi-pore arrangement of different pore sizes in a needle-free delivery device according to an embodiment of the present invention;

[0024] FIG13 is a schematic diagram showing a multi-pore arrangement of different pore sizes in a needle-free delivery device according to an embodiment of the present invention;

[0025] FIG14 shows a schematic diagram of a multi-pore arrangement with different pore sizes in a needle-free delivery device according to an embodiment of the present invention;

[0026] FIG15 is a schematic diagram showing a multi-pore arrangement of different pore sizes in a needle-free delivery device according to an embodiment of the present invention;

[0027] FIG16 shows a schematic diagram of a multi-hole annular arrangement of a needle-free delivery device according to an embodiment of the present invention;

[0028] FIG17 shows a schematic diagram of a multi-hole annular arrangement of a needle-free delivery device according to an embodiment of the present invention;

[0029] FIG18 shows a schematic diagram of a coaxial annular arrangement of multiple groups of holes in a needle-free delivery device according to an embodiment of the present invention;

[0030] FIG19 shows a schematic diagram of a coaxial annular arrangement of multiple groups of holes in a needle-free delivery device according to an embodiment of the present invention;

[0031] FIG20 shows a schematic diagram of multiple groups of coaxial rings of holes in a needle-free delivery device according to an embodiment of the present invention;

[0032] FIG21 shows a schematic diagram of a multi-hole arrangement of a central hole and peripheral holes in a needle-free delivery device according to an embodiment of the present invention;

[0033] FIG22 shows a schematic diagram of a multi-hole arrangement of a central hole and peripheral holes in a needle-free delivery device according to an embodiment of the present invention;

[0034] FIG23 shows a schematic diagram of a multi-hole arrangement of a central hole and peripheral holes in a needle-free delivery device according to an embodiment of the present invention;

[0035] FIG24 shows a schematic diagram of a multi-hole arrangement of a central hole and peripheral holes in a needle-free delivery device according to an embodiment of the present invention;

[0036] FIG25 shows a schematic diagram of a multi-hole arrangement of a central hole and peripheral holes in a needle-free delivery device according to an embodiment of the present invention;

[0037] FIG26 shows a schematic diagram of a multi-hole arrangement of a central hole and peripheral holes in a needle-free delivery device according to an embodiment of the present invention;

[0038] FIG27 shows a schematic diagram of a multi-hole arrangement of a central hole and peripheral holes in a needle-free delivery device according to an embodiment of the present invention;

[0039] FIG28 shows a schematic diagram of a multi-hole arrangement of a needle-free delivery device according to an embodiment of the present invention;

[0040] FIG29 shows a schematic diagram of a multi-hole arrangement of a needle-free delivery device according to an embodiment of the present invention;

[0041] FIG30 shows a schematic structural diagram of a needle-free delivery device according to an embodiment of the present invention;

[0042] FIG31 shows a schematic structural diagram of a needle-free delivery device according to an embodiment of the present invention;

[0043] FIG32 shows a schematic diagram of a multi-hole arrangement of a needle-free delivery device according to an embodiment of the present invention;

[0044] FIG33 shows a schematic diagram of the second end structure of the needle-free delivery device according to an embodiment of the present invention;

[0045] FIG34 shows a schematic structural diagram of a simulation model of a needle-free delivery device according to a specific embodiment of the present invention;

[0046] FIG35 is a schematic diagram showing the porous diffusion effect delivered by a needle-free delivery device according to an embodiment of the present invention;

[0047] FIG36 is a schematic diagram showing the porous diffusion effect delivered by a needle-free delivery device according to an embodiment of the present invention;

[0048] FIG37 is a schematic diagram showing the porous diffusion effect delivered by a needle-free delivery device according to an embodiment of the present invention;

[0049] FIG38 is a schematic diagram showing the porous diffusion effect delivered by a needle-free delivery device according to an embodiment of the present invention;

[0050] FIG39 is a schematic diagram showing the porous diffusion effect delivered by a needle-free delivery device according to an embodiment of the present invention;

[0051] FIG40 shows a schematic diagram of a multi-pore arrangement for delivery by a needle-free delivery device according to a specific embodiment of the present invention;

[0052] FIG41 is a line graph showing immunological test data delivered by a needle-free delivery device according to one embodiment of the present invention;

[0053] FIG42 shows a line graph of immunological test data delivered by a needle-free delivery device according to one embodiment of the present invention; and

[0054] 43 shows a line graph of immunological test data delivered by a needle-free delivery device according to one embodiment of the present invention. DETAILED DESCRIPTION

[0055] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be further described in detail below in conjunction with specific embodiments and accompanying drawings. Here, the exemplary embodiments of the present invention and their descriptions are used to explain the present invention, but are not intended to limit the present invention.

[0056] As used herein, the term "including" and its variations represent open inclusion, i.e., "including but not limited to." Unless otherwise stated, the term "or" means "and / or." The term "based on" means "based at least in part on." The terms "an example embodiment" and "an embodiment" mean "at least one example embodiment." The term "another embodiment" means "at least one additional embodiment." The terms "first," "second," etc. may refer to different or the same objects. Other explicit and implicit definitions may also be included below.

[0057] In various embodiments of the present invention, as shown in FIG1 , a needle-free delivery device is provided, in particular, a needle-free delivery device for drugs and vaccines. The needle-free delivery device may include a tube 100 and a power mechanism 200 (not specifically depicted), wherein the tube 100 is suitable for containing a fluid 130 and has a first end 110 and a second end 120, wherein a piston 210 for pushing the fluid 130 in the tube is provided in the first end 110, and a plurality of holes 121 are provided on the second end 120.

[0058] In some embodiments of the present invention, as shown in FIG. 2 , the second end 120 of the needle-free delivery device may further include a narrowed section 122 that gradually narrows axially from the tube 100 toward the distal end, and a plurality of holes 121 are provided on an end surface 123 of the narrowed section 122 , wherein the end surface 123 is configured to be circular.

[0059] In some embodiments of the present invention, as shown in Figures 1 and 2, the piston 210 may be provided as an independent component, and the power mechanism 200 is configured to be operatively connected to the piston 210 to apply delivery pressure to the piston 210. It is also conceivable that in other embodiments of the present invention, the power mechanism 200 may be integrally integrated with the piston 210.

[0060] In some embodiments of the present invention, the driving mode of the power mechanism 200 may include any one of compressed gas driving, spring driving, electromagnetic driving, or a combination of the above driving modes. For example, in some embodiments, the power mechanism 200 may be driven by compressed gas, such as compressed nitrogen or compressed carbon dioxide gas, or may be driven by a compressed mechanical spring, or may be driven by a piezoelectric actuator, which is not limited here.

[0061] In some embodiments of the present invention, a plurality of holes 121 may be provided in the second end 120, i.e., the number of the plurality of holes 121 is greater than or equal to 2. For example, Figures 3 to 5 illustrate the cases where 2, 3, and 4 holes 121 are provided on the second end 120. It is understood that, as shown in Figure 6, a plurality of holes 121 may be similarly arranged on the end surface 123, with the number of the plurality of holes 121 being greater than or equal to 2. The following embodiments of the present invention will all take the arrangement of the second end 120 as an example.

[0062] In some embodiments of the present invention, the total area of ​​the plurality of holes is 0.009 mm 2 Above, preferably 0.020mm 2 More preferably 0.053 mm 2 The single hole area of ​​the hole is 0.0028~0.035mm 2 , preferably 0.0028~0.020mm 2 , more preferably 0.0028 to 0.009 mm 2 .

[0063] In an embodiment of the present invention, the needle-free delivery device of the present invention can deliver 0.3 mm at a time without causing skin damage. 3 The volume of the drug or vaccine (pre-delivery volume) is preferably 1.0 mm 3 More than the volume (pre-delivery volume) of the drug or vaccine, more preferably 5.0mm 3 In some embodiments, the volume of the drug or vaccine delivered by the needle-free delivery device of the present invention at one time (the volume before delivery) can reach 14.0 mm 3 In a further embodiment, the volume of the drug or vaccine delivered by the needle-free delivery device of the present invention at one time (volume before delivery) can reach 46.0 mm 3 .

[0064] In some embodiments of the present invention, compared to manual needle injection (the pushing speed of the piston inside the needle tube is about 0.01 m / s), the piston speed of the needle-free delivery device 210 of the present invention when pushing the fluid 130 in the tube 100 is greater than or equal to 10 times the piston speed of manual needle injection. The piston speed of the piston 210 when pushing the fluid 130 is 0.05 m / s to 0.50 m / s, preferably 0.13 m / s to 0.15 m / s, and more preferably 0.14 m / s to 0.20 m / s.

[0065] In some embodiments of the present invention, compared to manual needle injection (in which the outlet jet velocity of the fluid ejected from the needle is about 2 m / s), the outlet jet velocity of the fluid 130 in the needle-free delivery device of the present invention when being pushed away from the plurality of holes 121 in the second end 120 by the piston 210 is greater than or equal to 10 m / s, preferably greater than or equal to 50 m / s, more preferably greater than or equal to 100 m / s, and more preferably greater than or equal to 150 m / s.

[0066] In some embodiments of the present invention, the needle-free delivery device is configured so that the fluid jets passing through the multiple holes 121 have different in vivo diffusivities; preferably, the apertures d of the multiple holes 121 of the needle-free delivery device are configured so that the fluid jets passing through the multiple holes 121 have different in vivo diffusivities; preferably, the fluid jet velocities v passing through the multiple holes 121 of the needle-free delivery device are configured so that the fluid jets passing through the multiple holes 121 have different in vivo diffusivities.

[0067] In some embodiments of the present invention, compared to existing manual needle injections (in which the injected fluid hardly diffuses in the body), the needle-free delivery device of the embodiments of the present invention allows the fluid 130 pushed out of the multiple holes 121 in the second end 120 by the piston 210 to have different diffusion in the body and different diffusion degrees.

[0068] In the embodiment of the present invention, the diffusivity refers to a comprehensive concept that describes the distribution characteristics of fluid in the body. Specifically, the diffusivity may include the fluid's diffusion volume ratio, diffusion depth, diffusion center, and edge liquid distribution density.

[0069] In some embodiments of the present invention, the diffusion volume ratio refers to the ratio of the volume of the diffusion area of ​​the fluid delivered by the needle-free delivery device in the body to the original volume of the fluid not delivered, that is:

[0070] In other embodiments of the present invention, the diffusion volume ratio may also refer to the ratio of the diffusion volume of the fluid delivered by the needle-free delivery device of the embodiment of the present invention to the diffusion volume of the fluid delivered by manual needle injection, that is:

[0071] The diffusion volume of the delivery fluid can be calculated in a variety of ways, which are not limited here. For example, in some embodiments of the present invention, a fluorescent marker can be added to the drug or vaccine in advance, and then scanned by medical imaging technology and image analysis software can be used to calculate the volume of the diffusion area. For example, the envelope diagram of the diffusion area can be calculated to estimate the volume of the diffusion area.

[0072] In some embodiments of the present invention, the diffusion depth refers to the farthest distance from the body surface to the diffusion area of ​​the fluid injected without needle; the diffusion center refers to the three-dimensional center of the diffusion area formed in the body by the fluid injected without needle, such as the centroid of the three-dimensional area, which is not limited here.

[0073] In some embodiments of the present invention, the needle-free delivery device is configured such that the diffusion volume of the fluid 130 in the body is greater than the volume of the non-delivered fluid or the volume of the fluid delivered with a needle. Preferably, the diffusion volume of the fluid in the body is more than 1.50 times the non-delivered volume, preferably more than 1.80 times, further preferably more than 2.40 times, more preferably more than 3.00 times, and even more preferably more than 3.60 times.

[0074] It is understandable that when the delivery fluid enters the body through the needle-free delivery device, the three-dimensional spatial area of ​​its distribution becomes larger due to the diffusion of the fluid in the body. This diffusion process will increase the surface area of ​​contact between the fluid, especially the drug or vaccine, and the tissues in the body, thereby improving the bioavailability and efficacy of the drug.

[0075] It is understandable that those skilled in the art can, under the guidance of the embodiments of the present invention, confirm the corresponding diffusion degrees of the dermis, epidermis, subcutaneous layer, muscle and human organs in the body of the inoculated object according to the needle-free delivery inoculated object, including but not limited to different types of animals or patients with different physical conditions.

[0076] In some embodiments of the present invention, the plurality of holes includes a first hole.

[0077] In a preferred embodiment, the first hole has a first pore size, and the size of the first pore size is configured to allow the fluid jet passing through the first hole to diffuse in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs. Preferably, the multiple holes have the same pore size, such as the first pore size.

[0078] In a preferred embodiment, the first hole has a first outlet jet velocity, and the first outlet jet velocity is configured to cause the fluid jet passing through the first hole to diffuse in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs. Preferably, multiple holes have the same outlet jet velocity, such as the first outlet jet velocity.

[0079] In other embodiments of the present invention, the plurality of holes include a first hole and a second hole.

[0080] In a preferred embodiment, the first hole has a first pore size, the size of which is configured such that the fluid jet passing through the first hole diffuses into at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; the second hole has a second pore size, the size of which is configured such that the fluid jet passing through the second hole diffuses into at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs. Preferably, the pore sizes of the plurality of holes can be configured to be unequal, for example, the plurality of holes may include a first hole and at least one second hole, wherein the first hole has a first pore size d1 and the second hole has a second pore size d2, wherein d1≠d2.

[0081] In a preferred embodiment, the first hole has a first outlet jet velocity, which is configured so that the fluid jet passing through the first hole diffuses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; the second hole has a second outlet jet velocity, which is configured so that the fluid jet passing through the second hole diffuses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs. Preferably, the jet velocities of the fluid 130 passing through the multiple holes can also be configured to be unequal, for example, the first hole has a first outlet jet velocity v1, and the second hole has a second outlet jet velocity v2, where v1≠v2.

[0082] In some embodiments of the present invention, the plurality of holes 121 may have different arrangements.

[0083] As shown in FIG. 7 to FIG. 9 , the plurality of holes 121 are arranged along a straight line.

[0084] As shown in FIG7 to FIG9 , the plurality of holes 121 are arranged in a straight line along the diameter or midline of the second end 120 . Preferably, one of the plurality of holes 121 arranged in a straight line along the diameter or midline of the second end 120 is located at the center of the circle or center of the second end.

[0085] In one embodiment of the present invention, as shown in FIG. 8 , three holes 121 are arranged in a straight line along the diameter (center line) of the second end 120 , including a hole 121 ′ located at the center (center) of the second end 120 .

[0086] In some embodiments of the present invention, preferably, the plurality of holes 121 arranged along a straight line are arranged at equal intervals.

[0087] In one embodiment of the present invention, as shown in FIG. 8 , a plurality of holes 121 are arranged on the second end 120 along a diameter straight line of the second end 120 , wherein the plurality of holes 121 are arranged at equal intervals.

[0088] In some embodiments of the present invention, preferably, as shown in FIG. 7 to FIG. 9 , the plurality of holes 121 arranged along a straight line are mirror-symmetrical with respect to the diameter or the center line of the second end 120 .

[0089] In some embodiments of the present invention, preferably, the holes 121 are arranged in multiple groups, and each group of holes 121 is arranged along a straight line. Preferably, each group of holes 121 is arranged along a diameter or a center line of the second end 120 .

[0090] In one embodiment of the present invention, as shown in FIG10 , three groups of holes 121 are arranged on the second end 120 , namely, Group A, Group B and Group C, wherein Group A and Group C each include two holes 121 arranged in a straight line, and Group B includes three holes 121 arranged in a straight line.

[0091] In some embodiments of the present invention, the plurality of holes 121 are arranged in an array. Preferably, the plurality of holes 121 arranged in an array are mirror-symmetrical with respect to the first and second diameters or the center line perpendicular to each other of the second end 120 .

[0092] In one embodiment of the present invention, as shown in FIG11 , four holes 121 are arranged in an array on the second end 120 , and the four holes 121 are mirror-symmetrical with respect to the first and second diameters (center lines) perpendicular to each other of the second end 120 .

[0093] In some embodiments of the present invention, the diameter of the hole 121 ′ located at the center or centre of the second end 120 is different from the diameters of the other holes in the plurality of holes 121 .

[0094] In one embodiment of the present invention, as shown in Figures 12 and 13, the second end 120 is provided with three holes arranged in a straight line, including a hole 121' with a diameter of d' located at the center or center of the second end 120, and the remaining two holes 121 with a diameter of d, where d'≠d.

[0095] In some embodiments of the present invention, preferably, the aperture d2 of at least one group of holes 121 among the multiple groups of holes 121 is different from the aperture d1 of the other groups of holes 121 .

[0096] In one embodiment of the present invention, as shown in Figures 14 and 15, three groups of holes 121, namely Group A, Group B and Group C, are arranged on the second end 120, wherein Group A and Group C each include two holes 121 arranged in a straight line, and Group B includes three holes 121' arranged in a straight line, wherein the aperture of the three holes 121' included in Group B is d', and the aperture of the holes 121 included in Group A and Group B is d, wherein d'≠d.

[0097] In some embodiments of the present invention, as shown in FIG8 , FIG12 and FIG13 , the outlet jet velocity v′ of the hole 121 ′ located at the center of the circle or center of the second end 120 is different from the outlet jet velocity v of the other holes 121 of the plurality of holes 121 .

[0098] In some embodiments of the present invention, preferably, the outlet jet velocity v2 of at least one group of holes among the plurality of groups of holes is different from the outlet jet velocity v1 of the other groups of holes.

[0099] In one embodiment of the present invention, as shown in Figures 14 and 15, three groups of holes 121, namely Group A, Group B and Group C, are arranged on the second end 120, wherein Group A and Group C each include two holes 121 arranged in a straight line, and Group B includes three holes 121' arranged in a straight line, wherein the outlet jet velocity v2 of the three holes 121' included in Group B, and the outlet jet velocity v1 of the holes 121 included in Group A and Group B, wherein v2≠v1.

[0100] In some embodiments of the present invention, the plurality of holes 121 on the second end 120 are arranged in a ring shape; preferably, the plurality of holes 121 are arranged in a ring shape with the center of the second end 120 as the center.

[0101] In one embodiment of the present invention, as shown in FIG. 16 and FIG. 17 , as an example, FIG. 16 shows that three holes 121 are arranged on the second end 120 , and the three holes 121 are arranged in a ring with the center O of the second end 120 as the center.

[0102] In some embodiments of the present invention, there are multiple groups of holes 121, and each group of holes 121 is arranged in a ring shape. Preferably, the multiple groups of holes 121 are coaxially arranged in a ring shape.

[0103] In one embodiment of the present invention, as shown in FIG18 , two groups of holes 121 , Group A and Group B, are arranged on the second end 120 , wherein Group A and Group B are arranged in a circular shape and are coaxially arranged in a circular shape with the center O of the second end 120 as the center.

[0104] In one embodiment of the present invention, as shown in Figures 19 and 20, two groups of holes 121, Group A and Group B, are arranged on the second end 120, wherein Group A and Group B are arranged in a ring shape and are coaxially arranged in a ring shape with the center of the second end 120 as the center, wherein the aperture of the three holes 121' included in Group B is d', and the aperture of the hole 121 included in Group A is d, wherein d'≠d; and in the configuration shown in Figure 19, the apertures of the holes 121 of Group A and Group B that are coaxially arranged in a ring shape decrease radially outward, that is, d'>d, while in the configuration shown in Figure 20, the holes 121 of Group A and Group B increase radially outward, that is, d'<d.

[0105] In some embodiments of the present invention, preferably, at least one of the plurality of holes 121 arranged in an annular manner has an outlet jet velocity different from that of the other holes;

[0106] In some embodiments of the present invention, preferably, the outlet jet velocity of at least one group of holes 121 of the plurality of groups of holes 121 is different from the outlet jet velocity of the other groups of holes;

[0107] In some embodiments of the present invention, the outlet jet velocities of the multiple groups of holes 121 coaxially arranged in an annular manner increase or decrease radially.

[0108] In some embodiments of the present invention, the plurality of holes 121 include a central hole 121 ″ located at the center of the second end and a plurality of peripheral holes 121 located around the central hole.

[0109] In one embodiment of the present invention, as shown in FIG. 21 to FIG. 24 , the second end 120 is provided with a central hole 121 ″ located at the center (center) of the second end and a plurality of peripheral holes 121 located around the central hole.

[0110] In one embodiment of the present invention, as shown in FIG. 21 , the second end 120 is provided with a central hole 121 ″ located at the center (center) of the second end and two peripheral holes 121 located around the central hole.

[0111] In some embodiments of the present invention, as shown in FIG. 22 to FIG. 24 , the plurality of peripheral holes 121 are arranged in a ring shape.

[0112] In some embodiments of the present invention, as shown in FIG. 22 to FIG. 24 , the plurality of peripheral holes 121 are arranged in a coaxial annular pattern around the central hole 121 ″.

[0113] In some embodiments of the present invention, as shown in FIG24 , the peripheral holes 121 are provided in multiple groups, and each group of peripheral holes 121 is arranged in a ring. Preferably, as shown in FIG24 , the multiple groups of peripheral holes 121 are arranged in a coaxial ring around the central hole 121 ″.

[0114] In one embodiment of the present invention, as shown in FIG24 , six peripheral holes 121 are provided on the second end 120 , and the six peripheral holes 121 are divided into two groups A and B that are evenly arranged in a ring shape, wherein each group A and B includes three peripheral holes 121 , and the two groups of peripheral holes 121 are coaxially arranged in a ring shape around the central hole 121 ″.

[0115] In some embodiments of the present invention, the diameter d″ of the central hole 121 ″ is different from the diameter d of the plurality of peripheral holes 121 .

[0116] In one embodiment of the present invention, as shown in Figures 25 and 26, the second end 120 is provided with a central hole 121" with a diameter of d" and three peripheral holes 121 with a diameter of d, wherein d"≠d, in the configuration shown in Figure 25, d"<d, and in the configuration shown in Figure 26, d">d.

[0117] In another embodiment of the present invention, as shown in Figures 27 to 29, the second end 120 is provided with a central hole 121" with a diameter of d" and 6 peripheral holes 121 with a diameter of d, wherein d"≠d, and the 6 peripheral holes 121 are divided into two groups A and B that are evenly arranged in a ring shape, wherein the two groups A and B each contain 3 peripheral holes 121, and the two groups of peripheral holes 121 are coaxially arranged in a ring shape around the central hole 121".

[0118] In some embodiments of the present invention, the aperture diameter d1 of at least one of the plurality of peripheral apertures 121 is different from the aperture diameter d2 of the other peripheral apertures. In some embodiments of the present invention, the aperture diameters of the plurality of coaxially annular apertures 121 and the central aperture 121" increase or decrease radially.

[0119] As shown in Figures 28 and 29, the aperture of the three peripheral holes 121 included in group A is d1, and the aperture of the three peripheral holes 121 included in group B is d2, and d1≠d2. In the configuration shown in Figure 28, d1>d2, and in the configuration shown in Figure 29, d1<d2. Figures 28 and 29 further show that the aperture of the one central hole 121" is d", the aperture of the three peripheral holes 121 included in the A group is d1, and the aperture of the three peripheral holes 121 included in the B group is d2, and d1≠d2; in the configuration shown in Figure 28, the apertures of the A and B holes 121 and the central hole 121" that are coaxially arranged in a ring decrease radially outward, that is: d">d1>d2, while in the configuration shown in Figure 29, the apertures of the A and B holes 121 and the central hole 121" that are coaxially arranged in a ring increase radially, that is: d"<d1<d2.

[0120] In some embodiments of the present invention, the outlet jet velocity v" of the central hole is different from the outlet jet velocity v of the plurality of peripheral holes.

[0121] In some embodiments of the present invention, the outlet jet velocity v1 of at least one group of peripheral holes 121 among the plurality of groups of peripheral holes 121 is different from the outlet jet velocity v2 of the other groups of peripheral holes 121 .

[0122] In some embodiments of the present invention, the outlet jet velocities of the multiple groups of holes 121 coaxially arranged in an annular pattern and the central hole 121 increase or decrease radially.

[0123] It is understandable that those skilled in the art can determine the aperture size and the number of the plurality of peripheral holes according to their needs, and no limitation is imposed herein.

[0124] In some embodiments of the present invention, the shapes of the holes 121 are cylindrical, conical, or streamlined.

[0125] In some embodiments of the present invention, any of the needle-free delivery devices described above can also be used in combination with a triple vaccine for feline rhinotracheitis, calicivirus, and panleukopenia. Thus, the present invention also provides corresponding drug-device combination products. In embodiments of the present invention, the drug-device combination product can include or can be a drug delivery system. In embodiments of the present invention, the triple vaccine is, for example, a feline triple vaccine.

[0126] In an embodiment of the present invention, the cat triple vaccine refers to an inactivated vaccine for preventing common infectious diseases of cats, which can prevent feline rhinotracheitis, feline calicivirus disease and feline panleukopenia. These three diseases are the most common infectious diseases of cats. When the cat triple vaccine is developed, it is based on the dominant epidemic strains of the three infectious diseases of cats screened from a large number of clinical samples. Therefore, it has good safety, rapid antibody production, long immune duration, and one-shot prevention of three diseases. It is suitable for cats over 8 weeks of age, and generally requires three shots of basic immunization at 8 weeks, 12 weeks, and 16 weeks of age. After completing basic immunization, a booster shot should be inoculated every year to maintain the immune effect.

[0127] In some embodiments of the present invention, the second end 120 of the needle-free delivery device used in combination with the feline triple vaccine is provided with three holes 121 arranged in a circular pattern at equal intervals around the center of the second end 120 , and the three holes 121 are 1.25 mm ± 20% away from the center of the second end 120 .

[0128] In some embodiments of the present invention, the pushing speed of the piston 210 of the needle-free delivery device used in combination with the feline triple vaccine is configured to be 0.12 m / s±20%.

[0129] In some embodiments of the present invention, the needle-free delivery device used in combination with the feline triple vaccine is configured so that the outlet jet velocity of the feline triple vaccine when pushed away from the hole 121 in the second end 120 by the pushing element 210 is 150.00 m / s±20%.

[0130] In some embodiments of the present invention, the needle-free delivery device used in combination with the feline triple vaccine is configured such that the diffusion volume of the feline triple vaccine in the body is more than 1.5 times the undelivered volume of the feline triple vaccine.

[0131] In some embodiments of the present invention, the needle-free delivery device used in combination with the feline triple vaccine is configured so that the average antibody titer of the feline triple vaccine 14 days after the second dose is more than 1.2 times, preferably more than 2.0 times, and more preferably more than 4.8 times the average antibody titer of needle injection.

[0132] In the present embodiments, the average antibody titer is a measure of the strength of an immune response, used to assess the level of antibodies produced by an organism against a specific antigen (such as a virus, bacteria, or vaccine). It is expressed as the average of the serum dilutions that can neutralize or bind to a certain amount of antigen under specific conditions. In other words, a higher average antibody titer indicates a stronger ability of the antibodies produced by the organism to fight a specific pathogen.

[0133] In some embodiments of the present invention, the needle-free delivery device used in combination with the feline triple vaccine is configured so that the average antibody titer of the feline triple vaccine 30 days after the second dose is more than 1.2 times, preferably more than 2.0 times, and more preferably more than 3.7 times the average antibody titer of needle injection.

[0134] In some embodiments of the present invention, the needle-free delivery device used in combination with the feline triple vaccine is configured so that the average antibody titer of the feline triple vaccine 60 days after the second dose is more than 1.2 times, preferably more than 2.0 times, and more preferably more than 6.3 times the average antibody titer of needle injection.

[0135] In some embodiments of the present invention, the needle-free delivery device used in combination with the feline triple vaccine is configured so that the average antibody titer of the feline triple vaccine 60 days after the second dose of 60% vaccine dose is more than 1.1 times, preferably more than 1.5 times, and more preferably more than 2.0 times the average antibody titer produced by needle injection of 100% vaccine dose.

[0136] In some embodiments of the present invention, any of the needle-free delivery devices described above can also be used in combination with a hepatitis B vaccine. Thus, embodiments of the present application also provide corresponding drug-device combination products. In embodiments of the present invention, the drug-device combination product can include or be a drug delivery system.

[0137] In the embodiments of the present invention, the hepatitis B vaccine refers to a recombinant yeast vaccine (Hansenula) for preventing hepatitis B (a viral liver disease). It is prepared by purifying the hepatitis B virus surface antigen (HBsAg) expressed by recombinant Hansenula and adding an aluminum adjuvant. The active ingredient is the hepatitis B virus surface antigen. The vaccine is suitable for people susceptible to hepatitis B, especially the following people: (1) newborns, especially those whose mothers are HBsAg or HBeAg positive, (2) people susceptible to hepatitis B aged 16 years and above, and (3) medical staff engaged in medical work and laboratory personnel who come into contact with blood. After vaccination, the immune system can be stimulated to produce protective antibodies, thereby giving the human body immunity to prevent hepatitis B, thereby achieving the purpose of preventing hepatitis B infection. The conventional immunization site is the deltoid muscle of the upper arm. The immunization program is 3 injections, one at birth (0 months), one at 1-2 months of age, and one at 6-18 months of age. Newborns are given the first injection within 24 hours after birth, and each injection is one dose.

[0138] In some embodiments of the present invention, the second end 120 of the needle-free delivery device used in combination with the hepatitis B vaccine is provided with three holes 121 arranged in a circular pattern at equal intervals around the center of the second end 120 , and the three holes 121 are 1.25 mm±20% away from the center of the second end 120 .

[0139] In some embodiments of the present invention, the pushing speed of the piston 210 of the needle-free delivery device used in combination with the hepatitis B vaccine is configured to be 0.12 m / s±20%.

[0140] In some embodiments of the present invention, the needle-free delivery device used in combination with the hepatitis B vaccine is configured so that the outlet jet velocity of the hepatitis B vaccine when pushed away from the hole 121 in the second end 120 by the pushing element 210 is 150.00 m / s±20%.

[0141] In some embodiments of the present invention, the needle-free delivery device used in combination with the hepatitis B vaccine is configured such that the diffusion volume of the hepatitis B vaccine in the body is more than 1.5 times the volume of the hepatitis B vaccine not delivered.

[0142] In some embodiments of the present invention, the needle-free delivery device used in combination with the hepatitis B vaccine is configured so that the average antibody titer of the hepatitis B vaccine 14 days after the second dose is more than 1.1 times the average antibody titer of needle injection, preferably more than 1.5 times, and more preferably more than 2.0 times.

[0143] In some embodiments of the present invention, the needle-free delivery device used in combination with the hepatitis B vaccine is configured so that the average antibody titer of the hepatitis B vaccine 42 days after the second dose is more than 1.1 times the average antibody titer of needle injection, preferably more than 1.5 times, and more preferably more than 2.0 times.

[0144] In some embodiments of the present invention, the needle-free delivery device used in combination with the hepatitis B vaccine is configured so that the average antibody titer of the hepatitis B vaccine 42 days after the second dose of 60% vaccine dose is more than 1.1 times, preferably more than 1.3 times, and more preferably more than 1.5 times the average antibody titer produced by needle injection of 100% vaccine dose.

[0145] In some embodiments of the present invention, the needle-free delivery device used in combination with the hepatitis B vaccine is configured so that the T lymphocyte positive expression rate of the hepatitis B vaccine 42 days after the second dose is higher than that of needle injection by more than 10%, preferably more than 20% higher, and more preferably more than 50% higher.

[0146] In some embodiments of the present invention, any needle-free delivery device in the above embodiments of the present invention can also be used in combination with a pneumonia vaccine for human use as a drug delivery system.

[0147] In the embodiments of the present invention, the pneumococcal vaccine is primarily used to prevent pneumonia caused by pneumococcus and can induce humoral immunity. It is suitable for healthy individuals aged 6 weeks and older at high risk to prevent pneumococcal pneumonia and systemic pneumococcal infection caused by various serotypes included in the vaccine. It can be injected subcutaneously or intramuscularly into the deltoid muscle on the lateral side of the upper arm, with each injection of 0.5 ml.

[0148] In some embodiments of the present invention, the second end 120 of the needle-free delivery device used in combination with a human pneumonia vaccine is provided with three holes 121 arranged in a circular pattern at equal intervals around the center of the second end 120 , and the three holes 121 are 1.25 mm ± 20% away from the center of the second end 120 .

[0149] In some embodiments of the present invention, the pushing speed of the piston 210 of the needle-free delivery device used in combination with a human pneumonia vaccine is configured to be 0.14 m / s±20%.

[0150] In some embodiments of the present invention, the needle-free delivery device used in combination with a pneumonia vaccine for humans is configured such that the exit jet velocity of the pneumonia vaccine for humans when pushed away from the hole 121 in the second end 120 by the pushing element 210 is 160.00 m / s±20%.

[0151] In some embodiments of the present invention, the needle-free delivery device used in combination with a human pneumonia vaccine is configured such that the diffusion volume of the human pneumonia vaccine in the body is more than 1.5 times the undelivered volume of the human pneumonia vaccine.

[0152] In some embodiments of the present invention, the needle-free delivery device used in combination with a human pneumonia vaccine is configured so that the average antibody titer of the human pneumonia vaccine after vaccination is 1.1 times or more, preferably 1.5 times or more, and even more preferably 2.0 times or more of the average antibody titer of needle injection.

[0153] In some embodiments of the present invention, the needle-free delivery device used in combination with a pneumonia vaccine for humans is configured so that the average antibody titer of the pneumonia vaccine for humans 42 days after the second dose is 1.1 times or more, preferably 1.5 times or more, and even more preferably 2.0 times or more of the average antibody titer of needle injection.

[0154] In some embodiments of the present invention, the needle-free delivery device used in combination with a pneumonia vaccine for humans is configured so that the average antibody titer of the pneumonia vaccine after 60% vaccine dose injection is more than 1.1 times, preferably more than 1.3 times, and even more preferably more than 1.5 times the average antibody titer produced by 100% vaccine dose injection with a needle.

[0155] In some embodiments of the present invention, any of the needle-free delivery devices described above can also be used in combination with a GLP-1 polypeptide. Thus, the present invention also provides corresponding drug-device combination products. In embodiments of the present invention, the drug-device combination product can include or be a drug delivery system.

[0156] In some embodiments of the present invention, the second end 120 of the needle-free delivery device used in combination with GLP-1 polypeptides is provided with three holes 121, which are arranged in a circular pattern with equal intervals around the center of the second end 120, and the three holes are 1.25 mm ± 20% away from the center.

[0157] In some embodiments of the present invention, the pushing speed of the piston 210 of the needle-free delivery device used in combination with a GLP-1 polypeptide is 0.16 m / s ± 20%;

[0158] In some embodiments of the present invention, the needle-free delivery device used in combination with a GLP-1 polypeptide is configured such that the outlet jet velocity of the GLP-1 polypeptide when pushed away from the hole 121 in the second end 120 by the pushing element 210 is 170.00 m / s±20%.

[0159] In some embodiments of the present invention, the needle-free delivery device used in combination with the GLP-1 polypeptide is configured such that the diffusion volume of the GLP-1 polypeptide in the body is more than 1.5 times the volume of the GLP-1 polypeptide not delivered.

[0160] In some embodiments of the present invention, the GLP-1 polypeptide includes semaglutide, and any of the needle-free delivery devices described in the embodiments of the present invention can also be used in combination with semaglutide. Thus, the present invention also provides corresponding drug-device combination products. In embodiments of the present invention, the drug-device combination product can include or be a drug delivery system.

[0161] In some embodiments of the present invention, the needle-free delivery device used in combination with semaglutide is configured such that the diffusion volume of the semaglutide in the body is more than 1.5 times the non-delivered volume of the semaglutide.

[0162] In some embodiments of the present invention, the needle-free delivery device used in combination with semaglutide is configured so that the weight loss effect of semaglutide on humans and animals is consistent with that of needle injection. Preferably, the weight loss effect is increased by more than 2% compared with needle injection, further preferably by more than 5%, and even more preferably by more than 10%.

[0163] In some embodiments of the present invention, the needle-free delivery device used in combination with semaglutide is configured so that the weight loss endpoint of semaglutide in vivo is consistent with that of needle injection, preferably increased by more than 2%, more preferably increased by more than 5%, and more preferably increased by more than 10%.

[0164] In some embodiments of the present invention, the needle-free delivery device used in combination with semaglutide is configured so that the ratio of side effects such as nausea, vomiting, and abdominal distension caused by semaglutide is consistent with that caused by needle injection, preferably reduced by more than 5%, further preferably reduced by more than 10%, and even more preferably reduced by more than 20%.

[0165] In some embodiments of the present invention, any needle-free delivery device of the present invention can also be used in combination with a drug preparation.

[0166] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a rabies vaccine for human use.

[0167] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a rabies vaccine for animals.

[0168] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a meningitis vaccine for human use.

[0169] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a hand, foot and mouth disease vaccine for animals.

[0170] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a new coronavirus vaccine for human use.

[0171] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a hepatitis A vaccine for human use.

[0172] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a vaccine for hemorrhagic fever with renal syndrome for humans.

[0173] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a mumps vaccine for human use.

[0174] In some embodiments of the present invention, optionally, the pharmaceutical preparation is an HPV vaccine for humans.

[0175] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a tumor chemotherapy drug for human use.

[0176] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a nuclear medicine for treating tumors in humans.

[0177] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a human tumor vaccine, including but not limited to polypeptide vaccines, mRNA vaccines, and DNA vaccines.

[0178] In some embodiments of the present invention, the pharmaceutical preparation is a combined porcine diarrhea vaccine. In some embodiments of the present invention, the combined porcine diarrhea vaccine may include a combined live vaccine for porcine transmissible gastroenteritis and porcine epidemic diarrhea (HB08 strain + ZJ08 strain). In some embodiments of the present invention, the combined porcine diarrhea vaccine may include a combined inactivated vaccine for porcine transmissible gastroenteritis and porcine epidemic diarrhea.

[0179] In some embodiments of the present invention, the pharmaceutical preparation is an inactivated blue ear vaccine. In some embodiments of the present invention, the inactivated blue ear vaccine may include an inactivated porcine reproductive and respiratory syndrome vaccine (CH-1a strain).

[0180] In some embodiments of the present invention, the pharmaceutical preparation is a foot-and-mouth disease vaccine. In some embodiments of the present invention, the foot-and-mouth disease vaccine can be used for pigs, cattle or sheep. In some embodiments of the present invention, the foot-and-mouth disease vaccine may include swine foot-and-mouth disease O type inactivated vaccine (O / Mya98 / XJ / 2010 strain + O / GX / 09-7 strain). In some embodiments of the present invention, the foot-and-mouth disease vaccine may include swine foot-and-mouth disease O type, A type bivalent inactivated vaccine (Re-O / MYA98 / JSCZ / 2013 strain + Re-A / WH / 09 strain). In some embodiments of the present invention, the foot-and-mouth disease vaccine may include foot-and-mouth disease O type inactivated vaccine (OJMS strain), which can be used for cattle or sheep. In some embodiments of the present invention, the foot-and-mouth disease vaccine may include foot-and-mouth disease O type, A type bivalent inactivated vaccine (O / HB / HK / 99 strain + AF / 72 strain, suspension culture), which can be used for cattle. In some embodiments of the present invention, the foot-and-mouth disease vaccine may include a bivalent inactivated foot-and-mouth disease type O and type A vaccine (O / MYA98 / BY / 2010 strain + Re-A / WH / 09 strain), which can be used for cattle or sheep.

[0181] In some embodiments of the present invention, the pharmaceutical preparation is a bovine bivalent vaccine. In some embodiments of the present invention, the bovine bivalent vaccine may include a bovine viral diarrhea / mucosal disease and infectious rhinotracheitis bivalent inactivated vaccine (NMG strain + LY strain).

[0182] In some embodiments of the present invention, the pharmaceutical preparation is a Pasteurella vaccine. In some embodiments of the present invention, the Pasteurella vaccine may include an inactivated bovine Pasteurella multocida vaccine.

[0183] In some embodiments of the present invention, optionally, the pharmaceutical preparation is insulin;

[0184] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a botulinum toxin cosmetic drug used for medical cosmetology.

[0185] In some embodiments of the present invention, there is also provided use of the needle-free delivery device according to any one of the above embodiments of the present invention in the preparation of human clinical medical and animal health drugs for needle-free injection administration.

[0186] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a feline triple vaccine.

[0187] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a hepatitis B vaccine.

[0188] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a pneumonia vaccine for human use.

[0189] In some embodiments of the present invention, optionally, the pharmaceutical preparation is semaglutide.

[0190] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a rabies vaccine for human use.

[0191] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a rabies vaccine for animals.

[0192] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a meningitis vaccine for human use.

[0193] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a hand, foot and mouth disease vaccine for animals.

[0194] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a new coronavirus vaccine for human use.

[0195] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a hepatitis A vaccine for human use.

[0196] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a vaccine for hemorrhagic fever with renal syndrome for humans.

[0197] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a mumps vaccine for human use.

[0198] In some embodiments of the present invention, optionally, the pharmaceutical preparation is an HPV vaccine for humans.

[0199] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a tumor chemotherapy drug for human use.

[0200] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a nuclear medicine for treating tumors in humans.

[0201] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a human tumor vaccine, including but not limited to polypeptide vaccines, mRNA vaccines, and DNA vaccines.

[0202] In some embodiments of the present invention, the pharmaceutical preparation is a pig diarrhea bivalent vaccine.

[0203] In some embodiments of the present invention, the pharmaceutical preparation is an inactivated blue ear vaccine.

[0204] In some embodiments of the present invention, the pharmaceutical preparation is a foot-and-mouth disease vaccine.

[0205] In some embodiments of the present invention, the pharmaceutical preparation is a bovine bivalent vaccine.

[0206] In some embodiments of the present invention, the pharmaceutical preparation is a Pasteurella vaccine.

[0207] In some embodiments of the present invention, optionally, the pharmaceutical preparation is insulin.

[0208] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a botulinum toxin cosmetic drug used for medical cosmetology.

[0209] The present invention also provides a drug-device combination product, including a needle-free delivery device and a drug preparation 300. In the present invention, the drug-device combination product may include or may be a drug delivery system.

[0210] As shown in Figures 30 and 31, the needle-free delivery device includes:

[0211] a tube 100 for containing a drug formulation 300, the tube 100 having a first end 110 and a second end 120, wherein the second end 120 is provided with a single hole 124 for dispensing the drug formulation 300 in the tube; and

[0212] a power mechanism 200, the power mechanism 200 including a piston 210 disposed in the first end 110 of the tube 100 capable of pushing the drug preparation 300, or the power mechanism 200 is operatively connected to the piston 210 to apply a delivery pressure to the piston 210 pushing the drug preparation 300;

[0213] The needle-free delivery device is configured such that the diffusion volume of the drug preparation 300 in the body is more than 1.5 times the non-delivered volume.

[0214] In some embodiments of the present invention, as shown in FIG31 , the second end 120 of the needle-free delivery device may further include a narrowed section 122 that gradually narrows axially from the tube 100 toward the distal end, and a single hole 124 is provided on the end surface 123 of the narrowed section 122. The end surface 123 is circular. The needle-free delivery device is configured such that the diffusion volume of the drug formulation 300 in the body is at least 1.50 times the undelivered volume.

[0215] In some embodiments of the present invention, as shown in Figures 30 and 31 , the piston 210 may be provided as an independent component, and the power mechanism 200 is configured to be operatively connected to the piston 210 to apply delivery pressure to the piston 210. It is also conceivable that in other embodiments of the present invention, the power mechanism 200 may be integrally integrated with the piston 210 and apply delivery pressure to the piston 210.

[0216] In some embodiments of the present invention, the driving mode of the power mechanism 200 may include any one of compressed gas driving, spring driving, electromagnetic driving, or a combination of the above driving modes. For example, in some embodiments, the power mechanism 200 may be driven by compressed gas, such as compressed nitrogen or compressed carbon dioxide gas, or may be driven by a compressed mechanical spring, or may be driven by a piezoelectric actuator, which is not limited here.

[0217] In some embodiments of the present invention, the needle-free delivery device is configured such that the diffusion volume of the drug preparation 300 in the body is greater than the volume of the non-delivered drug preparation 300 or the volume of the drug preparation 300 delivered with a needle. Preferably, the diffusion volume of the drug preparation 300 in the body is more than 1.50 times the non-delivered volume, preferably more than 1.80 times, further preferably more than 2.40 times, more preferably more than 3.00 times, and even more preferably more than 3.60 times.

[0218] In some embodiments of the present invention, compared to manual needle injection (the pushing speed of the piston inside the needle tube is about 0.01 m / s), the piston speed of the needle-free delivery device 210 of the present invention when pushing the drug preparation 300 in the tube 100 is greater than or equal to 10 times the piston speed of manual needle injection. The piston speed of the piston 210 when pushing the fluid 130 is 0.10 m / s to 0.20 m / s, preferably 0.13 m / s to 0.15 m / s, and more preferably 0.14 m / s.

[0219] In some embodiments of the present invention, the power mechanism is configured to apply different adjustable delivery pressures to the piston 210 that pushes the drug preparation 300 , and optionally, the delivery pressures include a first delivery pressure F1 and a second delivery pressure F2 ;

[0220] Preferably, the magnitude of the first delivery pressure F1 is configured such that the jet of the drug preparation 300 passing through the single hole 124 diffuses into at least one of the dermis, epidermis, subcutaneous layer, muscle, and human organs; the magnitude of the second delivery pressure F2 is configured such that the jet of the drug preparation 300 passing through the single hole 124 diffuses into another of the dermis, epidermis, subcutaneous layer, muscle, and human organs;

[0221] Preferably, the magnitude of the first delivery pressure F1 is configured such that the drug preparation jet passing through the single hole 124 has a first outlet jet velocity v1, and the first outlet jet velocity v1 is configured such that the drug preparation 300 jet passing through the single hole 124 diffuses in at least one of the dermis, epidermis, subcutaneous layer, muscle, and human organs;

[0222] Preferably, the magnitude of the second delivery pressure F2 is configured so that the drug preparation jet 300 passing through the single hole 124 has a second outlet jet velocity v2, and the second outlet jet velocity v2 is configured so that the drug preparation 300 jet passing through the single hole 124 diffuses in the dermis, epidermis, subcutaneous tissue, muscle and at least another human organ.

[0223] In some embodiments of the present invention, optionally, the pharmaceutical preparation 300 is a feline triple vaccine;

[0224] In some embodiments of the present invention, optionally, the pharmaceutical preparation 300 is a hepatitis B vaccine;

[0225] In some embodiments of the present invention, optionally, the pharmaceutical preparation 300 is a pneumonia vaccine for human use;

[0226] In some embodiments of the present invention, optionally, the pharmaceutical preparation 300 is semaglutide;

[0227] In some embodiments of the present invention, optionally, the pharmaceutical preparation 300 is a tumor vaccine for human use, including but not limited to polypeptide vaccines, mRNA vaccines, and DNA vaccines.

[0228] The needle-free delivery device of the embodiment of the present invention solves or improves at least one of the following problems or achieves at least one of the following technical effects by configuring the needle-free delivery device of the present invention, its components, and the related drug-device combination device, and by controlling the flow rate, delivery depth, and diffusion of the drug and vaccine jet:

[0229] (1) The needle-free delivery device of the embodiment of the present invention uses multiple holes for needle-free delivery. Compared with the traditional single-hole needle-free injection, the present invention uses a multi-hole setting to achieve a significant increase in the delivery amount of the delivery object without causing damage to the skin, especially increasing the single delivery amount of drugs and vaccines. It has a delivery efficiency far higher than the existing single-hole needle-free delivery and can meet a wider range of application scenarios.

[0230] (2) The needle-free delivery device of the embodiment of the present invention uses multiple holes for needle-free delivery. By optimizing the number and pore size of the multiple holes, the diffusion volume of the delivered substances, especially drugs and vaccines, in the body is significantly increased, thereby increasing the contact effect between the delivered drugs and vaccines and the tissues in the body, and significantly improving the bioavailability of drugs and vaccines.

[0231] (3) The needle-free delivery device of the embodiment of the present invention achieves precise control of the delivery depth of the delivered drug or vaccine by controlling the jet velocity of the delivery material ejected from the multiple holes, especially the jet velocity of the drug and vaccine jet, and achieves precise delivery of the drug or vaccine to the designated target location within the skin, subcutaneous tissue, muscle or human organ through high-speed jet according to the characteristics of the drug or vaccine.

[0232] (4) The needle-free delivery device of the embodiment of the present invention achieves the simultaneous and precise delivery of the delivery substance to at least one or more target locations or target areas within the skin, subcutaneous tissue, muscle or human organs by configuring the jet speed of different holes in the multiple holes.

[0233] (5) The needle-free delivery device of the embodiment of the present invention achieves different diffusion effects of the delivered substance, especially drugs or vaccines, at the delivery location by controlling the aperture and arrangement of the multiple holes. In particular, it achieves control of the diffusion volume ratio, diffusion width and diffusion center at the target location or target area, and can achieve specific diffusion effects according to different delivery requirements.

[0234] (6) The needle-free delivery device of the embodiment of the present invention is not limited to the site and receptor type of drug and vaccine delivery, and can be widely used for drug and vaccine delivery for human and veterinary use.

[0235] In addition to solving the above-mentioned problems and / or achieving the above-mentioned effects, the present invention is also used in combination with a cat triple vaccine, a hepatitis B vaccine, a human pneumonia vaccine, a GLP-1 peptide, especially semaglutide, to achieve further technical effects as described in the embodiments of the present invention.

[0236] Example 1

[0237] Reference is now made to Figures 32 and 33, which illustrate one structural configuration of a needle-free delivery device according to an embodiment of the present invention. Specifically, the second end 120 has a narrowed section 122 that gradually narrows from the axial direction of the tube 100 toward the distal end. Three holes 121 are provided on the end surface 123 of the narrowed section 122. The end surface 123 is configured as a circle with a diameter of 2.5 mm. The three holes 121 are arranged in an annular pattern at equal intervals around the center of the end surface 123. Adjacent lines connecting the three holes and the center of the end surface 123 form an angle of 120°. The three holes 121 have a uniform diameter of d and a uniform distance from the center of the end surface 123 of l.

[0238] Referring now to FIG. 34 , under the structure of the needle-free delivery device described above, an embodiment of the present invention utilizes the ANSYS workbench Fluent module shown in FIG. 34 to construct a needle-free injection diffusion penetration simulation model. A multiphase flow model is employed to simulate the diffusion of the fluid 130 contained in the tube 100 when the power mechanism 200 applies a delivery pressure of 400 N to the fluid 130. The volume of the fluid 130 to be delivered is 0.2 cm 3 , and the viscosity is 1 cp. The needle-free injection diffusion penetration simulation model utilizes a transient calculation method, an Eulerian model for the multiphase flow model, a K-epsilon Realizable model for the viscosity model, and a porous medium model for the in vivo model 140. Hybrid initialization is employed as the initialization method.

[0239] Under the above structure and simulation parameters, the diameters d of the three holes 121 and the distances l between the three holes 121 and the center of the end surface 123 are further configured to obtain the following porous needle-free delivery fluid diffusion data under different configurations:

[0240] Table 1. Fluid diffusion data for porous needle-free delivery

[0241] Table 1 above and Figures 35 to 37 illustrate the diffusion effect achieved by a needle-free delivery device according to one embodiment of the present invention using multiple holes 121. The present invention achieves different diffusion degrees of fluid 130 within the body 140, such that the fluid jets of fluid 130 passing through the multiple holes 121 achieve different diffusion volume ratios, diffusion depths, and diffusion widths within the body 10. Figure 35 shows the diffusion effect at d = 0.15 mm and l = 0.65 mm, Figure 36 shows the diffusion effect at d = 0.575 mm and l = 0.65 mm, and Figure 37 shows the diffusion effect at d = 1.00 mm and l = 0.65 mm.

[0242] At the same time, as shown in Figures 35 to 37, when the needle-free delivery device of an embodiment of the present invention delivers a fluid into the body, due to the different diffusion volume ratios, diffusion depths, and diffusion widths of the fluid in the body, the fluid will also have different diffusion centers and diffusion edge densities in the body.

[0243] Compared with the needle-free delivery of the control group, the porous needle-free delivery device of the embodiment of the present invention makes the diffusion volume of the delivery fluid 130 in the simulated body 140 2.09 to 2.77 times that before delivery, achieving a better diffusion effect for the delivery fluid. In other words, it achieves more sufficient contact between the delivery fluid and the target site in the body.

[0244] Example 2

[0245] Reference is now made to Figures 32 and 33 , which illustrate one structural configuration of a needle-free delivery device according to an embodiment of the present invention. Specifically, the second end 120 has a narrowed section 122 that gradually narrows from the axial direction of the tube 100 toward the distal end. The end surface 123 of the narrowed section 122 is configured as a circle with a diameter of 5 mm and is provided with a central hole 121″ located at the center (center) of the end surface 123 and three peripheral holes 121 located around the central hole 121″. The three peripheral holes 121 are arranged in an annular manner with equal intervals around the center (center) of the end surface 123. The three peripheral holes 121 form an angle of 120° between adjacent lines connecting the three peripheral holes 121 and the center (center) of the end surface 123. The diameter of the central hole 121″ is d″, and the diameter of the three peripheral holes 121 is uniformly set to d, with d″≠d. The distance between the three peripheral holes 121 and the center (center) of the end surface 123 is uniformly set to 1.1 mm.

[0246] Referring now to FIG34 , under the structure of the needle-free delivery device described above, an embodiment of the present invention utilizes the ANSYS workbench Fluent module shown in FIG34 to construct a needle-free injection diffusion penetration simulation model. A multiphase flow model is employed to simulate the diffusion of the fluid 130 contained in the tube 100 when the power mechanism 200 applies a delivery pressure of 400 N to the fluid 130. The viscosity of the fluid 130 to be delivered is 1 cp. The needle-free injection diffusion penetration simulation model utilizes a transient calculation method, an Eulerian model for the multiphase flow model, a K-epsilon Realizable model for the viscosity model, and a porous medium model for the in vivo model 140. Hybrid initialization is employed as the initialization method.

[0247] Under the above structure and simulation parameters, the diameter d' of the central hole 121' and the diameter d' of the three peripheral holes 121 are further configured, and the volume of the delivered fluid is 0.1 cm 3 , 0.2cm 3 and 0.3cm 3 , three sets of simulated experimental fluids were conducted to obtain the following porous needle-free delivery fluid diffusivity data:

[0248] Table 2. Group 1 - Porous Needle-Free Delivery Fluid Diffusion Data

[0249] Note: The volume of fluid to be delivered in this group is 0.1 cm 3 .

[0250] Table 3. Group 2 - Porous Needle-Free Delivery Fluid Diffusion Data

[0251] Note: The volume of fluid to be delivered in this group is 0.2 cm 3 .

[0252] Table 4. Group 3 - Porous Needle-Free Delivery Fluid Diffusion Data

[0253] Note: The volume of fluid to be delivered in this group is 0.3 cm 3 .

[0254] Tables 2 to 4 above and Figures 38 and 39 illustrate the diffusion effect achieved by a needle-free delivery device according to one embodiment of the present invention utilizing multiple holes 121. The provision of a central hole 121" and three peripheral holes 121 enables the fluid jet of the fluid 130 passing through the multiple holes to achieve a significantly enhanced diffusion effect compared to single-hole needle-free delivery. Specifically, the needle-free delivery device according to the embodiment of the present invention enables the diffusion volume of the delivered fluid 130 in the simulated body 140 to be 2.35 to 3.61 times greater than that before delivery. Furthermore, as can be seen from Table 2 and Figure 39, at a diffusion width of 0.1 cm, the needle-free delivery device according to the present invention achieves a significantly superior diffusion width compared to a single hole, achieving a significantly enhanced diffusion effect for the delivered fluid. In other words, more complete contact between the delivered fluid and the target site in the body is achieved.

[0255] Example 3

[0256] Reference is now made to Figures 32 and 33 , which illustrate one structural configuration of a needle-free delivery device according to an embodiment of the present invention. Specifically, the second end 120 has a narrowed section 122 that narrows axially from the tube 100 toward the distal end. The end surface 123 of the narrowed section 122 is configured as a circle with a diameter of 2.5 mm and is provided with three holes 121. The three holes 121 are arranged in an annular shape at equal intervals around the center of the end surface 123. Adjacent lines connecting the three holes and the center (center) of the end surface 123 form an angle of 120°. The diameter of the three holes 121 is uniformly set to 0.15 mm, and the distance from the center of the end surface 123 is uniformly set to 1.1 mm.

[0257] Under the structure of the needle-free delivery device, a specific embodiment of the present invention adopts a viscosity of 1 cp and a volume of 0.2 cm 3 The delivery fluid was tested to obtain the displacement change curve of the piston 210 of the needle-free delivery device of the present invention, and the movement speed of the piston 210 and the outlet jet speed of the jets ejected from the multiple holes 121 were obtained accordingly as follows:

[0258] Table 5. Piston speed and jet speed data

[0259] As can be seen from the table above, the needle-free delivery device of the present invention is configured in one embodiment such that the average velocity of the jets ejected from the plurality of holes 121 is greater than 135 m / s, and can reach a maximum of 156 m / s.

[0260] Example 4

[0261] In a specific embodiment of the present invention, the needle-free delivery device of the present invention is used in combination with a feline triple vaccine. Referring to Figures 32 and 33, one structural configuration of the needle-free delivery device of the embodiment of the present invention used in combination with a feline triple vaccine is shown. Specifically, the second end 120 has a narrowed section 122 that narrows axially from the tube 100 toward the distal end, wherein the diameter of the tube is 5 mm, and the end surface 123 of the narrowed section 122 is constructed as a circle with a diameter of 2.5 mm and is provided with three holes 121 thereon. The three holes 121 are arranged in an annular manner with equal intervals around the center of the end surface 123, and adjacent lines connecting the three holes and the center of the end surface 123 form an angle of 120°, wherein the pore diameters of the three holes 121 are measured to be 0.14 mm to 0.17 mm, and the distance between the three holes 121 and the center of the end surface 123 is uniformly set to 1.25 mm.

[0262] In an embodiment of the present invention, the feline triple vaccine is a triple inactivated vaccine for preventing feline rhinotracheitis, calicivirus disease, and panleukopenia. Each dose of the feline triple vaccine contains inactivated feline rhinotracheitis virus 605 strain, feline calicivirus 255 strain, and panleukopenia virus Cu-4 strain, and the RP value of each component should not be less than 1.0 to ensure the immunogenicity and efficacy of the feline triple vaccine. The feline triple vaccine is only used to vaccinate healthy cats aged 8 weeks or above, and can be injected subcutaneously, 1 ml per head per time; for healthy cats aged 8 weeks or above, booster immunization should be performed 3 to 4 weeks after the first vaccination, with 1 dose vaccinated; for cats vaccinated under 12 weeks of age, 1 dose should be boosted at 12 to 16 weeks of age to ensure lasting immune protection. The feline triple vaccine should be repeated with 1 dose per year to maintain immunity.

[0263] The following is a specific immune evaluation test of the needle-free delivery device of the present invention. In this test, a needle-free immune evaluation test of a cat vaccine was conducted according to the following test protocol under the structural configuration of the needle-free delivery device of the present invention:

[0264] 1. Test materials

[0265] 1.1. Experimental Animals: 27 healthy cats were used as experimental animals, all of which were negative for FPV, FHV, and FCV antigens, with two-thirds of the three neutralizing antibody titers being no higher than 1:4 and no history of feline triple vaccine immunization.

[0266] 1.2. Delivery vaccine: Feline rhinotracheitis, calicivirus disease, and panleukopenia triple inactivated vaccine produced by Zoetis (trade name: Feline Triple, batch number: E071201A).

[0267] 1.3. Neutralizing antigen for detection: FPV virus solution, FCV virus solution and FHV virus solution with a virus content of 200TCID50 / 0.1ml were selected.

[0268] 1.4. Cells used for detection: CRFK cells or F81 cells were used.

[0269] 1.5. Test equipment: needle-free delivery device according to the above embodiment of the present invention (delivery pressure: 330N, aperture: 0.14mm-0.17mm); traditional needle-equipped 1ml and 10ml syringes, medical cotton swabs, and alcohol cotton pads.

[0270] 1.6. Experimental location: Animal hospital.

[0271] 2. Test methods

[0272] 2.1. Animal Screening: From each of the 37 healthy cats, a nasal swab (superficial collection is permitted), an oral swab, and anal swab were collected and placed in a centrifuge tube containing 1 ml of PBS. Antigen testing was performed according to the methods in Notes 1 to 3. 2 to 3 ml of blood was collected from each healthy cat, and the serum was separated for neutralizing antibody testing.

[0273] 2.2 Animal Grouping: The healthy cats selected were allowed to acclimate to the environment for 7 days after entering the experimental site, and were gradually transitioned to cat food. They were then divided into 3 groups based on their sex, age, breed, or antibody data, with 7 cats in each group. These groups were numbered and recorded as experimental groups 1, 2, and 3. Six healthy cats that were not immunized with the feline triple vaccine were set up as sentinel animals and recorded as experimental group 4.

[0274] 2.3. Pre-immunization Preparation: 2-3 days prior to immunization, the injection sound was played in a loop for 10-15 minutes daily at the testing site. Cats were allowed to voluntarily contact and sniff the needle-free delivery device and electric shaver of the present invention. One day or two hours prior to immunization, the injection site of the test cats was shaved, approximately 1 cm in diameter. One to two people were assigned to perform the immunization.

[0275] 2.4 Immunity

[0276] The aforementioned groups 1, 2, and 3 were immunized, wherein:

[0277] Group 1: Immunization was performed using a conventional needle injection with a disposable 1 ml syringe with a needle hole diameter of 0.45 mm; the dose for each immunization was 1 ml.

[0278] Group 2: Immunization was performed using a three-hole needle-free injection, a needle-free syringe, a single-hole injection needle, and multi-hole injection. The needle hole diameter was 0.14mm to 0.17mm; the dose for each immunization was 1ml.

[0279] Group 3: Immunization was performed using needle-free multi-hole injection, using a needle-free syringe, a single-hole injection needle, and multi-hole injection, with a needle hole diameter of 0.14mm to 0.17mm; the dose for each immunization was 0.45ml.

[0280] 6. Immunization Information Form

[0281] Note: “ / ” means no operation.

[0282] 2.5. Sample Collection: On the day of the first vaccination and 21 and 35 days after the first vaccination, venous blood was collected from each cat according to Table 5 above. The serum was separated and stored at -20°C for testing. (If the immune response is particularly strong, whole blood may be collected 1-2 weeks after the 35th day.)

[0283] Table 7. Sample collection schedule

[0284] 3. Results after immunization

[0285] 3.1. Observation on the day of immunization:

[0286] Conventional injection immunization group (Group 1): The experimental cats were listless and listless;

[0287] In the needle-free immunization groups (Groups 2 and 3), the experimental cats were lively and energetic.

[0288] 3.2 Neutralizing Antibody Titer Determination Results

[0289] Neutralizing antibody titer determination was performed to obtain the following Tables 7 and 8, which show the antibody titer determination data of each group under the above experimental conditions:

[0290] Table 8. Antibody titer determination data table-1

[0291] Table 9. Antibody titer determination data table-2

[0292] As can be seen from Tables 7 and 8 and Figures 41 to 43, the needle-free delivery device comprising a plurality of holes 121 used in the embodiments of the present invention for delivering the feline triple vaccine achieves the following results compared to conventional needle-assisted delivery:

[0293] a. The needle-free three-hole immunization group using the needle-free delivery device of the present invention was compared to the same-dose immunization group with a needle. The needle-free three-hole antibody onset time using the needle-free delivery device of the present invention was 1 times faster than that of the needle group;

[0294] b. Found that under the same immune dose, the use of the needle-free delivery device of the present invention, three-hole needle-free immunization, produced antibodies 25 times higher than the conventional needle immunization group;

[0295] c. The antibody value produced by the needle-free three-hole half-dose group using the needle-free delivery device of the present invention was 2.4 times higher than that of the conventional needle immunization group.

[0296] Example 5

[0297] In a specific embodiment of the present invention, the needle-free delivery device of the present invention is used in combination with a hepatitis B vaccine. Referring to Figures 32 to 33, one structural configuration of the needle-free delivery device of the embodiment of the present invention used in combination with a hepatitis B vaccine is shown. Specifically, the second end 120 has a narrowed section 122 that narrows axially from the tube 100 toward the distal end, wherein the diameter of the tube is 5 mm, and the end surface 123 of the narrowed section 122 is constructed as a circle with a diameter of 2.5 mm and is provided with three holes 121 thereon. The three holes 121 are arranged in an annular manner with equal intervals around the center of the end surface 123, and adjacent lines connecting the three holes and the center of the end surface 123 form an angle of 120°, wherein the measured pore diameters of the three holes 121 are 0.14 mm to 0.17 mm, and the distance between the three holes 121 and the center of the end surface 123 is uniformly set to 1.25 mm.

[0298] In the embodiments of the present invention, the hepatitis B vaccine refers to a recombinant yeast vaccine (Hansenula) for preventing hepatitis B (a viral liver disease). It is prepared by purifying the hepatitis B virus surface antigen (HBsAg) expressed by recombinant Hansenula and adding an aluminum adjuvant. The active ingredient is the hepatitis B virus surface antigen. The vaccine is suitable for people susceptible to hepatitis B, especially the following people: (1) newborns, especially those whose mothers are HBsAg or HBeAg positive, (2) people susceptible to hepatitis B aged 16 years and above, and (3) medical staff engaged in medical work and laboratory personnel who come into contact with blood. After vaccination, the immune system can be stimulated to produce protective antibodies, thereby giving the human body immunity to prevent hepatitis B, thereby achieving the purpose of preventing hepatitis B infection. The conventional immunization site is the deltoid muscle of the upper arm. The immunization program is 3 injections, one at birth (0 months), one at 1-2 months of age, and one at 6-18 months of age. Newborns are given the first injection within 24 hours after birth, and each injection is one dose.

[0299] The following is a specific immunological evaluation test of the needle-free delivery device of the present invention. Under the structural configuration of the needle-free delivery device of the present invention, a needle-free injection immunological evaluation test of hepatitis B vaccine was conducted according to the following experimental protocol:

[0300] 1. Preparation before the test

[0301] 1.1. Experimental Materials: 64 male mice (BALB / c strain), weighing 17-19 g and aged 3 to 4 weeks, were selected and blood was collected after one week of acclimatization.

[0302] 1.2. Test equipment: The needle-free delivery device according to the above embodiment of the present invention traditionally has a needle, a medical cotton swab and an alcohol cotton pad.

[0303] 2. Test methods

[0304] 2.1. Animal grouping: The 64 mice were divided into 8 groups of 8 mice each, including 6 experimental groups and 2 control groups.

[0305] Table 10. Control trial group table

[0306] 2.2 Blood collection plan:

[0307] Mice were immunized according to the D0 / D21 immunization schedule, and blood was collected and serum was separated on D0 / D28 / D35 / D42 after immunization.

[0308] At the beginning of the experiment: On the morning of the experiment, shave the hair on the back and legs of the mice with an electric razor and depilatory cream. Before inoculation, blood was collected from all mice using the retroorbital bleeding method, with a blood volume of 0.2 ml per mouse.

[0309] After one vaccination: the second vaccination was performed on the 21st day; the second blood collection was performed on the 28th day, with peripheral blood collected from a group of 10 mice and spleen collected from six mice; the third blood collection was performed on all mice on the 35th day; the fourth blood collection was performed on the 42nd day, with peripheral blood collected from a group of 10 mice and spleen collected from six mice.

[0310] 2.3 Neutralization experiment

[0311] Neutralization endpoint was calculated using the Karber method (serum dilution converted to logarithms). The highest serum dilution that protected 50% of cells from infection with 100 CCID50 of the challenge virus was considered the serum antibody titer. A neutralizing antibody titer of <1:4 was considered negative, and ≥1:4 was considered positive.

[0312] Operating procedures (fixed virus dilution serum method):

[0313] (1) Inactivation of serum: Inactivate the serum to be tested at 56°C for 30 minutes

[0314] (2) Dilute serum: Take inactivated serum and dilute it with serum-free cell culture medium on a 96-well microplate. Make a series of serial dilutions starting from 1:4, tentatively (1:4, 1:28, 1:56, 1:128, 1:256...). The content of each well is 50 μL, and 2 to 4 wells are used for each dilution.

[0315] (3) Neutralization: Add 50 μL of diluted 200 TCID50 virus solution to each well and place in a CO2 incubator at 37°C for 2 h.

[0316] (4) Add cell suspension: After 2 hours of serum and virus neutralization, remove the cell plate and add 0.1 mL / well cell suspension to each well (it is best to allow the monolayer to grow for 24 hours, generally 1 million to 1.5 million cells per mL), place in a CO2 incubator for culture, and make a judgment after 72 hours.

[0317] 2.4 Control Experiment

[0318] (1) Negative and positive serum controls: 2 to 4 wells are set up for each. The titer of the negative and positive control antibodies should be established.

[0319] (2) Virus regression test: Dilute the 200 TCID50 virus solution into 0.1, 1, 10, and 100 TCID50 dilutions, and add 50 μL of each dilution to 2 to 4 wells. Add 50 μL of cell suspension. 0.1 TCID50 results in no pathological changes, while 100 TCID50 results in complete pathological changes. Otherwise, the experiment is invalid.

[0320] (3) Cell control: Set up 2 to 4 wells of normal cell control without virus and serum. The control cells should maintain good morphology and characteristics.

[0321] 2.5. Result determination and calculation

[0322] Only when the virus regression test, positive, negative, and cell controls are all established can the test be judged. 100% CPE in the serum wells tested is considered negative, and more than 50% of the cells are protected as positive. The results are calculated using the Karber method.

[0323] 3. Cell level detection

[0324] The spleens of mice were collected to determine the contents of various T and B cells in mice.

[0325] 3.1. Detection of T lymphocyte surface molecular markers:

[0326] Flow cytometry was used to detect T lymphocyte surface markers. Refrigerated mouse spleen cells were thawed in a water bath at 37°C to prepare a single-cell suspension (1 × 107 cells / ml). 0.1 ml was transferred to a falcon tube and CD3-FITC Ab, CD4-PE Ab, and CD8-PE Ab were added. The tubes were placed in a dark place at room temperature for 30 minutes, washed twice with PBS, and mixed with 0.5 ml of PBS. The positive expression rates of CD3-FITC, CD4-PE, and CD8-PE on T lymphocytes were analyzed using CELLQuest software, and the CD4 / CD8 ratio was calculated.

[0327] 3.2 Enzyme-linked immunosorbent assay:

[0328] After blood collection, the supernatant was collected from the ELISPOT plate and stored at -80°C for 24 hours prior to enzyme-linked immunosorbent assay (ELISA). Protein expression levels were measured at 450 nm using a Biotek enzyme-linked immunosorbent assay (ELISA). The absorbance of each cytokine or chemokine was divided by the absorbance of the pre-vaccination sample as a baseline control to calculate the fold change in cytokine and chemokine expression. Cellular immune responses were assessed by ELISPOT analysis of T cells producing hepatitis B surface antigen-specific IFN-γ, IL-2, and IL-4.

[0329] 3.2.1. Kit Contents:

[0330] PVDF 96-well plate, stored at room temperature; 0.1 ml capture antibody, stored at 4°C; 0.1 ml biotin-labeled detection antibody, stored at 4°C; 15 ul avidin alkaline phosphatase label, stored at 4°C; 0.25 g bovine serum albumin, stored at 4°C; 0.25 g skim milk, stored at 4°C; 11 ml substrate buffer, stored at 4°C; 11 ml concentrated PBS (10X), stored at room temperature; 11 ml concentrated wash buffer (200x), stored at room temperature.

[0331] 3.2.2 Preparation of reagents:

[0332] (1) Dilute 10 ml of phosphate buffered saline (PBS, 10X) with 90 ml of distilled water;

[0333] (2) Dissolve 0.22 g skim milk in 11 ml diluted PBS to a final concentration of 2%;

[0334] (3) 0.22g BSA was dissolved in 22ml diluted PBS to a final concentration of 1%

[0335] (4) Dilute 10 ml of concentrated washing solution (200x) with 1990 ml of distilled water;

[0336] (5) Dilute 10ul of avidin alkaline phosphatase with 10ml of PBS-1%, BSA

[0337] (6) Dilute 7 ml of alcohol with 3 ml of distilled water to a final concentration of 70%.

[0338] 3.2.3. Stimulation method:

[0339] Indirect method: Cells are first stimulated in a 24-well plate or flask and then placed into the coated wells.

[0340] Dilute PBMCs in culture medium (e.g., RPMI 1640 with 2 mM glutamate and 10% heat-inactivated calf serum) containing 1 ng / ml PMA and 500 ng / ml chloramphenicol (Sigma, Saint Louis, MO). Add 2.104 to 5.104 cells to the antibody-coated PVDF wells and incubate in an incubator for 10-15 hours. Incubation times may vary with other stimulants and should be optimized based on the abundance of cytokine-producing cells.

[0341] 3.2.4 Eli-spot operation process:

[0342] (1) Incubate the PVDF plate with 100ul of 70% alcohol at room temperature for 10 minutes.

[0343] (2) Pour off the alcohol and wash three times with 100ul PBS.

[0344] (3) Add 100ul of capture antibody to 10ml of PBS, mix, add 100ul to each well, cover the plate, and incubate at 4°C overnight.

[0345] (4) Pour off the liquid and wash once with 100ul PBS.

[0346] (5) Add 100ul of 2% skim milk PBS (see reagent preparation) to each well, cover the plate, and incubate at room temperature for 2 hours.

[0347] (6) Tap gently over the sink and onto absorbent paper to remove the liquid.

[0348] (7) Wash three times with 100ul PBS, three minutes each time.

[0349] (8) Add 100 μl of cell suspension (containing an appropriate amount of cells and the corresponding concentration of stimulant) to each well. The cells can be stimulated in vitro (indirect Eli-spot). Cover the well with a standard 96-well plastic plate cover and incubate in a 37°C CO2 incubator for a specified period of time (15-20 hours). Do not shake or move the well plate during this period.

[0350] (9) Tap gently over the sink and onto absorbent paper to remove the liquid.

[0351] (10) Add 100 μl of washing buffer to each well and incubate at 4°C for 10 minutes.

[0352] (11) Use pre-chilled ice water to break the cells.

[0353] (12) Wash the wells eight times with 100ul of PBST buffer for four minutes each time.

[0354] (13) Dilute 100 μl of detection antibody in 10 ml of PBS-1% BSA. This is the amount for one plate. Add 100 μl of this solution to each well, cover the plate, and incubate at 37°C for 2 hours.

[0355] (14) Pour off the liquid and wash five times with 100ul washing buffer.

[0356] (15) Dilute 10 μl of avidin alkaline phosphatase in 10 ml of PBS 1% BSA per plate. Add 100 μl of this solution to each well, cover the plate, and incubate at 37°C for 1 hour.

[0357] 4. Statistical analysis

[0358] Statistical analysis: One-way analysis of variance and t-test (GraphPad Prism 8.0) were used to analyze the statistically significant differences between the groups. Data are expressed as mean ± standard deviation (SD). A p value < 0.05 was considered statistically significant.

[0359] 5. Final Result

[0360] The needle-free delivery device of the present invention is configured so that the average antibody titer of the hepatitis B vaccine 14 days after the second dose is more than 1.1 times the average antibody titer of the needle injection;

[0361] The needle-free delivery device of the present invention is configured so that the average antibody titer of the hepatitis B vaccine 42 days after the second dose is more than 1.5 times the average antibody titer of the needle injection;

[0362] The needle-free delivery device of the present invention is configured so that the T lymphocyte positive expression rate of the hepatitis B vaccine 42 days after the second dose is administered is more than 10% higher than that of needle injection.

[0363] Example 6

[0364] In a specific embodiment of the present invention, the needle-free delivery device of the present invention is used in combination with a GLP-1 polypeptide, specifically, semaglutide. Referring to Figures 32 to 33, one structural configuration of the needle-free delivery device of the embodiment of the present invention used in combination with semaglutide is shown. Specifically, the second end 120 has a narrowed section 122 that narrows axially from the tube 100 toward the distal end. The diameter of the tube is 5 mm. The end face 123 of the narrowed section 122 is constructed as a circle with a diameter of 2.5 mm and is provided with three holes 121 thereon. The three holes 121 are arranged in an annular manner at equal intervals around the center of the end face 123. The adjacent lines connecting the three holes and the center of the end face 123 form an angle of 120°. The measured pore diameters of the three holes 121 are 0.14 mm to 0.17 mm, and the distance between the three holes 121 and the center of the end face 123 is uniformly set to 1.25 mm.

[0365] In the embodiment of the present invention, the semaglutide (Simeigelutai), also known as semaglutide, is a second-generation glucagon-like peptide-1 (GLP-1) analogue, and its molecular formula is C 187 H 291 N 45 O 59 It (molecular weight of 4113.58Da) has excellent blood sugar lowering and weight loss effects in diabetic patients, significantly better than sitagliptin, insulin glargine U100 or extended-release exenatide; it is also better than its fellow drug liraglutide in weight loss, especially in patients with BMI ≥ 30. Semaglutide can be taken orally or subcutaneously, for example, as a 7mg / 14mg oral dosage form once daily or a 0.5mg / 1.0mg subcutaneous injection once weekly. Semaglutide not only shows good efficacy in the treatment of diabetes, but also shows significant advantages in weight loss and cardiovascular protection.

[0366] The following is a specific semaglutide rat test using the needle-free delivery device of the present invention. Under the structural configuration of the needle-free delivery device of the present invention, the semaglutide rat test was conducted using semaglutide with the following structure according to the following experimental protocol:

[0367] 1. Test materials

[0368] 1.1. Experimental animals: Healthy male Wistar rats, aged 6-8 weeks, weighing 200-250 g, were selected.

[0369] 1.2. Experimental Grouping: The rats were randomly divided into four groups, with 10 rats in each group.

[0370] 1.3. Delivery agent: semaglutide;

[0371] 1.4. Test equipment: needle-free delivery device according to the above embodiment of the present invention (delivery pressure: 250N, aperture: 0.14mm-0.17mm); traditional syringe with needle, medical cotton swab and alcohol cotton.

[0372] 2. Test operation

[0373] 2.1. Drug Administration

[0374] In the needle-free delivery group, drugs were administered using a needle-free delivery device according to the set parameters, and in the needle delivery group, drugs were administered using traditional injections, where:

[0375] Group 1: 1x dose with injection, daily for 14 days;

[0376] Group 2: No needle, 1x dose, daily for 14 days;

[0377] Group 3: 10x dose with injection, weekly*2 weeks;

[0378] Group 4: needle-free 10x dose, weekly*2 weeks;

[0379] 2.2 Data Collection

[0380] The body weight changes, blood glucose and insulin levels of the rats were recorded daily.

[0381] 3. Result evaluation

[0382] a. Comparison between Group 1 and Group 2: Under the same dosing conditions (1x) and frequency (daily), Group 2 (needle-free delivery) achieved a 4% greater overall weight loss than Group 1 (needle-delivered delivery). Furthermore, Group 2 demonstrated a longer-lasting effect, with a delayed rebound effect compared to Group 1.

[0383] b. Comparison between Group 3 and Group 4: Under the conditions of higher dose (10x) and lower frequency (weekly), the total weight loss rate of Group 4 (no needle delivery) was 5.5% greater than that of Group 3 (with needle delivery).

[0384] Example 7

[0385] In a specific embodiment of the present invention, the needle-free delivery device of the present invention is used in combination with a polypeptide tumor vaccine. Referring to Figures 32 and 33, one structural configuration of the needle-free delivery device of the present invention in combination with a polypeptide tumor vaccine is shown. Specifically, the second end 120 has a narrowed section 122 that narrows axially from the tube 100 toward the distal end, wherein the diameter of the tube is 5 mm, and the end surface 123 of the narrowed section 122 is constructed as a circle with a diameter of 2.5 mm and is provided with three holes 121 thereon. The three holes 121 are arranged in an annular manner at equal intervals around the center of the end surface 123, and adjacent lines connecting the three holes and the center of the end surface 123 form an angle of 120°, wherein the measured pore diameters of the three holes 121 are 0.14 mm to 0.17 mm, and the distance between the three holes 121 and the center of the end surface 123 is uniformly set to 1.25 mm.

[0386] In the embodiments of the present invention, the polypeptide tumor vaccine is a new type of vaccine, which is essentially an immunogen that induces an effector cell immune response in the body. The tumor polypeptide vaccine is an antigen polypeptide eluted from the surface of tumor cells or a related polypeptide obtained from tumor cells that can enhance the body's anti-tumor humoral immunity and cellular immunity after immunization. Currently, the most widely studied tumor polypeptide vaccines include vaccines targeting folate receptors (FR) or HER2 targets.

[0387] The following is a specific polypeptide tumor vaccine rat immunization test using the needle-free delivery device of the present invention. The polypeptide tumor vaccine rat immunization test was conducted using the needle-free delivery device of the present invention according to the following experimental protocol:

[0388] 1. Test materials

[0389] 1.1. Experimental Animals

[0390] Sixty healthy male C57BL / 6 mice, aged 6-8 weeks and weighing 18-22 grams, were selected and divided into six experimental groups (G1, G2, G3, G4, G5, and G6) using a random number table method (10 mice in each group).

[0391] 1.2 Test equipment:

[0392] Neoantigens and positive control polypeptides, as well as a needle-free delivery device according to an embodiment of the present invention, wherein the pore diameter is 0.14-0.17 mm and the delivery pressure is 160N.

[0393] 2. Immunity test

[0394] 2.1 Experimental arrangement:

[0395] Three or four rounds of immune tests were performed in groups according to Table 6 below:

[0396] Table 11. Information of the peptide tumor vaccine rat immunization test

[0397] 3. Effect detection

[0398] 3.1. Detection method: After immunization, spleen cells from mice were taken for 4 rounds of ELISPOT detection.

[0399] 3.2 Test results:

[0400] a. After three / four rounds of immunization, positive signals of the new antigen group can be detected by Elispot assay, but the signals are weak.

[0401] b. There was no statistical difference in the number of parity spots between the needle-free injection group and the needle-injection group.

[0402] c. After the fourth round of immunization, the number of spots in each experimental group was lower than in the third round. Regarding the reduction ratio, the needle-free neoantigen group had 10% fewer spots than the needle-treated neoantigen group and 20% fewer spots than the positive peptide group. This indicates that the effectiveness of the needle-free plus neoantigen peptide vaccine lasts longer than the other two groups.

[0403] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A needleless delivery device, characterized in that, Comprising: A tube for containing a fluid, the tube having a first end and a second end, and a plurality of holes for dispensing the fluid in the second end; And A power mechanism, the power mechanism including a piston disposed in the first end of the tube that can push the fluid or the power mechanism is operatively connected to the piston to apply a delivery pressure to the piston that pushes the fluid.

2. The needleless delivery device according to claim 1, wherein Optionally, the power mechanism is driven by compressed gas, spring drive, electromagnetic drive, or any combination of the above drive methods; Optionally, the pushing speed of the piston of the needleless delivery device is 0.05 to 0.50 m / s, preferably 0.09 to 0.25 m / s, and more preferably 0.14 to 0.20 m / s; Optionally, the needleless delivery device is configured such that the outlet jet velocity when the fluid is pushed away from the holes in the second end by the pushing element is greater than or equal to 10 m / s, preferably greater than or equal to 50 m / s, further preferably greater than or equal to 100 m / s, and more preferably greater than or equal to 150 m / s.

3. The needleless delivery device according to claim 1, characterized in that, The needleless delivery device is configured such that the fluid jets through the plurality of holes have different in vivo dispersions; Preferably, the aperture diameters of the plurality of holes of the needleless delivery device are configured such that the fluid jets through the plurality of holes have different in vivo dispersions; Preferably, the fluid jet velocities through the plurality of holes of the needleless delivery device are configured such that the fluid jets through the plurality of holes have different in vivo dispersions.

4. The needleless delivery device according to claim 1, characterized in that, The total fluid delivery area of the plurality of holes is 0.009 mm 2 or more, preferably 0.020 mm 2 or more, more preferably 0.053 mm 2 or more, more preferably 0.28 mm 2 or more; the area of a single hole is 0.0028 to 0.035 mm 2 , preferably 0.0028 to 0.020 mm 2 , more preferably 0.0028 to 0.009 mm 2 .

5. The needleless delivery device according to claim 1, wherein The needleless delivery device is configured such that the dispersion volume of the fluid in vivo is greater than the undelivered fluid volume or the volume of fluid delivered by a needle. Preferably, the dispersion volume of the fluid in vivo is more than 1.50 times the undelivered volume, preferably more than 1.80 times, further preferably more than 2.40 times, More preferably more than 3.00 times, and even more preferably more than 3.60 times.

6. The needleless delivery device according to claim 1, wherein, The plurality of holes include a first hole; Preferably, the first hole has a first aperture diameter, and the size of the first aperture diameter is configured such that the fluid jet through the first hole disperses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; Preferably, the first hole has a first outlet jet velocity, and the first outlet jet velocity is configured such that the fluid jet through the first hole disperses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs.

7. The needleless delivery device according to claim 1, wherein The plurality of holes include a first hole and a second hole; Preferably, the first hole has a first aperture diameter, and the size of the first aperture diameter is configured such that the fluid jet through the first hole disperses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; the second hole has a second aperture diameter, and the size of the second hole is configured such that the fluid jet through the second hole disperses in at least the same or another one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; Preferably, the first hole has a first outlet jet velocity configured such that a fluid jet through the first hole diffuses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; the second hole has a second outlet jet velocity configured such that a fluid jet through the second hole diffuses in at least the same or another one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs.

8. The needle-free delivery device according to claim 1, wherein, The plurality of holes are arranged in a straight line; Preferably, the plurality of holes are arranged in a straight line along the diameter or median line of the second end. Preferably, one of the plurality of holes arranged in a straight line along the diameter or median line of the second end is located at the center or the center of the second end; Preferably, the plurality of holes arranged in a straight line are equally spaced; Preferably, the plurality of holes arranged in a straight line are mirror-symmetrical with respect to the diameter or median line of the second end; Preferably, there are multiple groups of the holes, and each group of holes is arranged in a straight line. Preferably, each group of holes is arranged along a diameter or a median line of the second end; The plurality of holes are arranged in an array. Preferably, the plurality of holes arranged in an array are mirror-symmetrical with respect to the first and second diameters or median lines perpendicular to each other of the second end, respectively.

9. The needleless delivery device according to claim 8, wherein the aperture of the hole located at the center or the center of the second end is different from the apertures of the other holes of the plurality of holes; Preferably, the aperture of at least one group of holes among the multiple groups of holes is different from the apertures of the other groups of holes; Preferably, the outlet jet velocity of the hole located at the center or the center of the second end is different from the outlet jet velocities of the other holes of the plurality of holes; Preferably, the outlet jet velocity of at least one group of holes among the multiple groups of holes is different from the outlet jet velocities of the other groups of holes.

10. The delivery device according to claim 1, characterized in that, The plurality of holes are arranged in a ring; Preferably, the plurality of holes are arranged in a ring with the center or the center of the second end as the center; There are multiple groups of the holes, and each group of holes is arranged in a ring. Preferably, the multiple groups of holes are arranged coaxially in a ring with each other.

11. The needleless delivery device according to claim 10, wherein at least one of the plurality of holes arranged in a ring has an aperture different from that of the other holes; Preferably, the aperture of at least one group of holes among the multiple groups of holes is different from the apertures of the other groups of holes; Preferably, the apertures of the multiple groups of holes arranged coaxially in a ring with each other increase or decrease radially; Preferably, at least one of the plurality of holes arranged in a ring has an outlet jet velocity different from that of the other holes; Preferably, the outlet jet velocity of at least one group of holes among the multiple groups of holes is different from the outlet jet velocities of the other groups of holes; Preferably, the outlet jet velocities of the multiple groups of holes arranged coaxially in a ring with each other increase or decrease radially.

12. The needle-free delivery device according to claim 1, wherein, The plurality of holes include a central hole located at the center or the center of the second end and a plurality of peripheral holes located around the central hole; Preferably, the plurality of peripheral holes are arranged in a ring. Preferably, the plurality of peripheral holes are arranged coaxially in a ring around the central hole; There are multiple groups of the peripheral holes, and each group of peripheral holes is arranged in a ring. Preferably, the multiple groups of peripheral holes are arranged coaxially in a ring around the central hole.

13. The needleless delivery device according to claim 12, wherein the aperture diameter of the central hole is different from the aperture diameters of the plurality of peripheral holes; Preferably, the aperture diameter of at least one group of the plurality of groups of peripheral holes is different from the aperture diameters of the other peripheral hole groups; Preferably, the aperture diameters of the plurality of groups of holes and the central hole arranged coaxially and annularly increase or decrease radially; Preferably, the outlet jet velocity of the central hole is different from the outlet jet velocities of the plurality of peripheral holes; Preferably, the outlet jet velocity of at least one group of the plurality of groups of peripheral holes is different from the outlet jet velocities of the other peripheral hole groups; Preferably, the outlet jet velocities of the plurality of groups of holes and the central hole arranged coaxially and annularly increase or decrease radially.

14. The needle-free delivery device according to any one of claims 1 to 13, characterized in that, The channel shapes of the plurality of holes are cylindrical, conical or streamlined.

15. A triple vaccine and medical device combination product for feline rhinotracheitis, calicivirus disease, and panleukopenia, characterized in that, Comprising a needleless delivery device and a feline triple vaccine, wherein the needleless delivery device is the needleless delivery device according to any one of claims 1 to 14.

16. The pharmaceutical device combination product according to claim 15, wherein, The second end is provided with three holes, the three holes are arranged annularly at equal intervals around the center of the second end, and the three holes are 1.25 mm ± 20% away from the center.

17. The pharmaceutical device combination product according to claim 15, wherein, The pushing speed of the piston of the needleless delivery device is 0.12 m / s ± 20%.

18. The pharmaceutical and medical device combination product according to claim 15, wherein, The needleless delivery device is configured such that the outlet jet velocity when the feline triple vaccine is pushed away from the holes in the second end by the pushing element is 150.00 m / s ± 20%.

19. The pharmaceutical and medical device combination product according to claim 15, wherein The needleless delivery device is configured such that the dispersion volume of the feline triple vaccine in the body is more than 1.5 times the undelivered volume of the feline triple vaccine.

20. The medicament-device combination product according to claim 15, wherein The needleless delivery device is configured such that the average antibody titer of the feline triple vaccine 14 days after the second dose is more than 1.2 times, preferably more than 2.0 times, and more preferably more than 4.8 times the average antibody titer of intramuscular injection.

21. The pharmaceutical and medical device combination product according to claim 15, wherein The needleless delivery device is configured such that the average antibody titer of the feline triple vaccine 60 days after the second dose is more than 1.2 times, preferably more than 2.0 times, and more preferably more than 3.7 times the average antibody titer of intramuscular injection.

22. The pharmaceutical device combination product according to claim 15, wherein, The needleless delivery device is configured such that the average antibody titer of the feline triple vaccine 60 days after 60% of the vaccine dose is injected for the second dose is more than 1.1 times, preferably more than 1.5 times, and more preferably more than 2.0 times the average antibody titer produced by 100% of the vaccine dose of intramuscular injection.

23. A hepatitis B vaccine drug-device combination product, characterized in that, Comprising a needleless delivery device and a hepatitis B vaccine, wherein the needleless delivery device is the needleless delivery device according to any one of claims 1 to 14.

24. The pharmaceutical and medical device combination product according to claim 23, wherein, The second end is provided with three holes, the three holes are arranged annularly at equal intervals around the center of the second end, the aperture diameters of the three holes are 0.14 mm to 0.17 mm, and the three holes are 1.25 mm ± 20% away from the center.

25. The pharmaceutical and medical device combination product according to claim 23, wherein The pushing speed of the piston of the needleless delivery device is 0.12 m / s ± 20%.

26. The drug-device combination product according to claim 23, wherein The needleless delivery device is configured such that the outlet jet velocity when the hepatitis B vaccine is pushed away from the holes in the second end by the pushing element is 150.00 m / s ± 20%.

27. The drug-device combination product according to claim 23, wherein, The needleless delivery device is configured such that the diffusion volume of the hepatitis B vaccine in the body is more than 1.5 times the undelivered volume of the hepatitis B vaccine.

28. The pharmaceutical device combination product according to claim 23, wherein The needleless delivery device is configured such that the average antibody titer of the hepatitis B vaccine 14 days after the second dose is administered is more than 1.1 times, preferably more than 1.5 times, and more preferably more than 2.0 times the average antibody titer of intramuscular injection.

29. The pharmaceutical device combination product according to claim 23, wherein The needleless delivery device is configured such that the average antibody titer of the hepatitis B vaccine 42 days after the second dose is administered is more than 1.1 times, preferably more than 1.5 times, and more preferably more than 2.0 times the average antibody titer of intramuscular injection.

30. The pharmaceutical device combination product according to claim 23, wherein, The needleless delivery device is configured such that the average antibody titer of the hepatitis B vaccine 42 days after 60% of the vaccine dose is injected for the second dose is more than 1.1 times, preferably more than 1.3 times, and more preferably more than 1.5 times the average antibody titer produced by intramuscular injection of 100% of the vaccine dose.

31. The pharmaceutical device combination product according to claim 23, wherein The needleless delivery device is configured such that the positive expression rate of T lymphocytes of the hepatitis B vaccine 42 days after the second dose is administered is more than 10% higher, preferably more than 20% higher, and more preferably more than 50% higher than that of intramuscular injection.

32. A human pneumococcal vaccine drug-device combination product, characterized in that, Comprising a needleless delivery device and a human pneumococcal vaccine, wherein the needleless delivery device is the needleless delivery device according to any one of claims 1 to 14.

33. The drug-device combination product according to claim 32, wherein The second end is provided with three holes, the three holes are arranged in an equally spaced circular pattern around the center of the second end, and the distance of the three holes from the center is 1.25 mm ± 20%.

34. The pharmaceutical and medical device combination product according to claim 32, wherein The pushing speed of the piston of the needleless delivery device is 0.14 m / s ± 20%.

35. The pharmaceutical and medical device combination product according to claim 32, wherein, The needleless delivery device is configured such that the outlet jet velocity of the human pneumococcal vaccine when it is pushed away from the hole in the second end by the pushing element is 160.00 m / s ± 20%.

36. The pharmaceutical device combination product according to claim 32, wherein, The needleless delivery device is configured such that the diffusion volume of the human pneumococcal vaccine in the body is more than 1.5 times the undelivered volume of the human pneumococcal vaccine.

37. The pharmaceutical and medical device combination product according to claim 32, wherein The needleless delivery device is configured such that the average antibody titer of the pneumococcal vaccine after vaccination is more than 1.1 times, preferably more than 1.5 times, and more preferably more than 2.0 times the average antibody titer of intramuscular injection.

38. The pharmaceutical device combination product according to claim 32, wherein, The needleless delivery device is configured such that the average antibody titer of the pneumococcal vaccine after 60% of the vaccine dose is injected is more than 1.1 times, preferably more than 1.3 times, and more preferably more than 1.5 times the average antibody titer produced by intramuscular injection of 100% of the vaccine dose.

39. A GLP-1 polypeptide drug-device combination product, characterized in that, Comprising a needleless delivery device and a GLP-1 polypeptide, wherein the needleless delivery device is the needleless delivery device according to any one of claims 1 to 14.

40. The pharmaceutical device combination product according to claim 39, wherein, The second end is provided with three holes, the three holes are arranged in an equally spaced circular pattern around the center of the second end, and the distance of the three holes from the center is 1.25 mm ± 20%.

41. The drug-device combination product according to claim 39, wherein The pushing speed of the piston of the needleless delivery device is 0.16 m / s ± 20%.

42. The pharmaceutical device combination product according to claim 39, wherein The needleless delivery device is configured such that the outlet jet velocity of the GLP-1 polypeptide when it is pushed away from the hole in the second end by the pushing element is 150.00 m / s ± 20%.

43. The medicament-device combination product according to claim 39, wherein The needleless delivery device is configured such that the diffusion volume of the GLP-1 polypeptide in vivo is more than 1.5 times the undelivered volume of the GLP-1 polypeptide.

44. The pharmaceutical and medical device combination product according to claim 39, wherein The GLP-1 polypeptide includes semaglutide, wherein Optionally, the needleless delivery device is configured such that the diffusion volume of the semaglutide in vivo is more than 1.5 times the undelivered volume of the semaglutide.

45. The pharmaceutical and medical device combination product according to claim 39, wherein, The needleless delivery device is configured such that the effect of semaglutide on reducing body weight in humans and animals is consistent with that of needle injection. Preferably, the effect of reducing body weight is increased by more than 2%, further preferably by more than 5%, and still more preferably by more than 10%.

46. The pharmaceutical and medical device combination product according to claim 39, wherein, The needleless delivery device is configured such that the body weight reduction endpoint of the semaglutide in vivo is consistent with that of needle injection. Preferably, it is increased by more than 2%, further preferably by more than 5%, and still more preferably by more than 10%.

47. The pharmaceutical device combination product according to claim 39, wherein The needleless delivery device is configured such that the proportion of side effects such as nausea, vomiting, and abdominal distension caused by the semaglutide is consistent with that of needle injection. Preferably, it is reduced by more than 5%, further preferably by more than 10%, and still more preferably by more than 20%.

48. A pharmaceutical and medical device combination product, characterized in that, It includes a needleless delivery device and a pharmaceutical preparation, and the needleless delivery device is the needleless delivery device according to any one of claims 1 to 14.

49. The pharmaceutical device combination product according to claim 48, wherein Optionally, the pharmaceutical preparation is a human rabies vaccine; Optionally, the pharmaceutical preparation is an animal rabies vaccine; Optionally, the pharmaceutical preparation is a human meningitis vaccine; Optionally, the pharmaceutical preparation is an animal hand, foot and mouth disease vaccine; Optionally, the pharmaceutical preparation is a human COVID-19 vaccine; Optionally, the pharmaceutical preparation is a human hepatitis A vaccine; Optionally, the pharmaceutical preparation is a human hemorrhagic fever with renal syndrome vaccine; Optionally, the pharmaceutical preparation is a human mumps vaccine; Optionally, the pharmaceutical preparation is a human HPV vaccine; Optionally, the pharmaceutical preparation is a human tumor chemotherapy drug; Optionally, the pharmaceutical preparation is a human tumor nuclear medicine treatment drug; Optionally, the pharmaceutical preparation is a human tumor vaccine, including but not limited to polypeptide vaccines, mRNA vaccines, and DNA vaccines; Optionally, the pharmaceutical preparation is a swine diarrhea bivalent vaccine; Optionally, the pharmaceutical preparation is a porcine reproductive and respiratory syndrome inactivated vaccine; Optionally, the pharmaceutical preparation is a foot-and-mouth disease vaccine; Optionally, the pharmaceutical preparation is a bovine bivalent vaccine; Optionally, the pharmaceutical preparation is a Pasteurella multocida vaccine; Optionally, the pharmaceutical preparation is insulin; Optionally, the pharmaceutical preparation is a botulinum toxin-based cosmetic drug for medical beauty.

50. Use of the needleless delivery device according to any one of claims 1 to 14 in the preparation of drugs for human clinical medicine and animal healthcare for needleless injection administration.

51. The use according to claim 50, wherein Optionally, the pharmaceutical preparation is a feline triple vaccine; Optionally, the pharmaceutical preparation is a hepatitis B vaccine; Optionally, the pharmaceutical preparation is a human pneumonia vaccine; Optionally, the pharmaceutical preparation is semaglutide; Optionally, the pharmaceutical preparation is a human rabies vaccine; Optionally, the pharmaceutical preparation is a rabies vaccine for animals; Optionally, the pharmaceutical preparation is a meningitis vaccine for humans; Optionally, the pharmaceutical preparation is a hand, foot and mouth disease vaccine for animals; Optionally, the pharmaceutical preparation is a COVID-19 vaccine for humans; Optionally, the pharmaceutical preparation is a hepatitis A vaccine for humans; Optionally, the pharmaceutical preparation is a hemorrhagic fever with renal syndrome vaccine for humans; Optionally, the pharmaceutical preparation is a mumps vaccine for humans; Optionally, the pharmaceutical preparation is an HPV vaccine for humans; Optionally, the pharmaceutical preparation is an anti-tumor chemotherapy drug for humans; Optionally, the pharmaceutical preparation is a nuclear medicine anti-tumor drug for humans; Optionally, the pharmaceutical preparation is an anti-tumor vaccine for humans, including but not limited to polypeptide vaccines, mRNA vaccines, and DNA vaccines; Optionally, the pharmaceutical preparation is a porcine diarrhea bivalent vaccine; Optionally, the pharmaceutical preparation is a porcine reproductive and respiratory syndrome inactivated vaccine; Optionally, the pharmaceutical preparation is a foot-and-mouth disease vaccine; Optionally, the pharmaceutical preparation is a bovine bivalent vaccine; Optionally, the pharmaceutical preparation is a Pasteurella multocida vaccine; Optionally, the pharmaceutical preparation is insulin; Optionally, the pharmaceutical preparation is a botulinum toxin-based cosmetic drug for medical beauty.

52. A needleless syringe for a needleless delivery device, characterized in that, Comprising: A tube for containing a fluid, the tube having a first end and a second end, wherein the first end is configured to be adapted to receive a piston for pushing the fluid, and the second end has a plurality of holes for dispensing the fluid in the tube.

53. The needleless syringe according to claim 52, wherein, The needleless syringe is configured such that the fluid jets through the plurality of holes have different in-vivo dispersions; Preferably, the apertures of the plurality of holes of the needleless syringe are configured such that the fluid jets through the plurality of holes have different in-vivo dispersions.

54. The needleless syringe according to claim 52, wherein, The plurality of holes includes a first hole; Preferably, the first hole has a first aperture, and the size of the first aperture is configured such that the fluid jet through the first hole disperses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs.

55. The needleless syringe according to claim 53, characterized in that, The plurality of holes includes a first hole and a second hole; Preferably, the first hole has a first aperture, and the size of the first aperture is configured such that the fluid jet through the first hole disperses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; the second hole has a second aperture, and the size of the second hole is configured such that the fluid jet through the second hole disperses in at least the same or another one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs.

56. The needleless syringe according to claim 52, characterized in that, The plurality of holes are arranged in a straight line; Preferably, the plurality of holes are arranged in a straight line along the diameter or the midline of the second end. Preferably, one of the plurality of holes arranged in a straight line along the diameter or the midline of the second end is located at the center of the second end; Preferably, the plurality of holes arranged in a straight line are equally spaced; Preferably, the plurality of holes arranged in a straight line are mirror-symmetrical with respect to the diameter or the midline of the second end; Preferably, there are multiple groups of the holes, and each group of holes is arranged in a straight line. Preferably, each group of holes is arranged along a diameter or a midline of the second end; Preferably, the plurality of holes are arranged in an array, and the plurality of holes arranged in an array are mirror-symmetrical with respect to the first and second diameters or midlines perpendicular to each other of the second end respectively; Preferably, the aperture diameter of the hole located at the center of the second end is different from that of the other holes of the plurality of holes; Preferably, the aperture diameter of at least one group of holes among the multiple groups of holes is different from that of the other groups of holes.

57. The needleless syringe according to claim 52, characterized in that, The plurality of holes are arranged in a ring; Preferably, the plurality of holes are arranged in a ring with the center of the second end as the center; The holes have multiple groups, and each group of holes is arranged in a ring. Preferably, the multiple groups of holes are arranged coaxially in a ring with each other; coaxial ring arrangement; Preferably, at least one of the plurality of holes arranged in a ring has an aperture diameter different from that of the other holes; Preferably, the aperture diameter of at least one group of holes among the multiple groups of holes is different from that of the other groups of holes; Preferably, the aperture diameters of the multiple groups of holes arranged coaxially in a ring increase or decrease radially.

58. The needleless syringe according to claim 52, characterized in that, The plurality of holes include a central hole located at the center of the second end and a plurality of peripheral holes located around the central hole; Preferably, the plurality of peripheral holes are arranged in a ring. Preferably, the plurality of peripheral holes are arranged coaxially in a ring around the central hole; The peripheral holes have multiple groups, and each group of peripheral holes is arranged in a ring. Preferably, the multiple groups of peripheral holes are arranged coaxially in a ring around the central hole; Preferably, the aperture diameter of the central hole is different from that of the plurality of peripheral holes.

59. A drug-device combination product, characterized in that, Comprising a needleless delivery device and a pharmaceutical preparation, wherein the needleless delivery device comprises: a tube for accommodating the pharmaceutical preparation, the tube having a first end and a second end, and a hole for dispensing the pharmaceutical preparation in the tube is provided in the second end; and a power mechanism, the power mechanism includes a piston capable of pushing the pharmaceutical preparation provided in the first end of the tube or the power mechanism is operatively connected to the piston to apply a delivery pressure to the piston for pushing the pharmaceutical preparation; Wherein, the needleless delivery device is configured such that the diffusion volume of the pharmaceutical preparation in the body is more than 1.50 times the undelivered volume.

60. The pharmaceutical and medical device combination product according to claim 59, wherein The needleless delivery device is configured such that the diffusion volume of the pharmaceutical preparation in the body is more than 1.80 times the undelivered volume, preferably more than 2.40 times, more preferably more than 3.00 times, and still more preferably more than 3.60 times.

61. The pharmaceutical device combination product according to claim 59, wherein, Optionally, the power mechanism is any one of compressed gas driven, spring driven, electromagnetic driven or a combination of the above driving methods; Optionally, the pushing speed of the piston of the multi-needleless delivery device is 0.05 - 0.50 m / s, preferably 0.09 - 0.25 m / s, and still more preferably 0.14 - 0.20 m / s; Optionally, the needleless delivery device is configured such that the pharmaceutical preparation is pushed by the pushing element; The outlet jet velocity when the pharmaceutical preparation is pushed away from the hole in the second end is greater than or equal to 10 m / s, preferably greater than or equal to 50 m / s, further preferably greater than or equal to 100 m / s, and still more preferably greater than or equal to 150 m / s.

62. The pharmaceutical and medical device combination product according to claim 59, wherein, The power mechanism is configured to apply different adjustable delivery pressures to the piston for pushing the pharmaceutical preparation. Optionally, the delivery pressures include a first delivery pressure and a second delivery pressure; Preferably, the magnitude of the first delivery pressure is configured such that the jet of the pharmaceutical preparation passing through the hole diffuses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; the magnitude of the second delivery pressure is configured such that the jet of the pharmaceutical preparation passing through the hole diffuses in another of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; Preferably, the magnitude of the first delivery pressure is configured such that the jet of the pharmaceutical preparation passing through the hole has a first outlet jet velocity, and the first outlet jet velocity is configured such that the jet of the pharmaceutical preparation passing through the single hole diffuses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; preferably, the magnitude of the second delivery pressure is configured such that the jet of the pharmaceutical preparation passing through the hole has a second outlet jet velocity, and the second outlet jet velocity is configured such that the jet of the pharmaceutical preparation passing through the hole diffuses in at least another of the dermis, epidermis, subcutaneous tissue, muscle, and human organs.

63. The pharmaceutical and medical device combination product according to claim 59, wherein Optionally, the pharmaceutical preparation is a feline triple vaccine; Optionally, the pharmaceutical preparation is a human hepatitis B vaccine; Optionally, the pharmaceutical preparation is a human pneumonia vaccine; Optionally, the pharmaceutical preparation is semaglutide; Optionally, the pharmaceutical preparation is a human tumor vaccine, including but not limited to polypeptide vaccines, mRNA vaccines, and DNA vaccines.

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