Needleless delivery device

Abstract

The invention relates to a delivery device for human or animal protection drugs and vaccines. Comprising a tube for containing a fluid, a plurality of apertures for dispensing and delivering the fluid within the tube, and a power mechanism. Through the arrangement of multiple holes and control of the jet flow velocity of the medicine and the vaccine, the dispersion degree after the medicine and the vaccine enter the body, the number of the holes, the aperture size and the distribution of the multiple holes, the single-time delivery amount and delivery efficiency of the medicine and the vaccine can be improved while painlessness and no damage to the skin are achieved; the drug and the vaccine are delivered to one or more target positions with different depths of a human body, and the pharmacokinetics is optimized by controlling the three-dimensional dispersion of the drug and the vaccine at the target positions, so that the contact effect and the bioavailability of the drug and the vaccine with in-vivo tissues are greatly improved. Components of the delivery device, systems, and related pharmaceutical and mechanical combinations are also provided.

Description

Technical Field

[0001] The present invention relates to the field of medical devices, and more particularly to a needleless delivery device and a drug-device combination product. Background Art

[0002] Needleless injection technology has many advantages over traditional needle injection. Although there are various needleless injection devices on the market currently, the clinical application of needleless injection in the fields of human clinical and animal health has basically not been popularized. The main reason is that the scientific research on the penetration and delivery performance of needleless injection is still insufficient, especially regarding the jet flow rate, drug chemical properties, needleless injection aperture design, and the influence of media such as the epidermis, subcutaneous tissue, and muscle of humans and animals on drug penetration and delivery performance. Most of the existing needleless syringes use single-hole injection, and the research and application of truly effective multi-hole injection technology are still blank. In the field of vaccine delivery, needleless injection has been clinically studied in the fields of inactivated vaccines, attenuated vaccines, recombinant protein vaccines, nucleic acid (mRNA) vaccines, and DNA vaccines, but it has not been popularized in practical applications because of unreliable effectiveness. In practical applications, the needleless delivery device has high requirements for skin fit, is prone to liquid leakage due to hair, and it is difficult to precisely control the injection position, depth, and dispersion of the liquid medicine. Because high-pressure jets have powerful destructive power, the injection aperture of current needleless injection devices on the market is generally below 0.15 mm. Therefore, when a large dose of drug delivery is required, the current needleless injection technology has limitations. In addition, drug metabolism and the immunogenicity stimulation of vaccines have high requirements for the three-dimensional dispersion and precise positioning of drugs and vaccines in the body, and the research and application of current needleless injection technology in this regard are still blank.

[0003] The content described in this background art is only for facilitating the understanding of the related technologies in this field and is not regarded as an admission of the prior art. Summary of the Invention

[0004] Therefore, aiming at the above-mentioned defects existing in needleless injection currently, the embodiments of the present invention intend to provide a needleless delivery device to at least partially solve the problems existing in the current needleless injection. The embodiments of the present invention also provide a related drug-device combination product and a needleless syringe for the needleless delivery device.

[0005] The embodiments of the present invention provide a needleless delivery device, comprising:

[0006] 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 tube are provided in the second end; and

[0007] a power mechanism, the power mechanism includes a piston capable of pushing the fluid 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 fluid.

[0008] Some of the other optional features and technical effects of the embodiments of the present invention are described below, and some can be understood by reading this article. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. The elements shown are not limited by the scale shown in the drawings, and the same or similar reference numerals in the drawings denote the same or similar elements, where:

[0010] Figure 1 A schematic structural diagram of a needleless delivery device according to an embodiment of the present invention is shown;

[0011] Figure 2 A schematic structural diagram of a needleless delivery device according to an embodiment of the present invention is shown;

[0012] Figure 3 A schematic diagram of a porous arrangement of a needleless delivery device according to an embodiment of the present invention is shown;

[0013] Figure 4 A schematic diagram of a porous arrangement of a needleless delivery device according to an embodiment of the present invention is shown;

[0014] Figure 5 A schematic diagram of a porous arrangement of a needleless delivery device according to an embodiment of the present invention is shown;

[0015] Figure 6 A schematic diagram of a porous arrangement of a needleless delivery device according to an embodiment of the present invention is shown;

[0016] Figure 7 A schematic diagram of a linear arrangement of pores of a needleless delivery device according to an embodiment of the present invention is shown;

[0017] Figure 8 A schematic diagram of a linear arrangement of pores of a needleless delivery device according to an embodiment of the present invention is shown;

[0018] Figure 9 A schematic diagram of a linear arrangement of pores of a needleless delivery device according to an embodiment of the present invention is shown;

[0019] Figure 10 A schematic diagram of a linear arrangement of pores of a needleless delivery device according to an embodiment of the present invention is shown;

[0020] Figure 11 A schematic diagram of an array arrangement of pores of a needleless delivery device according to an embodiment of the present invention is shown;

[0021] Figure 12 A schematic diagram of a porous arrangement with different pore sizes of a needleless delivery device according to an embodiment of the present invention is shown;

[0022] Figure 13 Schematic diagram of a porous arrangement with different pore diameters of a needleless delivery device according to an embodiment of the present invention;

[0023] Figure 14 Schematic diagram of a porous arrangement with different pore diameters of a needleless delivery device according to an embodiment of the present invention;

[0024] Figure 15 Schematic diagram of a porous arrangement with different pore diameters of a needleless delivery device according to an embodiment of the present invention;

[0025] Figure 16 Schematic diagram of a porous annular arrangement of a needleless delivery device according to an embodiment of the present invention;

[0026] Figure 17 Schematic diagram of a porous annular arrangement of a needleless delivery device according to an embodiment of the present invention;

[0027] Figure 18 Schematic diagram of a coaxial annular arrangement of multiple groups of holes of a needleless delivery device according to an embodiment of the present invention;

[0028] Figure 19 Schematic diagram of a coaxial annular arrangement of multiple groups of holes of a needleless delivery device according to an embodiment of the present invention;

[0029] Figure 20 Schematic diagram of a coaxial annular arrangement of multiple groups of holes of a needleless delivery device according to an embodiment of the present invention;

[0030] Figure 21 Schematic diagram of a porous arrangement of a central hole and peripheral holes of a needleless delivery device according to an embodiment of the present invention;

[0031] Figure 22 Schematic diagram of a porous arrangement of a central hole and peripheral holes of a needleless delivery device according to an embodiment of the present invention;

[0032] Figure 23 Schematic diagram of a porous arrangement of a central hole and peripheral holes of a needleless delivery device according to an embodiment of the present invention;

[0033] Figure 24 Schematic diagram of a porous arrangement of a central hole and peripheral holes of a needleless delivery device according to an embodiment of the present invention;

[0034] Figure 25 Schematic diagram of a porous arrangement of a central hole and peripheral holes of a needleless delivery device according to an embodiment of the present invention;

[0035] Figure 26 Schematic diagram of a porous arrangement of a central hole and peripheral holes of a needleless delivery device according to an embodiment of the present invention;

[0036] Figure 27Schematic diagram of the porous arrangement of the central hole and peripheral holes of a needleless delivery device according to an embodiment of the present invention;

[0037] Figure 28 Schematic diagram of the porous arrangement of a needleless delivery device according to an embodiment of the present invention;

[0038] Figure 29 Schematic diagram of the porous arrangement of a needleless delivery device according to an embodiment of the present invention;

[0039] Figure 30 Schematic structural diagram of a needleless delivery device according to an embodiment of the present invention;

[0040] Figure 31 Schematic structural diagram of a needleless delivery device according to an embodiment of the present invention;

[0041] Figure 32 Schematic diagram of the porous arrangement of a needleless delivery device according to an embodiment of the present invention;

[0042] Figure 33 Schematic diagram of the structure of the second end of a needleless delivery device according to an embodiment of the present invention;

[0043] Figure 34 Schematic structural diagram of a schematic simulation model of the delivery of a needleless delivery device according to a specific embodiment of the present invention;

[0044] Figure 35 Schematic diagram of the porous dispersion effect of the delivery of a needleless delivery device according to an embodiment of the present invention;

[0045] Figure 36 Schematic diagram of the porous dispersion effect of the delivery of a needleless delivery device according to an embodiment of the present invention;

[0046] Figure 37 Schematic diagram of the porous dispersion effect of the delivery of a needleless delivery device according to an embodiment of the present invention;

[0047] Figure 38 Schematic diagram of the porous dispersion effect of the delivery of a needleless delivery device according to an embodiment of the present invention;

[0048] Figure 39 Schematic diagram of the porous dispersion effect of the delivery of a needleless delivery device according to an embodiment of the present invention;

[0049] Figure 40 Schematic diagram of the porous arrangement of the delivery of a needleless delivery device according to a specific embodiment of the present invention;

[0050] Figure 41 Line graph of immunological test data of the delivery of a needleless delivery device according to a specific embodiment of the present invention;

[0051] Figure 42 A line graph showing immunological test data delivered by a needleless delivery device according to a specific embodiment of the present invention; and

[0052] Figure 43 A line graph showing immunological test data delivered by a needleless delivery device according to a specific embodiment of the present invention. Detailed Description

[0053] To make the objectives, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below in conjunction with the detailed implementation manners and the accompanying drawings. Herein, the illustrative embodiments of the present invention and their descriptions are used to explain the present invention, but not to limit the present invention.

[0054] As used herein, the term "comprising" and its variants mean open inclusion, that is, "including but not limited to". Unless specifically stated, the term "or" means "and / or". The term "based on" means "at least partially based on". The terms "an exemplary embodiment" and "an embodiment" mean "at least one exemplary embodiment". The term "another embodiment" means "at least one additional embodiment". The terms "first", "second", etc. may refer to different or the same objects. There may also be other explicit and implicit definitions hereinafter.

[0055] In multiple embodiments of the present invention, as Figure 1 shown, a needleless delivery device is provided, especially a needleless delivery device for drugs and vaccines. The needleless delivery device may include a tube 100 and a power mechanism 200 not specifically depicted. Among them, the tube 100 is adapted to accommodate a fluid 130 and has a first end 110 and a second end 120. Among them, 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.

[0056] In some embodiments of the present invention, as Figure 2 shown, the second end 120 of the needleless delivery device may further have a tapered section 122 that gradually narrows axially and distally from the tube 100, and a plurality of holes 121 are provided on the end face 123 of the tapered section 122, wherein the end face 123 is configured to be circular.

[0057] In some embodiments of the present invention, as Figure 1 and Figure 2 shown, the piston 210 may be provided as an independent component, and the power mechanism 200 is configured to be operably connected to the piston 210 to apply a delivery pressure to the piston 210. It is also conceivable that in some other embodiments of the present invention, the power mechanism 200 may be integrally integrated with the piston 210.

[0058] 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, and electromagnetic driving, or a combination of the above driving modes. For example, in some embodiments, the power mechanism 200 may use compressed gas, such as compressed nitrogen or compressed carbon dioxide gas, for driving, or may also use a compressed mechanical spring for driving, or may also be driven by a piezoelectric actuator, which is not limited herein.

[0059] In some embodiments of the present invention, a plurality of holes 121 may be provided in the second end 120, that is, the number of the plurality of holes 121 is greater than or equal to 2. For example Figures 3 to 5 shows the cases where 2, 3, and 4 holes 121 are provided on the second end 120. It can be understood that, as Figure 6 shown, a plurality of holes 121 may also be similarly arranged on the end face 123, and the number of the plurality of holes 121 is greater than or equal to 2. In the following embodiments of the present invention, the arrangement of the second end 120 will be taken as an example.

[0060] In some embodiments of the present invention, the total area of the plurality of holes is 0.009 mm 2 Above, preferably 0.020 mm 2 Above, more preferably 0.053 mm 2 Above; the area of a single hole of the holes is 0.0028 - 0.035 mm 2 Preferably, it is 0.0028 - 0.020 mm 2 More preferably, it is 0.0028 - 0.009 mm 2 .

[0061] In the embodiments of the present invention, the needleless delivery device of the present invention can deliver a drug or a vaccine with a volume (pre-delivery volume) of 0.3 mm 3 or more at one time without causing skin damage. Preferably, it is a drug or a vaccine with a volume (pre-delivery volume) of 1.0 mm 3 or more. More preferably, it is a drug or a vaccine with a volume (pre-delivery volume) of 5.0 mm 3 or more; in some embodiments, the volume (pre-delivery volume) of the drug or vaccine delivered at one time by the needleless delivery device of the present invention can reach 14.0 mm 3 , and in further embodiments, the volume (pre-delivery volume) of the drug or vaccine delivered at one time by the needleless delivery device of the present invention can reach 46.0 mm 3 .

[0062] In some embodiments of the present invention, compared with manual needle injection (where the pushing speed of the piston inside the syringe is about 0.01 m / s), the piston speed when the piston 210 of the needleless delivery device of the present invention pushes 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 when the piston 210 pushes 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.

[0063] In some embodiments of the present invention, compared with manual needle injection (where the outlet jet speed of the fluid ejected from the needle is about 2 m / s), the outlet jet speed when the fluid 130 in the needleless delivery device of the present invention is 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 even more preferably greater than or equal to 150 m / s.

[0064] In some embodiments of the present invention, the needleless delivery device is configured such that the fluid jets passing through the plurality of holes 121 have different in-vivo dispersions; preferably, the aperture d of the plurality of holes 121 of the needleless delivery device is configured such that the fluid jets passing through the plurality of holes 121 have different in-vivo dispersions; preferably, the fluid jet speed v passing through the plurality of holes 121 of the needleless delivery device is configured such that the fluid jets passing through the plurality of holes 121 have different in-vivo dispersions.

[0065] In some embodiments of the present invention, compared with existing manual needle injection (where the injected fluid hardly disperses in the body), the needleless delivery device of the present invention enables the fluid 130 pushed away from the plurality of holes 121 in the second end 120 by the piston 210 to have different dispersions in the body and different degrees of dispersion.

[0066] In an embodiment of the present invention, the degree of dispersion refers to a comprehensive concept describing the distribution characteristics of the fluid in the body. Specifically, the degree of dispersion may include the dispersion volume ratio, dispersion depth, dispersion center, and edge liquid distribution density of the fluid.

[0067] In some embodiments of the present invention, the dispersion volume ratio refers to the ratio of the dispersion region volume of the fluid delivered by the needleless delivery device in the body to the original volume of the fluid without delivery, that is:

[0068]

[0069] In other embodiments of the present invention, the dispersion volume ratio may also refer to the ratio of the dispersion volume of the fluid delivered by the needleless delivery device of the embodiments of the present invention in the body to the dispersion volume of the fluid delivered by the artificial needle injection method in the body, that is:

[0070]

[0071] Wherein, the dispersion volume of the delivered fluid can be calculated in various ways, which is not limited herein. 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 an image analysis software can be used to calculate the volume of the dispersion region. For example, the envelope of the dispersion region can be calculated to estimate the volume of the dispersion region.

[0072] In some embodiments of the present invention, the dispersion depth refers to the maximum distance from the body surface of the dispersion region of the fluid injected by needleless injection in the body; the dispersion center refers to the three-dimensional center of the dispersion region formed by the fluid injected by needleless injection in the body, such as the centroid of the three-dimensional region, which is not limited herein.

[0073] In some embodiments of the present invention, the needleless delivery device is configured such that the dispersion volume of the fluid 130 in the body is greater than the volume of the undelivered fluid or the volume of the fluid delivered by needle injection. Preferably, the dispersion volume of the fluid in the body 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 still more preferably more than 3.60 times.

[0074] It can be understood that when the delivered fluid enters the body through the needleless delivery device, due to the dispersion effect of the fluid in the body, the three-dimensional space region of its distribution becomes larger. This dispersion process will increase the surface area of contact between the fluid, especially the drug or vaccine and the body tissues, thereby improving the bioavailability and efficacy of the drug.

[0075] It can be understood that those skilled in the art can confirm the corresponding dispersion degrees of the dermis, epidermis, subcutaneous, muscle and human organs in the body of the inoculated body according to the needleless delivery, including but not limited to different types of animals or patients with different physical conditions under the teaching of the embodiments of the present invention.

[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 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, muscle and human organs. Preferably, the plurality of holes have the same aperture, such as the first aperture.

[0078] In a preferred embodiment, 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. Preferably, a plurality of 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 includes a first hole and a second hole.

[0080] In a preferred embodiment, the first hole has a first hole diameter sized 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 hole diameter sized 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. Preferably, the hole diameters of the plurality of holes can be configured to be unequal. For example, the plurality of holes can include a first hole and at least one second hole, where the first hole has a first hole diameter d1 and the second hole has a second hole diameter d2, where d1 ≠ d2.

[0081] In a preferred embodiment, 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. Preferably, the jet velocities of the fluid 130 through the plurality of 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 can have different arrangements.

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

[0084] As Figures 7 to 9 shown, the plurality of holes 121 are arranged in a straight line along the diameter or median line of the second end 120. Preferably, one of the plurality of holes 121 arranged in a straight line along the diameter or median line of the second end 120 is located at the center of the second end.

[0085] In one embodiment of the present invention, as Figure 8 shown, there are 3 holes 121 arranged in a straight line along the diameter (median line) of the second end 120 on the second end 120, including the 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 in a straight line are equally spaced.

[0087] In one embodiment of the present invention, as Figure 8 shown, a plurality of holes 121 are arranged in a straight line along the diameter of the second end 120, and the plurality of holes 121 are equally spaced.

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

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

[0090] In one embodiment of the present invention, as Figure 10 shown, three groups of holes 121, namely group A, group B, and group C, are arranged on the second end 120. Among them, both group A and group C include 2 holes 121 arranged in a straight line, while group B includes 3 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 median lines perpendicular to each other of the second end 120, respectively.

[0092] In one embodiment of the present invention, as Figure 11 shown, 4 holes 121 arranged in an array are arranged on the second end 120, and the 4 holes 121 are mirror-symmetrical with respect to the first and second diameters (median lines) perpendicular to each other of the second end 120, respectively.

[0093] In some embodiments of the present invention, the aperture of the hole 121' located at the center of the second end 120 is different from the apertures of the other holes of the plurality of holes 121.

[0094] In one embodiment of the present invention, as Figures 12 to 13 shown, 3 holes arranged in a straight line are provided on the second end 120, including the hole 121' with an aperture of d' located at the center of the second end 120 and the other two holes 121 with apertures of d, where d'≠d.

[0095] In some embodiments of the present invention, preferably, the aperture d2 of at least one group of the plurality of 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 Figures 14 to 15 shown, there are three groups of holes 121, namely Group A, Group B, and Group C, arranged on the second end 120. Among them, both Group A and Group C include 2 holes 121 arranged in a straight line, while Group B includes 3 holes 121' arranged in a straight line. Among them, the aperture of the 3 holes 121' included in Group B is d', and the aperture of the holes 121 included in Group A and Group B is d, where d'≠d.

[0097] In some embodiments of the present invention, as Figure 8 , Figure 12 and Figure 13 shown, the outlet jet velocity v' of the hole 121' located at the center of the second end 120 is different from the outlet jet velocity v of the other holes 121 among the multiple 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 multiple 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 Figure 14 and Figure 15 shown, there are three groups of holes 121, namely Group A, Group B, and Group C, arranged on the second end 120. Among them, both Group A and Group C include 2 holes 121 arranged in a straight line, while Group B includes 3 holes 121' arranged in a straight line. Among them, the outlet jet velocity of the 3 holes 121' included in Group B is v2, and the outlet jet velocity of the holes 121 included in Group A and Group B is v1, where v2≠v1.

[0100] In some embodiments of the present invention, the multiple holes 121 on the second end 120 are arranged in a circular pattern; preferably, the multiple holes 121 are arranged in a circular pattern centered on the center or center of the second end 120.

[0101] In one embodiment of the present invention, as Figure 16 and Figure 17 shown, by way of example, Figure 16 shows that there are 3 holes 121 arranged on the second end 120, and the 3 holes 121 are arranged in a circular pattern centered on the center O of the second end 120.

[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 circular pattern. Preferably, the multiple groups of holes 121 are arranged in a coaxial circular pattern with each other.

[0103] In one embodiment of the present invention, as Figure 18As shown, there are two groups of holes 121, namely Group A and Group B, arranged on the second end 120. Among them, both Group A and Group B are arranged in a circular pattern and are coaxially arranged in a circular pattern with the center O of the second end 120 as the center of the circle.

[0104] In an embodiment of the present invention, as Figure 19 and Figure 20 shown, there are two groups of holes 121, namely Group A and Group B, arranged on the second end 120. Among them, both Group A and Group B are arranged in a circular pattern and are coaxially arranged in a circular pattern with the center of the second end 120 as the center of the circle. Among them, the aperture of the three holes 121' included in Group B is d', and the aperture of the holes 121 included in Group A is d, where d'≠d; and in Figure 19 the configuration shown, the apertures of the holes 121 of Group A and Group B arranged coaxially in a circular pattern decrease radially outward, that is: d' > d, while in Figure 20 the configuration shown, 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 a circular pattern has an outlet jet velocity different from that of other holes;

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

[0107] In some embodiments of the present invention, the outlet jet velocities of the plurality of groups of holes 121 arranged coaxially in a circular pattern 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 an embodiment of the present invention, as Figures 21 to 24 shown, there is 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 arranged on the second end 120.

[0110] In an embodiment of the present invention, as Figure 21 shown, there is a central hole 121” located at the center (center) of the second end and two peripheral holes 121 located around the central hole arranged on the second end 120.

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

[0112] In some embodiments of the present invention, as Figures 22 to 24 shown, 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 Figure 24 shown, there are multiple groups of the peripheral holes 121, and each group of the peripheral holes 121 is arranged in a ring. Preferably, as Figure 24 shown, the multiple groups of the peripheral holes 121 are arranged in a coaxial annular pattern around the central hole 121”.

[0114] In one embodiment of the present invention, as Figure 24 shown, 6 peripheral holes 121 are provided on the second end 120, and the 6 peripheral holes 121 are divided into two groups, namely group A and group B, which are evenly arranged in a ring. Among them, each of group A and group B contains 3 peripheral holes 121, and the two groups of peripheral holes 121 are arranged in a coaxial annular pattern around the central hole 121”.

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

[0116] In one embodiment of the present invention, as Figures 25 to 26 shown, 1 central hole 121” with an aperture of d” and 3 peripheral holes 121 with an aperture of d are provided on the second end 120, where d”≠d. In the configuration shown in Figure 25 d”<d, while in the configuration shown in Figure 26 d”>d.

[0117] In another embodiment of the present invention, as Figures 27 to 29 shown, 1 central hole 121” with an aperture of d” and 6 peripheral holes 121 with an aperture of d are provided on the second end 120, where d”≠d, and the 6 peripheral holes 121 are divided into two groups, namely group A and group B, which are evenly arranged in a ring. Among them, each of group A and group B contains 3 peripheral holes 121, and the two groups of peripheral holes 121 are arranged in a coaxial annular pattern around the central hole 121”.

[0118] In some embodiments of the present invention, the aperture d1 of at least one group of the multiple groups of peripheral holes 121 is different from the aperture d2 of other peripheral hole groups. In some embodiments of the present invention, the apertures of the multiple groups of holes 121 and the central hole 121” that are arranged in a coaxial annular pattern increase or decrease radially.

[0119] As Figure 28 and Figure 29 shown, the 3 peripheral holes 121 included in group A have an aperture of d1, while the 3 peripheral holes 121 included in group B have an aperture of d2, and d1≠d2. InFigure 28 In the configuration shown, d1 > d2, while in Figure 29 the configuration shown, d1 < d2. Figure 28 and Figure 29 As further shown, the aperture of the one central hole 121” is d”, 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 Figure 28 the configuration shown, the apertures of the A and B holes 121 and the central hole 121” arranged coaxially and annularly with each other decrease radially outward, that is: d” > d1 > d2, while in Figure 29 the configuration shown, the apertures of the A and B holes 121 and the central hole 121” arranged coaxially and annularly with each other 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 the plurality of groups of peripheral holes 121 is different from the outlet jet velocity v2 of the other peripheral groups of holes 121.

[0122] In some embodiments of the present invention, the outlet jet velocities of the plurality of groups of holes 121 and the central hole 121 arranged coaxially and annularly with each other increase or decrease radially.

[0123] It can be understood 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 made here.

[0124] In some embodiments of the present invention, the channel shape of the plurality of holes 121 is cylindrical or conical or streamlined.

[0125] 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 triple vaccine against feline rhinotracheitis, calicivirus disease, and panleukopenia. Thus, the embodiments of the present application also provide corresponding drug-device combination products. In the embodiments of the present invention, the drug-device combination products can include or can be a drug delivery system. In the embodiments of the present invention, the triple vaccine is, for example, a feline triple vaccine.

[0126] In an embodiment of the present invention, the feline triple vaccine refers to an inactivated vaccine for preventing common infectious diseases in cats. It can prevent feline rhinotracheitis, feline calicivirus disease, and feline panleukopenia. These three diseases are the most common infectious diseases in cats. When the feline triple vaccine was developed, dominant epidemic strains of three feline infectious diseases were screened from a large number of clinical samples. Therefore, it has the characteristics of good safety, rapid antibody production, long immune duration, and prevention of three diseases with one injection. It is applicable to cats over 8 weeks old, and generally, three doses of the basic immunization vaccine need to be administered at 8 weeks, 12 weeks, and 16 weeks of age. After completing the basic immunization, one booster dose should be administered annually to maintain the immune effect.

[0127] In some embodiments of the present invention, on the second end 120 of the needleless delivery device used in combination with the feline triple vaccine, there are 3 holes 121 arranged in an equidistant circular pattern around the center of the second end 120. The distance between the centers of the three holes 121 and the center of the second end 120 is 1.25 mm ± 20%.

[0128] In some embodiments of the present invention, the pushing speed of the piston 210 of the needleless 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 needleless delivery device used in combination with the feline triple vaccine is configured such that the exit jet velocity of the feline triple vaccine when it is 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 needleless 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 needleless delivery device used in combination with the feline triple vaccine is configured such that the average antibody titer 14 days after the second dose of the feline triple vaccine 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 an embodiment of the present invention, the average antibody titer is an index to measure the intensity of the immune response and is used to evaluate the antibody level produced by an organism against a specific antigen (such as a virus, bacterium, or vaccine). It is expressed as the average value of the serum dilution multiples that can neutralize or bind a certain amount of antigen under specific conditions. In other words, the higher the average antibody titer, the stronger the ability of the antibodies produced by the organism to fight against specific pathogens.

[0133] 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 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 that of the average antibody titer of intramuscular injection.

[0134] 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 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 that of the average antibody titer of intramuscular injection.

[0135] 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 average antibody titer of the feline triple vaccine 60 days after the second dose of 60% of the vaccine dose is more than 1.1 times, preferably more than 1.5 times, and more preferably more than 2.0 times that of the average antibody titer produced by 100% of the vaccine dose of intramuscular injection.

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

[0137] In the embodiments of the present invention, the hepatitis B vaccine refers to the recombinant hepatitis B yeast vaccine (Hansenula) used to prevent hepatitis B (a viral liver disease), which is prepared by purifying the hepatitis B virus surface antigen (HBsAg) expressed by recombinant Hansenula yeast, adding aluminum adjuvant, and the active ingredient is the hepatitis B virus surface antigen. The vaccine is suitable for hepatitis B susceptible individuals, especially the following persons: (1) newborns, especially those whose mothers are positive for HBsAg and HBeAg, (2) hepatitis B susceptible individuals aged 16 and above, (3) medical staff engaged in medical work and laboratory personnel exposed to blood. After vaccination, it can stimulate the immune system to produce protective antibodies, so that the human body has immunity to prevent hepatitis B infection, so as to achieve the purpose of preventing hepatitis B infection. The conventional immunization site is intramuscular injection in the deltoid muscle of the upper arm. The immunization schedule is 3 injections, which are administered once at birth (0 month), 1-2 months of age, and 6-18 months of age respectively. The first injection is given to newborns within 24 hours after birth, and 1 dose is injected each time.

[0138] In some embodiments of the present invention, three holes 121 are arranged in an equally spaced circular arrangement around the center of the second end 120 on the second end 120 of the needle-free delivery device used in combination with the hepatitis B vaccine, and the distance between the three holes 121 and the center of the second end 120 is 1.25 mm ± 20%.

[0139] In some embodiments of the present invention, the pushing speed of the piston 210 of the needleless 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 needleless delivery device used in combination with the hepatitis B vaccine is configured such that the outlet jet velocity when the hepatitis B vaccine is 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 needleless delivery device used in combination with the hepatitis B vaccine is configured such that the dispersion volume of the hepatitis B vaccine in the body is more than 1.5 times the undelivered volume of the hepatitis B vaccine.

[0142] In some embodiments of the present invention, the needleless delivery device used in combination with the hepatitis B vaccine is configured such that the average antibody titer of the hepatitis B vaccine 14 days after 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 of intramuscular injection.

[0143] In some embodiments of the present invention, the needleless delivery device used in combination with the hepatitis B vaccine is configured such that the average antibody titer of the hepatitis B vaccine 42 days after 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 of intramuscular injection.

[0144] In some embodiments of the present invention, the needleless delivery device used in combination with the hepatitis B vaccine is configured such that the average antibody titer of the hepatitis B vaccine 42 days after injecting 60% of the vaccine dose 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 injecting 100% of the vaccine dose by intramuscular injection.

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

[0146] In some embodiments of the present invention, any of the needleless delivery devices in the above embodiments of the present invention can also be used in combination with a human pneumococcal vaccine in a drug delivery system.

[0147] In an embodiment of the present invention, the pneumococcal vaccine is mainly a vaccine for preventing pneumonia caused by Streptococcus pneumoniae and can induce humoral immunity in the body. It is applicable to high-risk healthy people over 6 weeks old to prevent pneumococcal pneumonia and systemic pneumococcal infections caused by various serotypes included in this vaccine, and can be administered subcutaneously or intramuscularly in the deltoid muscle on the outer side of the upper arm, with each injection being 0.5 ml.

[0148] In some embodiments of the present invention, three holes 121 are provided on the second end 120 of the needleless delivery device for use in combination with a human pneumonia vaccine, which are arranged in an equidistant annular pattern around the center of the second end 120. The distance between the centers of the three holes 121 and the center of the second end 120 is 1.25 mm ± 20%.

[0149] In some embodiments of the present invention, the pushing speed of the piston 210 of the needleless delivery device for use 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 needleless delivery device for use in combination with a human pneumonia vaccine is configured such that the exit jet velocity of the human pneumonia vaccine when it is 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 needleless delivery device for use in combination with a human pneumonia vaccine is configured such that the dispersion 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 needleless delivery device for use in combination with a human pneumonia vaccine is configured such that the average antibody titer of the human pneumonia 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.

[0153] In some embodiments of the present invention, the needleless delivery device for use in combination with a human pneumonia vaccine is configured such that the average antibody titer of the human pneumonia vaccine 42 days after 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 of intramuscular injection.

[0154] In some embodiments of the present invention, the needleless delivery device for use in combination with a human pneumonia vaccine is configured such that the average antibody titer of the pneumonia 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 100% of the vaccine dose of intramuscular injection.

[0155] In some embodiments of the present invention, any of the needleless delivery devices in the above embodiments of the present invention can also be used in combination with GLP-1 polypeptides. Accordingly, the embodiments of the present application also provide corresponding drug-device combination products. In the embodiments of the present invention, the drug-device combination products can include or can be a drug delivery system.

[0156] In some embodiments of the present invention, the second end 120 of the needleless delivery device used in combination with GLP-1 polypeptides is provided with three holes 121, and the three holes 121 are arranged in an equally spaced circular pattern around the center of the second end 120, and the distance of the three holes from the center is 1.25 mm ± 20%.

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

[0158] In some embodiments of the present invention, the needleless delivery device used in combination with GLP-1 polypeptides is configured such that the exit jet velocity of the GLP-1 polypeptides when being pushed away from the holes 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 needleless delivery device used in combination with GLP-1 polypeptides is configured such that the diffusion volume of the GLP-1 polypeptides in the body is more than 1.5 times the undelivered volume of the GLP-1 polypeptides.

[0160] In some embodiments of the present invention, the GLP-1 polypeptides include semaglutide, and any of the needleless delivery devices in the above embodiments of the present invention can also be used in combination with semaglutide. Thus, the embodiments of the present application also provide corresponding drug-device combination products. In the embodiments of the present invention, the drug-device combination products can include or can be drug delivery systems.

[0161] In some embodiments of the present invention, the needleless 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 undelivered volume of the semaglutide.

[0162] In some embodiments of the present invention, the needleless delivery device used in combination with semaglutide is configured such that the effect of semaglutide on reducing the body weight of humans and animals is consistent with that of needle injection, preferably the weight reduction effect is increased by more than 2% compared with needle injection, more preferably increased by more than 5%, and still more preferably increased by more than 10%.

[0163] In some embodiments of the present invention, the needleless delivery device used in combination with semaglutide is configured such that the body weight reduction endpoint of the semaglutide in the body is consistent with that of needle injection, preferably increased by more than 2%, more preferably increased by more than 5%, and still 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 such that the proportion of side effects such as nausea, vomiting, and abdominal distension caused by semaglutide is the same as that of needle injection, preferably reduced by more than 5%, further preferably reduced by more than 10%, and still more preferably reduced by more than 20%.

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

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

[0167] In some embodiments of the present invention, optionally, the pharmaceutical preparation is an animal rabies vaccine.

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

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

[0170] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a human COVID-19 vaccine.

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

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

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

[0174] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a human HPV vaccine.

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

[0176] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a human tumor nuclear medicine treatment drug.

[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 porcine diarrhea bivalent vaccine. In some embodiments of the present invention, the porcine diarrhea bivalent vaccine may include a live bivalent vaccine against transmissible gastroenteritis of swine and porcine epidemic diarrhea (HB08 strain + ZJ08 strain). In some embodiments of the present invention, the porcine diarrhea bivalent vaccine may include an inactivated bivalent vaccine against transmissible gastroenteritis of swine and porcine epidemic diarrhea.

[0179] In some embodiments of the present invention, the pharmaceutical preparation is a porcine reproductive and respiratory syndrome inactivated vaccine. In some embodiments of the present invention, the porcine reproductive and respiratory syndrome inactivated vaccine may include a porcine reproductive and respiratory syndrome inactivated 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 an inactivated vaccine against foot-and-mouth disease O type for pigs (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 a bivalent inactivated vaccine against foot-and-mouth disease O type and A type for pigs (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 an inactivated vaccine against foot-and-mouth disease O type (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 a bivalent inactivated vaccine against foot-and-mouth disease O type and A type (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 vaccine against foot-and-mouth disease O type and A type (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 an inactivated bivalent vaccine against bovine viral diarrhea / mucosal disease and infectious bovine rhinotracheitis (NMG strain + LY strain).

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

[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-based cosmetic drug for medical aesthetics.

[0185] In some embodiments of the present invention, there is also provided the use of the needle-free delivery device described in any one of the above embodiments of the present invention in the preparation of human clinical medical and animal health care 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 human pneumococcal vaccine.

[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 human rabies vaccine.

[0191] In some embodiments of the present invention, optionally, the pharmaceutical preparation is an animal rabies vaccine.

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

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

[0194] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a human COVID-19 vaccine.

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

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

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

[0198] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a human HPV vaccine.

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

[0200] In some embodiments of the present invention, optionally, the pharmaceutical preparation is a human tumor nuclear medicine treatment drug.

[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 porcine diarrhea bivalent vaccine.

[0203] In some embodiments of the present invention, the pharmaceutical preparation is a porcine reproductive and respiratory syndrome inactivated 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 multocida 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-based cosmetic drug for medical aesthetics.

[0209] Embodiments of the present invention further provide a pharmaceutical device combination product, including a needle-free delivery device and a pharmaceutical preparation 300. In embodiments of the present invention, the pharmaceutical device combination product may include or may be a drug delivery system.

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

[0211] A tube 100 for accommodating the pharmaceutical preparation 300, the tube 100 having a first end 110 and a second end 120, and a single hole 124 for dispensing the pharmaceutical preparation 300 in the tube is provided in the second end 120; and

[0212] A power mechanism 200, the power mechanism 200 includes a piston 210 capable of pushing the pharmaceutical preparation 300 provided in the first end 110 of the tube 100 or the power mechanism 200 is operably connected to the piston 210 to apply a delivery pressure to the piston 210 that pushes the pharmaceutical preparation 300;

[0213] Wherein, the needle-free delivery device is configured such that the diffusion volume of the pharmaceutical preparation 300 in the body is more than 1.5 times the undelivered volume.

[0214] In some embodiments of the present invention, as Figure 31As shown, the second end 120 of the needleless delivery device may further have a tapered section 122 that tapers axially distally from the tube 100, and a single hole 124 is provided on the end face 123 of the tapered section 122. The end face 123 is configured to be circular. The needleless delivery device is configured such that the diffusion volume of the pharmaceutical formulation 300 in the body is more than 1.50 times the undelivered volume.

[0215] In some embodiments of the present invention, as Figure 30 and Figure 31 shown, the piston 210 may be provided as an independent component, and the power mechanism 200 is configured to be operably connected to the piston 210 to apply a delivery pressure to the piston 210. It is also conceivable that in some other embodiments of the present invention, the power mechanism 200 may be integrally integrated with the piston 210 and apply a 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 use compressed gas, such as compressed nitrogen or compressed carbon dioxide gas for driving, may also use a compressed mechanical spring for driving, and may also be driven by a piezoelectric actuating device, which is not limited herein.

[0217] In some embodiments of the present invention, the needleless delivery device is configured such that the diffusion volume of the pharmaceutical formulation 300 in the body is greater than the volume of the undelivered pharmaceutical formulation 300 or the volume of the pharmaceutical formulation 300 delivered by a needle. Preferably, the diffusion volume of the pharmaceutical formulation 300 in the body 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 still more preferably more than 3.60 times.

[0218] In some embodiments of the present invention, compared with manual needle injection (the pushing speed of the piston inside the needle tube is about 0.01 m / s), the piston speed of the piston 210 of the needleless delivery device of the present invention when pushing the pharmaceutical formulation 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 still 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 pharmaceutical formulation 300. 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 pharmaceutical preparation 300 passing through the single hole 124 diffuses in at least one of the dermis, epidermis, subcutaneous tissue, muscle, and human organs; the magnitude of the second delivery pressure F2 is configured such that the jet of the pharmaceutical preparation 300 passing through the single hole 124 diffuses in another of the dermis, epidermis, subcutaneous tissue, muscle, and human organs;

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

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

[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 human pneumococcal vaccine;

[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 human tumor vaccine, including but not limited to polypeptide vaccines, mRNA vaccines, and DNA vaccines.

[0228] By configuring the needleless delivery device of the present invention, the components of the needleless delivery device and the related drug-device combination device, and by controlling the flow rate, delivery depth, and dispersion degree of the drug and vaccine jets, at least one of the following problems is solved or improved, or at least one of the following technical effects is achieved:

[0229] (1) The needle-free delivery device of the embodiments of the present invention uses multiple pores for needle-free delivery. Compared with traditional single-pore needle-free injection, the present invention uses the setting of multiple pores to significantly increase the delivery amount of the delivery substance while not causing harm to the skin. In particular, it increases the single-dose delivery amount of drugs and vaccines, and has a delivery efficiency far higher than that of existing single-pore needle-free delivery, and can meet a wider range of application scenarios.

[0230] (2) The needle-free delivery device of the embodiments of the present invention uses multiple pores for needle-free delivery. By optimizing the number and pore diameter of the multiple pores, the diffusion volume of the delivery substance, especially drugs and vaccines in the body, is significantly increased. Furthermore, the contact effect between the delivered drugs and vaccines and the tissues in the body is increased, and the bioavailability of drugs and vaccines is significantly improved.

[0231] (3) The needle-free delivery device of the embodiments of the present invention controls the jet flow of the delivery substance ejected from the multiple pores, especially the jet flow velocity of the drug and vaccine jets, to achieve precise control of the delivery depth of the delivered drug or vaccine, and to accurately deliver it to the specified target position in the dermis, subcutaneous tissue, muscle or human organ through high-speed jet flow according to the characteristics of the drug and vaccine.

[0232] (4) The needle-free delivery device of the embodiments of the present invention configures the jet flow velocities of different pores in the multiple pores to simultaneously and accurately deliver the delivery substance to at least one or more target positions or target areas in the dermis, subcutaneous tissue, muscle or human organ.

[0233] (5) The needle-free delivery device of the embodiments of the present invention controls the pore diameter and arrangement mode of the multiple pores to achieve different diffusion effects of the delivery substance, especially drugs or vaccines at the delivery position. In particular, it realizes the control of the diffusion volume ratio, diffusion breadth and diffusion center at the target position or target area, and can achieve specific diffusion effects according to different delivery requirements.

[0234] (6) The parts and receptor types for which the needle-free delivery device of the embodiments of the present invention delivers drugs and vaccines are not limited, and it can be widely used for the delivery of drugs and vaccines for human and veterinary use.

[0235] Based on the above problems solved and / or achieved effects, the present invention is also used in combination with feline triple vaccine, hepatitis B vaccine, human pneumonia vaccine, GLP-1 polypeptides, especially semaglutide, to achieve further technical effects as described in the embodiments of the present invention.

[0236] Example 1

[0237] Now refer to Figures 32 to 33, which shows one of the structural configurations of the needleless delivery device according to an embodiment of the present invention. Specifically, the second end 120 has a tapered section 122 that gradually narrows axially and distally from the tube 100, and three holes 121 are provided on the end face 123 of the tapered section 122. The end face 123 is configured as a circle with a diameter of 2.5 mm. The three holes 121 are arranged in an equally spaced circular pattern around the center of the end face 123. The adjacent connecting lines between the three holes and the center of the end face 123 form an angle of 120°. The diameters of the three holes 121 are uniformly set to d, and the distances from the centers of the three holes 121 to the center of the end face 123 are uniformly set to l.

[0238] Now referring to Figure 34 , under the above structural configuration of the needleless delivery device, an embodiment of the present invention uses the ANSYS workbench Fluent module shown in Figure 34 to build a needleless injection dispersion and penetration simulation model. When the power mechanism 200 applies a delivery pressure of 400 N to the fluid 130 contained in the tube 100, the ANSYS workbench Fluent module is used to simulate the dispersion of the fluid 130 in the body 140 by using a multiphase flow model. Among them, the volume of the fluid 130 to be delivered is 0.2 cm3, the viscosity is 1 cp, the calculation method of the needleless injection dispersion and penetration simulation model adopts transient, the multiphase flow model selects the Euler model (Eulerian), the viscosity model selects the K-epsilon Realizable model, the body 140 model is set as a porous medium, and the initialization method adopts hybrid initialization.

[0239] Under the above structure and simulation parameters, the diameter d of the three holes 121 and the distance l from the centers of the three holes 121 to the center of the end face 123 are further configured, and the following data on the dispersion degree of the porous needleless delivery fluid under different configurations are obtained:

[0240] Table 1. Data table of the dispersion degree of the porous needleless delivery fluid

[0241]

[0242] Combined with Table 1 above and Figures 35 to 37 shown, it shows the dispersion effect achieved by the needleless delivery device according to an embodiment of the present invention by using the multiple holes 121. The present invention realizes different dispersion degrees of the fluid 130 in the body 140, so that the fluid jets of the fluid 130 passing through the multiple holes 121 achieve different dispersion volume ratios, dispersion depths and dispersion breadths in the body 10. Among them, Figure 35 shows the dispersion effect diagram when d = 0.15 mm and l = 0.65 mm, Figure 36 shows the dispersion effect diagram when d = 0.575 mm and l = 0.65 mm, Figure 37The diffusion effect diagram at d = 1.00 mm and l = 0.65 mm is shown.

[0243] Meanwhile, as Figures 35 to 37 shown, when the needleless delivery device of the embodiment of the present invention delivers fluid into the body, due to the different diffusion volume ratios, diffusion depths, and diffusion breadths of the fluid in the body, the above-mentioned fluid will also have different diffusion centers and diffusion edge densities in the body.

[0244] Compared with the needleless delivery of the control group, the needleless delivery device of the embodiment of the present invention enables the diffusion volume of the delivery fluid 130 in the simulated body 140 to be 2.09 to 2.77 times that before delivery, achieving a better diffusion effect for the delivery fluid. In other words, more sufficient contact between the delivery fluid and the target site in the body is achieved.

[0245] Embodiment 2

[0246] Now refer to Figures 32 to 33 , which shows one structural configuration of the needleless delivery device of the embodiment of the present invention. Specifically, the second end 120 has a narrowing section 122 that gradually narrows axially and distally from the tube 100. The end face 123 of the narrowing section 122 is configured as a circle with a diameter of 5 mm, and a central hole 121” located at the center (center) of the end face 123 and three peripheral holes 121 located around the central hole 121” are provided thereon. The three peripheral holes 121 are arranged in an equally spaced circular pattern around the center of the end face 123. The included angle between the adjacent connecting lines of the three peripheral holes 121 and the center (center) of the end face 123 is 120°. Among them, the aperture of the central hole 121” is d”, the apertures of the three peripheral holes 121 are uniformly set to d, and d”≠d. The distance from them to the center of the end face 123 is uniformly set to 1.1 mm.

[0247] Now refer to Figure 34 , under the above structural configuration of the needleless delivery device, the embodiment of the present invention uses the ANSYS workbench Fluent module shown in Figure 34 to build a needleless injection diffusion and penetration simulation model. When the power mechanism 200 applies a delivery pressure of 400 N to the fluid 130 contained in the tube 100, the diffusion situation of the fluid 130 in the body 140 is simulated. Among them, the viscosity of the fluid 130 to be delivered is 1 cp. The calculation method of the needleless injection diffusion and penetration simulation model adopts a transient state. The multiphase flow model selects the Euler model (Eulerian), the viscosity model selects the K-epsilon Realizable model, the body 140 model is set as a porous medium, and the initialization method adopts hybrid initialization.

[0248] Under the above structure and simulation parameters, further configure the aperture d" of the central hole 121" and the aperture d of the 3 peripheral holes 121. When the delivered fluid volume is 0.1 cm 3 , 0.2 cm 3 and 0.3 cm 3 , three groups of simulated experimental fluids are carried out to obtain the following porous needleless delivery fluid dispersion data:

[0249] Table 2. Group 1 - Data table of porous needleless delivery fluid dispersion

[0250]

[0251] Note: The volume of the fluid to be delivered in this group is 0.1 cm 3 .

[0252] Table 3. Group 2 - Data table of porous needleless delivery fluid dispersion

[0253]

[0254] Note: The volume of the fluid to be delivered in this group is 0.2 cm 3 .

[0255] Table 4. Group 3 - Data table of porous needleless delivery fluid dispersion

[0256]

[0257] Note: The volume of the fluid to be delivered in this group is 0.3 cm 3 .

[0258] Combined with Table 2 to 4 above and Figures 38 to 39 shown, it shows the dispersion effect achieved by the needleless delivery device of an embodiment of the present invention using multiple holes 121. Through the setting of the central hole 121" and 3 peripheral holes 121, the fluid jet of the fluid 130 passing through the multiple holes achieves a significantly enhanced dispersion effect compared with the single-hole needleless delivery. Specifically, the needleless delivery device of the embodiment of the present invention enables the dispersion volume of the delivered fluid 130 in the simulated body 140 to be 2.35 to 3.61 times that before delivery. At the same time, as can be seen from Table 2 above and Figure 39 , in the case of 0.1 cm, the needleless delivery device of the present invention achieves a significantly better dispersion breadth than the single hole, and achieves a significantly enhanced dispersion effect on the delivered fluid. In other words, it realizes a more sufficient contact between the delivered fluid and the target site in the body.

[0259] Example 3

[0260] Now refer to Figures 32 to 33, which shows one of the structural configurations of the needleless delivery device according to an embodiment of the present invention. Specifically, the second end 120 has a narrowed section 122 that axially narrows distally from the tube 100. The end face 123 of the narrowed section 122 is configured to be circular with a diameter of 2.5 mm, and three holes 121 are provided thereon. The three holes 121 are arranged in an equally spaced circular pattern around the center of the end face 123. An angle of 120° is formed between the adjacent connecting lines of the three holes and the center (center) of the end face 123. Among them, the aperture diameters of the three holes 121 are uniformly set to 0.15 mm, and the distances from the centers of the three holes 121 to the center of the end face 123 are uniformly set to 1.1 mm.

[0261] Under the above structural configuration of the needleless delivery device, in a specific embodiment of the present invention, a delivery fluid with a viscosity of 1 cp and a volume of 0.2 cm 3 was used for testing to obtain the displacement change curve of the piston 210 of the needleless 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 plurality of holes 121 were obtained as follows:

[0262] Table 5. Data table of piston speed and jet speed

[0263]

[0264] As can be seen from the above table, in a specific embodiment, the needleless delivery device of the present invention is configured such that the average speed of the jets ejected from the plurality of holes 121 is greater than 135 m / s, and the maximum can reach 156 m / s.

[0265] Example 4

[0266] In a specific embodiment of the present invention, the needleless delivery device of the present invention is used in combination with a feline triple vaccine. Refer to Figures 32 to 33 , which shows one of the structural configurations of the needleless delivery device of the present invention used in combination with a feline triple vaccine. Specifically, the second end 120 has a narrowed section 122 that axially narrows distally from the tube 100. Among them, the diameter of the tube is 5 mm. The end face 123 of the narrowed section 122 is configured to be circular with a diameter of 2.5 mm, and three holes 121 are provided thereon. The three holes 121 are arranged in an equally spaced circular pattern around the center of the end face 123. An angle of 120° is formed between the adjacent connecting lines of the three holes and the center of the end face 123. The measured aperture diameters of the three holes 121 are 0.14 mm to 0.17 mm, and the distances from the centers of the three holes 121 to the center of the end face 123 are uniformly set to 1.25 mm.

[0267] In the embodiments 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 605 strains of inactivated feline rhinotracheitis virus, 255 strains of feline calicivirus, and Cu-4 strain of panleukopenia virus. The R.P. 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 for inoculating healthy cats at 8 weeks of age or older, and can be administered subcutaneously, 1 ml per cat each time; for healthy cats at 8 weeks of age or older, a booster immunization should be carried out 3 to 4 weeks after the first inoculation, with 1 dose; for cats inoculated at less than 12 weeks of age, a booster dose of 1 dose should be given at 12 to 16 weeks of age to ensure long-lasting immune protection. The feline triple vaccine should be repeatedly inoculated with 1 dose annually to maintain immunity.

[0268] The following is a specific immune evaluation test of the needle-free delivery device of the present invention. Among them, under the structural configuration of the needle-free delivery device of the present invention described above, a needle-free injection immune evaluation test for feline vaccines was carried out according to the following test protocol:

[0269] 1. Test materials

[0270] 1.1. Test animals: 27 healthy cats were used as experimental animals. Among them, the 27 cats were all negative for FPV, FHV, and FCV antigens, and the neutralizing antibody titers of 2 / 3 of them were not higher than 1:4 and they had no immunization history with the feline triple vaccine.

[0271] 1.2. Delivered vaccine: A triple inactivated vaccine for feline rhinotracheitis, calicivirus disease, and panleukopenia (trade name: Miao San Duo, batch number: E071201A) produced by Zoetis.

[0272] 1.3. Neutralizing antigen for detection: FPV virus solution, FCV virus solution, and FHV virus solution with a virus content of 200 TCID50 / 0.1 ml were selected.

[0273] 1.4. Cells for detection: CRFK cells or F81 cells were used.

[0274] 1.5. Test equipment: The needle-free delivery device according to the above embodiments of the present invention (delivery pressure: 330 N, pore diameter: 0.14 mm to 0.17 mm); traditional 1 ml syringe, 10 ml syringe, medical cotton swabs, and alcohol cotton.

[0275] 1.6. Test location: Animal hospital.

[0276] 2. Test method

[0277] 2.1 Animal screening: Nasal swabs (superficial collection is possible), oral swabs, and anal swabs were collected from each of the 37 healthy cats and placed in centrifuge tubes containing 1 ml of PBS; antigen detection was performed according to the methods in Annex 1-3; 2-3 ml of blood was collected from each healthy cat, serum was separated, and neutralizing antibody detection was carried out.

[0278] 2.2 Animal grouping: After the screened healthy cats entered the test site, they were allowed to adapt to the environment for 7 days, and the cat food was gradually transitioned. Then, according to the gender, age, breed, or antibody data of the healthy cats, they were evenly divided into 3 groups of 7 cats each, numbered and respectively recorded as experimental groups 1, 2, and 3; another 6 healthy cats were set as sentinel animals without immunizing with feline triple vaccine, recorded as experimental group 4.

[0279] 2.3 Preparation before immunization: 2-3 days before immunization, the injection sound was played in the test site for 10-15 minutes every day, and at the same time, the cats could be allowed to autonomously contact and smell the odor of the needle-free delivery device and electric hair clipper of the present invention. 1 day or 2 hours before injection, the injection site of the test cats was shaved, and the diameter of the shaved area was about 1 cm; 1-2 inoculation personnel were arranged.

[0280] 2.4 Immunization

[0281] The foregoing groups 1, 2, and 3 were immunized, among which:

[0282] Group 1: Immunization was performed using conventional needle injection, a disposable 1 ml syringe with a needle hole diameter of 0.45 mm; the immunization dose each time was 1 ml.

[0283] Group 2: Immunization was performed using a three-hole needle-free injection, a needle-free syringe, a single-hole injection needle, multi-hole injection, with a needle hole diameter of 0.14 mm - 0.17 mm; the immunization dose each time was 1 ml.

[0284] Group 3: Immunization was performed using needle-free multi-hole injection, a needle-free syringe, a single-hole injection needle, multi-hole injection, with a needle hole diameter of 0.14 mm - 0.17 mm; the immunization dose each time was 0.45 ml.

[0285] 6. Immunization information table

[0286]

[0287] Note: " / " indicates no operation.

[0288] 2.5 Sample collection: On the day of the first immunization and 21 days and 35 days after the first immunization, each cat was subjected to intravenous blood collection according to Table 5 above, the serum was separated and stored at -20 °C for later inspection. (If the immune response is particularly strong, consider collecting whole blood 1-2 weeks after 35 days).

[0289] Table 7. Sample collection schedule

[0290]

[0291] 3. Results after immunization

[0292] 3.1 Observation on the immunization day:

[0293] Conventional injection immunization group (Group 1): The experimental cats were listless and in low spirits;

[0294] Needle-free injection immunization groups (Groups 2 and 3), the experimental cats were lively.

[0295] 3.2 Results of neutralizing antibody titer determination

[0296] The neutralizing antibody titer was determined to obtain Table 7 and Table 8 below, which show the data tables of the antibody titer determination of each group under the above test conditions:

[0297] Table 8. Data table of antibody titer determination - 1

[0298]

[0299] Table 9. Data table of antibody titer determination - 2

[0300]

[0301] From Table 7 and Table 8 above and Figures 41 to 43 it can be seen that in the embodiments of the present invention, the delivery of feline triple vaccine using a needle-free delivery device including a plurality of holes 121 achieves the following compared with the traditional needle delivery:

[0302] a. For the needle-free three-hole immunization group using the needle-free delivery device of the present invention compared with the needle injection equivalent-dose immunization group, the onset time of the antibody of the needle-free three holes using the needle-free delivery device of the present invention is 1 time faster than that of the needle injection group;

[0303] b. It is found that under the same immunization dose, the antibody produced by needle-free three-hole immunization using the needle-free delivery device of the present invention is 25 times higher than that produced by the needle injection conventional immunization group;

[0304] c. For the needle-free three-hole dose halved group using the needle-free delivery device of the present invention compared with the needle injection conventional immunization group, the antibody value is 2.4 times higher.

[0305] Example 5

[0306] In a specific embodiment of the present invention, the needle-free delivery device of the present invention is used in combination with hepatitis B vaccine, referring to Figures 32 to 33, which shows one of the structural configurations of the needleless delivery device of the embodiments of the present invention in combination with the hepatitis B vaccine. Specifically, the second end 120 has a narrowed section 122 that axially narrows distally from the tube 100. The diameter of the tube is 5 mm, and the end face 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 thereon. The three holes 121 are arranged in an equally spaced circular pattern around the center of the end face 123. The adjacent connecting lines between the three holes and the center of the end face 123 form an angle of 120°. The measured aperture of the three holes 121 is 0.14 mm to 0.17 mm, and the distance from the center of the end face 123 to the three holes 121 is uniformly set to 1.25 mm.

[0307] In the embodiments of the present invention, the hepatitis B vaccine refers to the recombinant hepatitis B yeast vaccine (Hansenula polymorpha) used for preventing hepatitis B (a viral liver disease), which is prepared by purifying the hepatitis B virus surface antigen (HBsAg) expressed by recombinant Hansenula polymorpha and adding aluminum adjuvant. The active ingredient is the hepatitis B virus surface antigen. The vaccine is suitable for people who are susceptible to hepatitis B, especially the following personnel: (1) newborns, especially those whose mothers are positive for HBsAg and HBeAg; (2) hepatitis B susceptible individuals aged 16 and above; (3) medical staff engaged in medical work and laboratory personnel who come into contact with blood. After vaccination, it can stimulate the immune system to produce protective antibodies, so that the human body has immunity to prevent hepatitis B, so as to achieve the purpose of preventing hepatitis B infection. The conventional immunization site is intramuscular injection in the deltoid muscle of the upper arm. The immunization program is 3 injections, which are administered once at birth (0 month), 1-2 months of age, and 6-18 months of age respectively. The first injection is given to newborns within 24 hours after birth, and 1 dose is injected each time.

[0308] The following is a specific immune evaluation test of the needleless delivery device of the present invention. Among them, under the structural configuration of the needleless delivery device of the present invention described above, the needleless injection immune evaluation test of the hepatitis B vaccine was carried out according to the following test plan:

[0309] 1. Preparation before the test

[0310] 1.1 Test materials: 64 male mice (strain: BALB / c) with a body weight of 17-19 g and an age of 3 to 4 weeks were selected. After being adapted to feeding for one week, blood was collected from them.

[0311] 1.2 Test equipment: According to the needleless delivery device of the above embodiments of the present invention, traditional needles, medical cotton swabs and alcohol cotton.

[0312] 2. Test method

[0313] 2.1 Animal grouping: The above 64 mice were divided into 8 groups of 8 mice each, including 6 experimental groups and 2 control groups.

[0314] Table 10. Grouping Table for Control Experiments

[0315]

[0316] 2.2. Blood Sampling Protocol:

[0317] Immunize mice according to the D0 / D21 immunization protocol, and collect blood and isolate serum on D0 / D28 / D35 / D42 after immunization.

[0318] At the start of the experiment: On the morning of the day when the experiment starts, use an electric razor and depilatory cream to shave the hair on the backs and legs of the mice. Before inoculation, collect blood from all mice by retro-orbital bleeding, and the blood collection volume is 0.2 ml per mouse.

[0319] After one injection: Give the second injection on the 21st day; conduct the second blood collection on the 28th day, collect peripheral blood from 10 mice in one group and spleens from 6 mice; conduct the third blood collection from all mice on the 35th day; conduct the fourth blood collection on the 42nd day for one group, collect peripheral blood from 10 mice and spleens from 6 mice.

[0320] 2.3. Neutralization Experiment

[0321] Adopt the micro-method and use the Karber method to calculate the neutralization endpoint (convert the serum dilution to logarithm), that is, the highest dilution of the serum that can protect 50% of the cells from the attack of 100 CCID50 virus is the antibody titer of the serum. The neutralizing antibody titer <1:4 is negative, and ≥1:4 is positive.

[0322] Operating procedure (fixed virus and diluted serum method):

[0323] (1) Inactivate the serum: Inactivate the serum to be tested at 56°C for 30 minutes

[0324] (2) Dilute the serum: Take the inactivated serum and dilute it with serum-free cell culture medium on a 96-well microplate. Start a series of two-fold dilutions from 1:4 (tentatively 1:4, 1:28, 1:56, 1:128, 1:256...), with 50 μL in each well, and 2 - 4 wells for each dilution.

[0325] (3) Neutralize: Add 50 μL of the diluted 200 TCID50 virus solution to each well, and incubate in a CO₂ incubator at 37°C for 2 h for neutralization.

[0326] (4) Add cell suspension: After 2 h of neutralization of serum and virus, take out the cell plate, add 0.1 mL / well of cell suspension (it is appropriate to grow into a monolayer in 24 h, generally 1 million - 1.5 million cells per milliliter), incubate in a CO₂ incubator, and judge after 72 h.

[0327] 2.4. Control Experiment

[0328] (1) Negative and positive serum controls: Set up 2 - 4 wells each. The antibody titers of the negative and positive controls should be valid.

[0329] (2) Virus recovery test: Dilute the 200 TCID50 virus solution to 0.1, 1, 10, 100 TCID50, with 2 - 4 wells for each dilution, 50 μL per well; add 50 μL of cell suspension. There should be no cytopathic effect (CPE) at 0.1 TCID50 and complete CPE at 100 TCID50, otherwise the experiment is not valid.

[0330] (3) Cell control: Set up 2 - 4 wells of normal cells without virus and serum. These control cells should maintain good morphology and characteristics.

[0331] 2.5. Result determination and calculation

[0332] Determination can only be carried out when the virus recovery test, positive, negative, and cell controls are all valid. If 100% CPE appears in the tested serum wells, it is judged negative; if more than 50% of the cells show protection, it is positive; calculate the results using the Karber method.

[0333] 3. Cellular level detection

[0334] Collect mouse spleens to measure the content of various T and B cells in mice.

[0335] 3.1. Detection of surface molecular markers of T lymphocytes:

[0336] Detect the surface molecular markers of T lymphocytes by flow cytometry. Place the refrigerated mouse spleen cells in a water bath at 37°C to thaw and prepare a single-cell suspension (1×107 cells / ml). Take 0.1 ml and put it into a falcon tube, add CD3-FITC Ab, CD4-PE Ab, CD8-PE Ab, place it in the dark at room temperature for 30 min, wash twice with PBS, and add 0.5 ml of PBS and mix. Use CELLQuest functional software to analyze the positive expression rates of the two parameters of CD3-FITC, CD4-pe, and CD8-pe of T lymphocytes and calculate the CD4 / CD8 ratio.

[0337] 3.2. Enzyme-linked immunosorbent assay:

[0338] After blood collection, the samples were placed for 24 hours, and the supernatants were collected from the ELISPOT plates and stored at -80 °C for enzyme-linked immunosorbent assay (ELISA) detection. The protein expression levels were detected using a Biotek enzyme-linked immunosorbent assay instrument at 450 nm. The absorbance values of each cytokine or chemokine were divided by the absorbance value of the sample before inoculation as the baseline control to obtain the fold change of cytokines and chemokines. T cells producing hepatitis B surface antigen-specific IFN-γ, IL-2, and IL-4 were analyzed by ELISPOT to evaluate the cellular immune response.

[0339] 3.2.1, Contents of the kit:

[0340] PVDF 96-well plates, stored at room temperature; 0.1 ml of capture antibody, stored at 4 °C; 0.1 ml of biotinylated detection antibody, stored at 4 °C; 15 μl of avidin alkaline phosphatase conjugate, stored at 4 °C; 0.25 g of bovine serum albumin, stored at 4 °C; 0.25 g of skim milk powder, stored at 4 °C; 11 ml of substrate buffer, stored at 4 °C; 11 ml of concentrated PBS (10X), stored at room temperature; 11 ml of concentrated washing buffer (200X), stored at room temperature.

[0341] 3.2.2 Preparation of reagents:

[0342] (1) Dilute 10 ml of phosphate-buffered saline (PBS, 10X) with 90 ml of distilled water;

[0343] (2) Dissolve 0.22 g of skim milk powder in 11 ml of diluted PBS to a final concentration of 2%;

[0344] (3) Dissolve 0.22 g of BSA in 22 ml of diluted PBS to a final concentration of 1%

[0345] (4) Dilute 10 ml of concentrated washing buffer (200X) with 1990 ml of distilled water;

[0346] (5) Dilute 10 μl of avidin alkaline phosphatase with 10 ml of PBS-1%, BSA

[0347] (6) Dilute 7 ml of alcohol with 3 ml of distilled water to a final concentration of 70%.

[0348] 3.2.3, Stimulation method:

[0349] Indirect method: First stimulate the cells in a 24-well plate or flask, and then place them in the pre-coated wells.

[0350] Dilute PBMC in culture medium (e.g., RPMI 1640 supplemented with 2 mM glutamate and 10% heat-inactivated fetal calf serum), containing 1 ng / ml PMA and 500 ng / ml ionomycin (Sigma, Saint Louis, MO). Add 2×10⁴ to 5×10⁴ cells to antibody-coated PVDF wells and incubate in an incubator for 10 - 15 hours. Incubation times for other stimulants may vary and should be optimized according to the amount of cytokine-producing cells in different cases.

[0351] 3.2.4, Eli-spot operation procedure:

[0352] (1). Incubate PVDF well plates with 100 μl of 70% alcohol for 10 minutes at room temperature.

[0353] (2). Pour off the alcohol and wash three times with 100 μl of PBS.

[0354] (3). Add 100 μl of capture antibody to 10 ml of PBS, mix, add 100 μl to each well, cover the plate, and incubate overnight at 4°C.

[0355] (4). Pour off the liquid and wash once with 100 μl of PBS.

[0356] (5). Add 100 μl of 2% skim milk in PBS (see reagent preparation) to each well, cover the plate, and incubate for 2 hours at room temperature.

[0357] (6). Tap gently over a sink and blotting paper to pour off the liquid.

[0358] (7). Wash three times with 100 μl of PBS, 3 minutes each time.

[0359] (8). Add 100 μl of cell suspension (containing appropriate amount of cells and corresponding concentration of stimulant) to each well. Cells can be pre-stimulated in vitro (indirect Eli-spot). Cover with a standard 96-well plate plastic lid and incubate in a 37°C CO₂ incubator for a certain period of time (15 - 20 hours). Do not shake or move the plate during this period.

[0360] (9). Tap gently over a sink and blotting paper to pour off the liquid.

[0361] (10). Add 100 μl of wash buffer to each well and incubate at 4°C for 10 minutes.

[0362] (11). Lyse the cells with pre-chilled ice water.

[0363] (12). Wash the wells eight times with 100 μl of wash PBST buffer, 4 minutes each time.

[0364] (13). Dilute 100 μl of the detection antibody in 10 ml of PBS-1% BSA. This is the amount for one plate. Add 100 μl of this liquid to each well, cover the plate lid, and incubate at 37 °C for 2 hours.

[0365] (14). Pour out the liquid and wash 5 times with 100 μl of the washing buffer.

[0366] (15). Dilute 10 μl of avidin alkaline phosphatase in 10 ml of PBS1% BSA for each plate. Add 100 μl of this liquid to each well, cover the plate lid, and incubate at 37 °C for 1 hour.

[0367] 4. Statistical analysis

[0368] Statistical analysis was performed using one-way ANOVA and t-tests (GraphPad Prism 8.0). The differences between groups were considered statistically significant. The data were expressed as the mean ± standard deviation (SD). A p-value < 0.05 was considered statistically significant.

[0369] 5. Final results

[0370] The needle-free delivery device of the present invention is configured such that the average antibody titer of the hepatitis B vaccine is more than 1.1 times that of the needle injection 14 days after the second dose is administered;

[0371] The needle-free delivery device of the present invention is configured such that the average antibody titer of the hepatitis B vaccine is more than 1.5 times that of the needle injection 42 days after the second dose is administered;

[0372] The needle-free delivery device of the present invention is configured such that the positive expression rate of T lymphocytes of the hepatitis B vaccine is more than 10% higher than that of the needle injection 42 days after the second dose is administered.

[0373] Example 6

[0374] 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, with semaglutide. Refer to Figures 32 to 33 , which shows one of the structural configurations of the needle-free delivery device of the present invention in combination with semaglutide. Specifically, the second end 120 has a tapered section 122 that tapers axially distally from the tube 100. The diameter of the tube is 5 mm. The end face 123 of the tapered section 122 is configured as a circle with a diameter of 2.5 mm and is provided with 3 holes 121 thereon. The 3 holes 121 are arranged in an equally spaced circular pattern around the center of the end face 123. The adjacent connecting lines between the 3 holes and the center of the end face 123 form an angle of 120°. The measured pore diameters of the 3 holes 121 are 0.14 mm to 0.17 mm, and the distance from the center of the end face 123 to the 3 holes 121 is uniformly set to 1.25 mm.

[0375] In an embodiment of the present invention, the semaglutide (also known as semaplutide) is a second-generation glucagon-like peptide-1 (GLP-1) analogue with a molecular formula of C 187 H 291 N 45 O 59 (with a molecular weight of 4113.58 Da), which has excellent hypoglycemic and weight loss effects on diabetic patients, significantly superior to sitagliptin, insulin glargine U100 or extended-release exenatide; it is also superior to its peer drug liraglutide in terms of weight loss, especially in patients with a BMI ≥ 30. Semaglutide can be administered orally or subcutaneously, for example, an oral dosage form of 7 mg / 14 mg once a day or a subcutaneous injection dosage form of 0.5 mg / 1.0 mg once a week. Semaglutide not only shows good efficacy in the treatment of diabetes, but also exhibits significant advantages in weight loss and cardiovascular protection.

[0376] The following is a specific semaglutide rat experiment of the needle-free delivery device of the present invention. Among them, under the structural configuration of the needle-free delivery device of the present invention described above, semaglutide with the following structure was used, and the semaglutide rat experiment was carried out according to the following experimental protocol:

[0377]

[0378] 1. Experimental materials

[0379] 1.1. Experimental animals: Healthy male Wistar rats, 6 - 8 weeks old, weighing 200 - 250 grams, were selected.

[0380] 1.2. Experimental grouping: The rats were randomly divided into four groups, with 10 rats in each group.

[0381] 1.3. Delivery agent: Semaglutide;

[0382] 1.4. Experimental equipment: The needle-free delivery device according to the above embodiment of the present invention (delivery pressure: 250 N, pore diameter: 0.14 mm - 0.17 mm); traditional hypodermic syringes, medical cotton swabs, and alcohol cotton.

[0383] 2. Experimental operation

[0384] 2.1. Administration

[0385] In the needle-free delivery group, administration was carried out using the needle-free delivery device according to the set parameters. In the needle delivery group, administration was carried out using the traditional injection method, where:

[0386] Group 1: Needle delivery, 1x dose, once a day for 14 days;

[0387] Group 2: needle-free 1x dose, once daily * for 14 days;

[0388] Group 3: needle 10x dose, once weekly * for 2 weeks;

[0389] Group 4: needle-free 10x dose, once weekly * for 2 weeks;

[0390] 2.2 Data collection

[0391] Record the daily changes in the body weight of rats, and monitor blood glucose and insulin levels.

[0392] 3 Result evaluation

[0393] a. Comparison between Group 1 and Group 2: Under the conditions of the same dosing dose (1x) and frequency (once daily), the total weight loss ratio of Group 2 (needle-free delivery) is 4% greater than that of Group 1 (needle delivery). In addition, the effect duration of Group 2 is long, and the rebound time is delayed compared with that of Group 1.

[0394] b. Comparison between Group 3 and Group 4: Under the conditions of a higher dose (10x) and a lower frequency (once weekly), the total weight loss ratio of Group 4 (needle-free delivery) is 5.5% greater than that of Group 3 (needle delivery).

[0395] Example 7

[0396] 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. Refer to Figures 32 to 33 which shows one of the structural configurations of the needle-free delivery device of the embodiment of the present invention used in combination with a polypeptide tumor vaccine. Specifically, the second end 120 has a constricted section 122 that tapers axially distally from the tube 100. Wherein, the diameter of the tube is 5 mm, the end face 123 of the constricted section 122 is configured as a circle with a diameter of 2.5 mm and is provided with 3 holes 121 thereon. The 3 holes 121 are arranged in an equally spaced circular pattern around the center of the end face 123. The adjacent connecting lines between the 3 holes and the center of the end face 123 form an angle of 120°. Wherein, the aperture measurement values of the 3 holes 121 are 0.14 mm to 0.17 mm, and the distances of the 3 holes 121 from the center of the end face 123 are uniformly set to 1.25 mm.

[0397] In the embodiment of the present invention, the polypeptide tumor vaccine is a new type of vaccine, which is essentially an immunogen that causes an effector cell immune response to form in vivo. The tumor polypeptide vaccine is an antigen polypeptide eluted from the surface of tumor cells or a related polypeptide obtained from tumor cells and capable of enhancing the humoral immunity and cellular immunity of the body against tumors after immunizing the body. Currently, the widely studied tumor polypeptide vaccines include vaccines targeting folate receptor (FR) or developed against the HER2 target.

[0398] The following is a specific polypeptide tumor vaccine rat immunization test of the needleless delivery device of the present invention. Among them, under the structural configuration of the needleless delivery device of the present invention described above, the polypeptide tumor vaccine rat immunization test was carried out according to the following test protocol:

[0399] 1. Test materials

[0400] 1.1 Test animals:

[0401] Select 60 healthy male C57BL / 6 mice, 6-8 weeks old, weighing 18-22 grams, and divide them into six experimental groups, namely G1, G2, G3, G4, G5, and G6 (10 mice in each group) by the random number table method.

[0402] 1.2 Test equipment:

[0403] Neoantigen and positive control polypeptide, and the needleless delivery device according to the embodiment of the present invention, wherein the pore size is 0.14-0.17 mm and the delivery pressure is 160 N.

[0404] 2. Immunization test

[0405] 2.1 Experimental arrangement:

[0406] Carry out 3 or 4 rounds of immunization tests according to the grouping in Table 6 below:

[0407] Table 11. Information table of polypeptide tumor vaccine rat immunization test

[0408]

[0409] 3. Effect detection

[0410] 3.1 Detection method: After the immunization, take the spleen cells of the mice and perform 4 rounds of ELISPOT detection on the detection results

[0411] 3.2 Detection results:

[0412] a. After three / four rounds of immunization of the mice, positive signals of the neoantigen group can be detected by the Elispot experiment, but the signals are weak.

[0413] b. There is no statistical difference in the average number of spots between the needleless injection group and the needle injection group.

[0414] c. The number of spots in each experimental group after the fourth round is less than that after the third round of immunization. Regarding the reduction ratio, the needleless neoantigen group is 10% less than the needle neoantigen group and 20% less than the positive polypeptide group. It can be seen that the duration of effectiveness of the needleless plus neoantigen polypeptide vaccine is longer than that of the other two groups.

[0415] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A needleless delivery device, characterized in that, Comprising: A tube for containing 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 modes; 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 exit 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 needle-free 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 dispersities; 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 dispersities; 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 dispersities.

4. The needleless delivery device according to claim 1, wherein, 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 of the holes 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 the body is greater than the volume of the undelivered fluid or the volume of the fluid delivered with a needle. Preferably, the dispersion volume of the fluid in the body 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 still more preferably more than 3.60 times.

6. The needle-free 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 exit jet velocity, and the first exit 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 needle-free 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, 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 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 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 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, wherein, 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 respect to 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 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 respect to 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 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 respect to each other increase or decrease radially.

12. The needleless 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 needleless 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 and medical 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, characterized in that, 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, characterized in that, 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 device combination product according to claim 15, wherein The needleless delivery device 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.

20. 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 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, characterized in that, 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, characterized in that, The needleless delivery device is configured such that the average antibody titer of the feline triple vaccine 60 days after injecting 60% of the vaccine dose 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 injecting 100% of the vaccine dose by 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 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 drug-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 pharmaceutical 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 pharmaceutical device combination product according to claim 23, characterized in that, 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 injecting 100% of the vaccine dose by intramuscular injection.

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

34. The pharmaceutical 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 drug-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 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 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 injecting 100% of the vaccine dose by intramuscular injection.

39. A GLP-1 polypeptide drug-device combination product, characterized in that, It includes 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, characterized in that, The second end is provided with three holes, and the three holes are arranged in an equally spaced circular pattern around the center of the second end. The distance between the three holes and the center is 1.25 mm ± 20%.

41. The pharmaceutical and medical 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 and medical 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 pharmaceutical and medical 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%, more preferably by more than 5%, and still more preferably by more than 10%.

46. The pharmaceutical 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%, more 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%, more preferably by more than 10%, and still more preferably by more than 20%.

48. A drug-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 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.

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

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 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 aesthetics.

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 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, characterized in that, 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, 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, and 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 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-symmetric with respect to the diameter or median line of the second end; Preferably, the holes are in multiple groups, and each group of holes is arranged in a straight line, and preferably, each group of holes is arranged along a diameter or a median line 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-symmetric with respect to the first and second diameters or median lines perpendicular to each other of the second end; Preferably, the aperture of the hole located at the center of the second end is different from the apertures of the other holes among 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.

57. The needleless syringe according to claim 52, wherein, The plurality of holes are arranged in a ring; Preferably, the plurality of holes are arranged in a ring centered on the center of the second end; The holes are in multiple groups, and each group of holes is arranged in a ring. Preferably, the multiple groups of holes are arranged in coaxial rings with each other; Preferably, 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 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 in coaxial rings 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 in a coaxial ring around the central hole; The peripheral holes are in multiple groups, and each group of peripheral holes is arranged in a ring. Preferably, the multiple groups of peripheral holes are arranged in a coaxial ring around the central hole; Preferably, the aperture of the central hole is different from the apertures 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 holes for dispensing the pharmaceutical preparation in the tube are provided in the second end; and A power mechanism, the power mechanism comprising 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 multiple needleless delivery devices 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 outlet jet velocity when the pharmaceutical preparation is pushed away from the hole 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 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 panleukopenia virus, feline calicivirus, and feline rhinotracheitis combined vaccine; Optionally, the pharmaceutical preparation is a hepatitis B vaccine for human use; Optionally, the pharmaceutical preparation is a pneumonia vaccine for human use; Optionally, the pharmaceutical preparation is semaglutide; Optionally, the pharmaceutical preparation is a tumor vaccine for human use, including but not limited to polypeptide vaccines, mRNA vaccines, and DNA vaccines. It should be noted that in the original text, the description of the "cat triple vaccine" in is inaccurate. The correct name is "feline panleukopenia virus, feline calicivirus, and feline rhinotracheitis combined vaccine". This translation is based on the corrected content.

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