Drug-containing device, suprachoroidal space implant, and injection adapter

Abstract

A pre-filled syringe for injecting a pharmaceutical composition into an eye, comprising: a syringe barrel (1) having a proximal end and a distal end; a floating seal member (3) located within the syringe barrel (1); a needle hub located at the proximal end of the floating seal member (3), the floating seal member (3) and the needle hub being elastically engaged with each other; the pharmaceutical composition contained in a chamber (7) formed by the needle hub, the floating seal member (3) and the distal end of the syringe barrel (1); and a needle (6) for intraocular puncture, the needle (6) a needle (6) including (i) a needle proximal end engaged with a needle hub, (ii) a needle distal end, (iii) a needle distal end opening (6a), (iv) a needle body opening (6b) located between the needle proximal end and the needle distal end, the needle body opening (6b) being located at a proximal end of the needle distal end opening (6a), and (v) a needle body passage connecting the needle distal end opening (6a) and the needle body opening (6b), wherein the needle hub is configured to advance the needle distally toward and / or through the floating seal member.

Description

Detailed Description of the Invention

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority to International Application No. PCT / CN2022131454, filed November 11, 2022, the entire text of which is incorporated herein by reference.

[0002] [Technical field] In some aspects, the present disclosure relates to the field of medical devices and equipment, and in particular to devices, kits, assemblies, or systems for medical puncture and drainage.

[0003] [Background technology] Conventional treatments for the suprachoroidal space (SCS) typically involve injecting medication into the SCS using a syringe. During puncture, the needle's puncture depth must be manually controlled, and healthcare professionals must rely on their experience to determine whether the needle has entered the SCS. However, the structure of the eye typically varies from patient to patient, which can lead to inaccurate judgment of needle depth by healthcare professionals. Therefore, accurate placement of the needle in the SCS cannot be guaranteed. Furthermore, the syringe plunger must be manually and continuously pressed during drug injection. Stabilizing the injection rate and preventing flow rate fluctuations requires skilled operation by healthcare professionals. However, in practice, ensuring consistent injections every time is challenging. Therefore, improved devices and methods for medical punctures, such as SCS injections, are needed.

[0004] Furthermore, medications used to treat SCS must achieve a high level of sterility and be injected with minimal dosage error. Therefore, it is necessary to develop an injection device or system that not only enables accurate injection into the SCS, but also minimizes environmental contamination, eliminates dosage error, and provides convenience to medical professionals.

[0005] The present disclosure addresses these and other needs by providing a preloaded or prefilled injection device containing an instrument suitable for precise injection into the SCS and one or more therapeutic agents. [Summary of the Invention]

[0006] In some embodiments, provided herein is a pre-filled syringe for injecting a pharmaceutical composition into an eye, the pre-filled syringe comprising: a syringe barrel having a proximal end and a distal end; a floating seal member located within the syringe barrel; a needle hub located at the proximal end of the floating seal member or provided on the floating seal member; the pharmaceutical composition contained in a chamber formed by the floating seal member and one end of the syringe barrel; and a needle for intraocular puncture, the needle comprising: (i) a needle proximal end engaged with the needle hub, (ii) a needle distal end, and (iii) a needle distal end opening, wherein the needle hub is configured to advance the needle distally toward the tissue of a subject.

[0007] In some embodiments, provided herein is a pre-filled syringe for injecting a pharmaceutical composition into an eye, the pre-filled syringe comprising: a syringe barrel having a proximal end and a distal end; a floating seal member located within the syringe barrel; a needle hub located at the proximal end of the floating seal member, wherein the floating seal member and the needle hub are resiliently engaged with each other; the pharmaceutical composition contained in a chamber formed by the floating seal member and the distal end of the syringe barrel; and a needle for intraocular puncture, the needle comprising: (i) a needle proximal end engaged with the needle hub; (ii) a needle distal end; (iii) a needle distal end opening; (iv) a needle body opening located between the needle proximal end and the needle distal end, the needle body opening being proximal to the needle distal end opening; and (v) a needle body passage connecting the needle distal end opening and the needle body opening; wherein the needle hub is configured to advance the needle distally toward and / or through the floating seal member.

[0008] In any of the embodiments herein, the pharmaceutical composition may include a triamcinolone formulation. In some embodiments, the triamcinolone formulation includes (i) triamcinolone or a pharmaceutically acceptable salt thereof, (ii) hyaluronic acid or a pharmaceutically acceptable derivative, analog, salt, or solvate thereof, (iii) one or more buffering agents, and (iv) one or more osmolality-adjusting agents.

[0009] In some embodiments, provided herein is a method for placing a stent in an eye, the method comprising: (a) inserting a needle into an injection site of an eye between the sclera and choroid of the eye; (b) delivering a flowable composition through the needle to form a suprachoroidal space; (c) removing the needle from the eye; and (d) placing a stent in the suprachoroidal space through the injection site. In some embodiments, the flowable composition comprises a viscoelastic material. In some embodiments, the injection site is expanded, and then the stent is implanted in the suprachoroidal space through the expanded injection site. In some embodiments, the stent is placed in the suprachoroidal space in an equator-parallel plane of the eye. In some embodiments, the stent implanted in the suprachoroidal space is configured to maintain the suprachoroidal space in an expanded state compared to the state before the flowable composition is delivered into the eye, and the expanded state is maintained for at least 4 months, 8 months, 12 months, 18 months, 24 months, 30 months, 36 months, or more.

[0010] In some embodiments, provided herein is an adapter set for a syringe comprising: a contact member extending from a proximal end to a distal end; and a pushing unit including a first elastic element, wherein the syringe comprises: a syringe barrel extending from the proximal end to the distal end and forming a chamber extending from the proximal end to the distal end; a push shaft extending from the proximal end to the distal end and forming a seal between the distal end and the syringe barrel; and a needle extending from the proximal end to the distal end and including an end opening that allows fluid to pass through the chamber, through the needle hub, to the distal end of the syringe barrel, and out of the chamber; wherein the contact member can be attached to the distal end of the injection needle such that the distal end of the contact member is located at the distal end of the needle distal end opening, and the distal end of the contact member can directly contact surface tissue of a target injection site; and wherein the pushing unit can be attached to the syringe barrel and / or push shaft of the syringe such that the pushing unit is resiliently engaged with the push shaft and / or syringe barrel of the syringe via the first elastic element.

[0011] In some embodiments, the adapter set further includes a second resilient element configured to be attached between the contact member and the needle hub, the second resilient element resiliently connecting the proximal end of the contact member and the needle hub, hi some embodiments, the second resilient element is a spring or a resilient sheath.

[0012] In some embodiments, the adapter set may be used in combination with any syringe disclosed herein, including any pre-filled syringe disclosed herein.

[0013] [Brief description of the drawing] The drawings illustrate specific embodiments that demonstrate the features and advantages of the present disclosure. These embodiments are not intended to limit the scope of the appended claims in any way.

[0014] 1A-1E show schematic diagrams of various stages of operating an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. FIG. 1F shows a step of operating an exemplary medical puncture device without a contact member (e.g., 1b shown in FIGS. 1A-1E), allowing the distal end seal member (e.g., 8 shown in FIGS. 1A-1E) to directly contact tissue.

[0015] 2A-2E show schematic diagrams of various stages of operation of an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. FIG. 2F shows a step of operating an exemplary medical puncture device without a contact member (e.g., 1b shown in FIGS. 2A-2E), allowing the distal end seal member (e.g., 8 shown in FIGS. 2A-2E) to directly contact tissue. FIG. 2G shows a step of operating an exemplary medical puncture device including an additional drive member 2′ engaged with a floating seal member 3 via another spring 4′, the drive member 2 being engaged with the floating seal member 3 via a spring 4.

[0016] [Figure 3] Figures 3A to 3F are partial structural diagrams of an exemplary medical puncture device including a floating seal member 3, one or more needle body openings (6b or 6b1, 6b2 and / or 6b3), and a needle distal end opening 6a.

[0017] 4A to 4C are partial structural views of an exemplary medical puncture device including a floating seal member 3 and a needle body opening 6b.

[0032] FIG.

[0018] [FIG. 5] FIGS. 5A to 5F are partial structural views of an exemplary medical puncture device including floating seal members 3a and 3b and one or more needle body openings (6b or 6b1 and / or 6b2).

[0019] FIG. 6 shows a partial structural view of an exemplary medical puncture device including a through-slant guide groove 3a and a one-way valve 9.

[0020] FIG. 7 shows a partial structural view of an exemplary medical puncture device including a through-slant guide groove 3a and a one-way valve 9.

[0021] FIG. 8 shows a partial structural view of an exemplary medical puncture device including a non-penetrating inclined guide groove 3a.

[0022] FIG. 9 shows a partial structural view of an exemplary medical puncture device including an inclined guide needle hole 6c and a one-way valve 9.

[0023] FIG. 10 shows a partial structural view of an exemplary medical puncture device including an inclined guide needle hole 6c and a needle hole plug 10.

[0024] 11A-11B show schematic diagrams of implanting a catheter 11 into an SCS 14 using an exemplary medical device assembly including a central guide groove 2c. FIG. 11A shows a contact member 1b in contact with tissue, and FIG. 11B shows a distal end seal member 8 in contact with tissue without an intermediate contact member.

[0025] 12A to 12C show schematic diagrams of various stages in operating an exemplary medical puncture device.

[0026] The reference numerals and corresponding exemplary structures in the drawings shown below, such as with reference to Figures 1A-1E through 11A-11B, are for illustrative purposes only and should not be considered limiting. 1 syringe barrel, 1a axial stopper, 1b annular contact element, 2 pushing element, 2c central guide groove, 3 floating seal element, 3a inclined guide groove, 4 elastic sheath, 5 spring, 6 hollow puncture needle, 6a needle distal end opening, 6b needle body opening, 6c inclined guide needle hole, 7 flowable composition cavity, 8 distal end seal element, 9 one-way valve, 10 needle hole plug, 11 catheter, 12 auxiliary guide needle, 13 sclera, 14 suprachoroidal space (SCS).

[0027] FIG. 13 shows a schematic diagram of the elements and features of an exemplary medical puncture device. For example, the device may include a hollow housing 22 engaged with a proximal control knob 17. A push / push shaft 2 slidably passes through the control knob and is engaged with a guide tube 16 within the housing. The push / push shaft 2 is configured to apply a distal force to a compression spring 5, which functions as a force element that applies a distal force to a plunger rod 15. A beveled needle 6 is connected to and fixed to a needle hub or base fixed to the push / push shaft. When force is applied to the push / push shaft, causing it to move distally, the distal end of the needle 6 may be positioned within the chamber of the plunger rod 15 and may move distally. The distal end of the needle may be advanced and pass through a seal member 3 at the distal end of the plunger rod 15 into a chamber formed by the syringe barrel 1 and the distal seal member 8. The retaining member 23 may be simultaneously engaged with the syringe barrel 1 and the distal end seal member 8, thereby advantageously achieving a sealing engagement. The distal end seal member 8 may be brought into contact with tissue, and the needle 6 may be advanced through the distal end seal member 8 to puncture the tissue. The needle 6 may include a needle distal end opening and a needle body opening, each similar to FIGS. 6a and 6b, and used as shown and described in FIGS. 1A-1E through 11A-11B.

[0028] In some embodiments, the devices disclosed herein include a stopper, such as limiter 18 in FIG. 13 . In some embodiments, the stopper may be used to limit the maximum length of axial movement of the push shaft, e.g., to achieve precise injection. In some embodiments, the stopper may be used to limit rotational and / or radial movement of the push shaft, e.g., to prevent or minimize displacement of the push shaft (and associated needle hub and injection needle) from the central axis of the assembled device. In some embodiments, the stopper may be engaged with a guide tube. In some embodiments, the stopper may be fixedly or removably engaged with the proximal end of the guide tube. In some embodiments, the guide tube may be used to guide the movement of the push shaft and plunger rod, e.g., through corresponding structure on a member, to achieve precision in the axial movement of the push shaft and plunger rod and precision in the movement of the injection needle. In some embodiments, the device uses a combination of features (e.g., a stopper and guide tube) to prevent or minimize rotation and / or displacement (e.g., from a central axis) of the pusher shaft, plunger rod, needle hub or base, and / or injection needle during shipping and storage of the assembled device, and during medical punctures with the device.

[0029] In some embodiments, a device disclosed herein includes a ruler, such as ruler 19 in FIG. 13 . In some embodiments, the ruler may be used to measure or otherwise determine the distance between the puncture site (e.g., the site punctured by the injection needle) and the limbus, which is the boundary between the cornea and the sclera. In some embodiments, the distal end of the ruler may be configured to contact a portion of the eye at the injection site. In some embodiments, a protrusion on the ruler may be configured to leave a mark on a portion of the eye, such as the injection site. For example, the mark may indicate the injection site. For example, the mark may appear as parallel marked lines on the conjunctiva of the eye, indicating to the user that the injection should be administered in the area between the parallel marked lines. In some embodiments, the ruler may be removably coupled to the delivery device (e.g., to distal end seal member 8 in FIG. 13 or to contact element 1 b in FIG. 1A ), for example, at the distal end of the delivery device. In such embodiments, the ruler may be detached from the delivery device after marking the injection site on the target tissue.

[0030] 14A to 14F show schematic diagrams of various stages in operating an exemplary medical puncture device.

[0031] The reference numerals and corresponding exemplary structures in the drawings shown below, with reference to, for example, Figures 14A-14F in Figure 14, are for illustrative purposes only and should not be considered limiting. 1 syringe having a syringe barrel forming a chamber, 2 pushing element (e.g., pushing shaft), 3 floating seal member (e.g., plunger seal member), 5 elastic element (e.g., spring), 6 hollow puncture needle (needle distal end opening and needle body opening not shown), 8 distal end seal member, 15 plunger rod (e.g., push shaft), 16 guide tube, 17 control knob, 18 limiter, 19 ruler, 20 adapter, 21 handle, 22 housing, 23 presser member.

[0032] 15A-15H show schematic diagrams of an exemplary contact member, second elastic element, and connector as part of an adapter. The distal seal member may function as a contact member that contacts the tissue surface at the beginning of the puncture operation. The distal seal member may be rigid or substantially incompressible, or may include a combination of rigid, semi-rigid, soft, and / or elastic materials. The needle hub may be connected to the distal seal member by one or more springs or other elastic materials configured to control pressure during puncture and / or injection, thereby improving safety. A sandwich structure (see, e.g., Figures 15D and 15E) may be provided between the needle hub and the tissue surface, including a rigid or substantially incompressible material (e.g., in the distal seal member) sandwiched between a first soft and / or elastic material at the distal end and a second soft and / or elastic material at the proximal end (e.g., a spring or an elastic sheath surrounding the needle). The first and second soft and / or elastic materials can be the same or different. The distal seal member, spring, and / or elastic sheath surrounding the needle can help reduce the risk of axial movement (e.g., axial misalignment) and / or sliding of the needle during puncture. The soft and / or elastic material used at the distal end can improve the tight or sealing engagement between the contact member (e.g., the distal seal member) and the tissue, particularly when the tissue surface is uneven and / or the needle is not perpendicular to the tissue surface, as shown, for example, in Figures 15G and 15H.

[0033] The reference numerals and corresponding exemplary structures in the drawings shown below, with reference to, for example, Figures 15A-15H in Figure 15, are for illustrative purposes only and should not be considered limiting: 1 syringe barrel, 6 hollow puncture needle (needle distal end opening not shown), 25 contact member, 25a first portion of contact member, 25b second portion of contact member, 26 second elastic element, 27 connector.

[0034] [Figure 16] Figures 16A-16B show schematic diagrams of an exemplary pressing element as part of an adapter (e.g., for use with a suitable syringe, such as a syringe with or without a floating seal member) for applying pressure to the plunger of a syringe (e.g., after liquid has been drawn into the syringe and before the needle is inserted into tissue).

[0035] The reference numerals and corresponding exemplary structures in the drawings shown below, with reference to, for example, Figures 16A-16B in Figure 16, are for illustrative purposes only and should not be considered limiting: 1 syringe barrel, 2 push shaft, 30 pressing element, 31 elastic element, 32 stopper or locking element.

[0036] 17A and 17B are schematic diagrams showing various stages of operation for operating a syringe equipped with an adapter described herein.

[0037] The reference numerals and corresponding exemplary structures in the drawings shown below, with reference to Figures 17A-17B in Figure 17, are for illustrative purposes only and should not be considered limiting. 1 syringe barrel, 2 push shaft, 3 floating seal member, 25 contact member, A high density tissue, B low density tissue.

[0038] In FIG. 17A , step a shows the initial state of a syringe (e.g., a conventional syringe), and step b shows the state of the syringe after liquid has been drawn into the syringe. At this time, when the injection needle is inserted into a contact member (e.g., a distal seal member) that seals the needle opening, the liquid in the syringe can be retained within the sealed space, as shown in step c. Tissue A may be a high-resistance tissue (e.g., a high-density tissue), and tissue B may be a low-resistance tissue (e.g., a low-density tissue), or a potential or obvious void, chamber, or blood vessel. To inject liquid into tissue B, pressure can be applied to the surface of tissue A in step d, bringing the distal seal member into contact with the surface of tissue A. As the needle is advanced, the needle tip first advances through the distal seal member (shown in step e) and then reaches the interface between the distal seal member and tissue A (shown in step f). Next, the needle tip enters tissue A (shown in step g) and is then advanced to the interface between tissue A and tissue B (shown in step h). If an appropriate force is applied to the syringe plunger in steps e to h, when the needle tip is in the position shown in steps e to g, the fluid cannot be ejected into the distal seal member or tissue A due to the large compressive resistance of the distal seal member and tissue A. When the needle tip reaches the interface between tissue A and tissue B in step h, the fluid pressure at the needle tip is higher than the pressure in tissue B (e.g., a potential or apparent void, chamber, or blood vessel), so the fluid can be automatically ejected into tissue B, and the plunger seal member moves distally toward the tissue, indicating to the operator that the needle tip is at the interface between tissue A and tissue B. If pressure is applied to the plunger even after the needle advancement stops, as long as the fluid pressure at the needle tip is still higher than the pressure in tissue B, the fluid will continue to be ejected into tissue B until the pressures are balanced or the plunger seal member has already reached its limit (e.g., it is stopped by a stopper that may be provided in the syringe). This realizes that the needle tip is accurately positioned at the interface between tissue A and tissue B and automatic injection is performed (step i).The distal seal member applied to the needle tip in step c (as a syringe adapter) can help retain the liquid in the sealed chamber, and another adapter for the syringe (e.g., a pressing element for applying pressure) can be used to apply an appropriate pressure to the liquid in the syringe via the plunger. During operation, the operator only needs to pay attention to the force applied to the plunger or syringe barrel to advance the needle, the needle advancement speed, and whether the plunger seal member suddenly moves downward (distal to the tissue). Furthermore, the operator does not need to simultaneously monitor and / or adjust the pressure applied to the liquid in the syringe (to ensure that it is higher than the pressure in tissue B). This reduces the number of aspects the operator needs to pay attention to during tissue puncture, improving the safety of tissue puncture (e.g., avoiding puncturing too deeply and damaging deep tissue). By applying the distal seal member to the needle tip, the actual advancement distance of the needle during puncture is longer than the advancement distance of the needle in tissue A. When tissue A is a relatively thin tissue, increasing the actual needle advance distance during puncture can provide better control of the injection and reduce the difficulty of operation. Furthermore, the distal seal member can help shorten the maximum needle advance distance (the maximum distance the needle protrudes beyond the distal seal member) during puncture, which, if properly controlled, can help reduce the risk of over-penetration. Furthermore, in step c, the distal seal member can increase the rigidity of the needle, thereby reducing the risk of needle bending, axial movement (e.g., axial displacement), and / or sliding during puncture.

[0039] In Figure 17B, step a shows the initial state of the syringe (e.g., there are two seal members, a proximal plunger seal member and a distal floating seal member), and step b shows the state of the syringe after liquid is drawn into it. At this time, when the injection needle is inserted into a contact member (e.g., a distal seal member) that seals the needle opening, the liquid in the syringe can be retained within the sealed space, as shown in step c. Tissue A may be a high-resistance tissue (e.g., a high-density tissue), and tissue B may be a low-resistance tissue (e.g., a low-density tissue) or a potential or obvious void, chamber, or blood vessel. To inject liquid into tissue B, pressure is applied to the surface of tissue A in step d, bringing the distal seal member into contact with the surface of tissue A. When the plunger is pressed to advance the needle, the needle tip first advances through the distal seal member (shown in step e) and then reaches the interface between the distal seal member and tissue A (shown in step f). Next, the needle tip enters tissue A (shown in step g) and is then advanced to the interface between tissue A and tissue B (shown in step h). When the needle tip is in the position shown in steps e-g, fluid cannot be expelled into the distal end seal member or tissue A due to the greater compressive resistance of the distal end seal member and tissue A. When the needle tip reaches the interface between tissue A and tissue B in step h, fluid can be expelled into tissue B if the fluid pressure at the needle tip is now higher than the pressure in tissue B (e.g., potential or apparent gaps, chambers, or blood vessels). At this time, if the plunger continues to advance to the distal end and the pressure is within an appropriate range, the liquid pressure at the needle tip can be maintained higher than the tissue pressure in tissue B (e.g., a potential or apparent cavity, a ventricle, a blood vessel), while the liquid pressure at the floating seal member (engaged with the needle hub and connected to the needle) is smaller than the friction force, allowing the liquid to continue to be discharged into tissue B without the needle tip advancing further distally until the pressures are balanced or the plunger seal member has already reached its limit (e.g., it is received by a stopper that may be provided in the syringe) (step i). The friction force may be the sum of the static friction forces between the needle and the distal seal member and between the needle and tissue A.By applying a distal seal member to the needle tip, the actual advance distance of the needle during puncture is longer than the advance distance of the needle within tissue A. When tissue A is a relatively thin tissue, increasing the actual advance distance of the needle during puncture can provide better control of the injection and reduce the difficulty of the operation. Once the liquid is discharged into tissue B (step i), to prevent the needle from advancing further distally into tissue B, the liquid pressure at the floating seal member is less than the sum of the static friction forces between the needle and the distal seal member and between the needle and tissue A. Therefore, once the liquid is discharged into tissue B (step i), compared to an operation without a distal seal member (where the static friction between the needle and the distal seal member is zero due to the absence of the distal seal member), the use of the distal seal member allows the puncture operation to tolerate the application of a greater force to the plunger (this force is transmitted to the floating seal member via the substantially incompressible liquid) without the risk of the needle tip penetrating too deeply, thereby improving the safety of the puncture operation. Additionally, the distal seal member can help reduce the maximum needle advance distance (maximum distance the needle protrudes beyond the distal seal member) during puncture, which, if properly controlled, can help reduce the risk of oversticking. Additionally, in step c, the distal seal member can increase the stiffness of the needle, reducing the risk of needle bending, axial movement (e.g., axial displacement), and / or sliding during puncture.

[0040] [Figure 18] Figures 18A-18B show schematic diagrams of exemplary methods and compositions for drainage via the SCS. In the exemplary ab externo method shown in Figure 18A, a viscoelastic agent is injected between the sclera and choroid to form the SCS, followed by implantation of a permanent or semi-permanent structure (e.g., a stent) to maintain the SCS in an expanded state for extended periods. This implant can form a ring-shaped or partially ring-shaped structure in the equator-parallel plane of the eye, as shown in Figure 18B.

[0041] [Mode for Carrying Out the Invention] Below is a detailed description of some embodiments of the present disclosure. It is understood that the specific implementations described herein are intended to illustrate and explain the embodiments of the present disclosure and should not be considered limiting.

[0042] It should be noted that the embodiments and features of the embodiments of the present disclosure may be combined in any suitable manner unless they are inconsistent.

[0043] In some embodiments, descriptions of positions such as "front," "rear," "forward," "rearward," "distal end," "proximal end," etc. are based on the perspective of an operator of the medical puncture device or medical instrument assembly, i.e., when the operator is using the medical puncture device or medical instrument assembly, the forward direction is away from and relatively far from the operator, and the rearward direction is toward and relatively closer to the operator.

[0044] As used herein, the terms "proximal end" and "distal end" refer to directions closer to and farther from an operator (e.g., surgeon, physician, nurse, operator, etc.) inserting a medical device into a patient, where the tip (distal end) of the device is inserted into the patient first. Thus, for example, the end of a needle (e.g., a microneedle) described herein that is inserted into the patient first is the distal end, and the opposite end of the needle (e.g., the end of the medical device that is manipulated by the operator) is the proximal end of the needle.

[0045] As used herein, the singular forms "a," "an," and "the" are intended to include plural referents unless the context clearly indicates otherwise. For example, "one" or "one" means "at least one" or "one or more." Similarly, the term "element" is intended to refer to a single element or a combination of elements, and "material" is intended to refer to one or more materials or any combination thereof.

[0046] As used herein, the term "about" or "approximately" refers to a normal error range for the corresponding value known to those skilled in the art. A value or parameter referred to herein as "about" includes (and describes) embodiments related to the value or parameter itself. For example, "about" may mean within one standard deviation or more than one standard deviation, in accordance with the practice of the relevant art. Alternatively, "about" may mean a range of up to 20%, up to 10%, up to 5%, or up to 1% of a particular value.

[0047] As used herein, the terms "prefilled," "preloaded," and "prepackaged" refer to the state of an injection device or system in which a composition (e.g., a drug or agent) has already been loaded into the injection device or system prior to use of the injection device or system. In some embodiments, "prefilled," "preloaded," and "prepackaged" injection devices or systems include injection devices or systems that are loaded with a drug and stored in this prefilled form for a period of time before administering the drug to a subject. In some embodiments, "prefilled," "preloaded," and "prepackaged" injection devices or systems include injection devices or systems that are loaded with all of the drugs to be administered and stored in this prefilled form for a period of time before administering the drug to a subject. In some embodiments, "prefilled," "preloaded," and "prepackaged" injection devices or systems include injection devices or systems that are loaded with a portion or certain components of the drug to be administered, stored in this prefilled form for a period of time before administering the drug to a subject, and the remaining portions and components are loaded immediately before administration.

[0048] Throughout this disclosure, each aspect is presented in a range format. It is understood that the description in range format is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the disclosure. Thus, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, when a range of values ​​is provided, it is understood that each intermediate value between the upper and lower limits of that range, as well as any other stated or intermediate value within that range, is also encompassed within the scope of the disclosure. The upper and lower limits of these smaller ranges may be independently included in the smaller ranges and are encompassed within the scope of the disclosure, subject to any specifically excluded limit within the range. If a stated range includes one or both of the limits, then ranges excluding one or both of those included limits are also encompassed within the disclosure. This is true no matter how broad the range.

[0049] The use of ordinal numbers such as "first," "second," "third," etc. in a claim to modify a claim element does not, in itself, imply that the claim element has priority, precedence, or sequential precedence over other claim elements or over the chronological order of acts performing a method, but is merely used as a label to distinguish a claim element having a certain name from another element having the same name (but using an ordinal number). Similarly, the use of a), b), etc. or i), ii), etc. does not, in itself, imply any priority, precedence, or order of steps in a claim. Likewise, the use of these terms in the specification does not, in itself, imply any necessary priority, precedence, or order.

[0050] As used herein, the terms "piercing member" and "pierced member" may be used interchangeably and refer to an article, such as a needle or microneedle, configured to pierce a tissue layer to deliver a substance to a target tissue layer.

[0051] As used herein, the terms "drug container" and "drug chamber" may be used interchangeably and refer to an article (e.g., a syringe) configured to contain a predetermined volume of a substance (e.g., a drug or pharmaceutical).

[0052] As used herein, the term "syringe" may include any commonly used type of syringe, including a needle having a proximal end and a distal end, a syringe barrel having a distal end and an open proximal end, and a push shaft having a distal end and a proximal end, where the proximal end of the needle is connected to the distal end of the syringe barrel, forming a fluid cavity between the distal end of the push shaft and the distal end of the syringe barrel, and establishing fluid communication from the fluid cavity to the proximal end of the needle and further to the distal end of the needle. The term "syringe" may include all common syringes, regardless of size or capacity. For example, a 1 μL syringe is included in the "syringe" described herein, and a 1 L syringe is also included in the "syringe" described herein. In some embodiments, a syringe may not include any valves. In some embodiments, a syringe may not include any springs. In some embodiments, a syringe may not include any floating seals.

[0053] In some embodiments, the terms "connected" and "engaged" are intended to encompass situations where two connected or engaged members are joined together and cannot be separated, as well as situations where the two members are not joined together but are in contact with each other. For example, a resilient element connected to a needle hub may mean that the resilient element is joined to the needle hub and is held together with the needle hub at all times, or it may mean that the resilient element may contact the needle hub when the needle moves to a certain position, but may not contact the needle hub at certain times.

[0054] All publications (including patent documents, scientific articles, and databases) mentioned in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication was individually incorporated by reference. In the event that a definition set forth herein is reversed or otherwise inconsistent with a definition set forth in a patent, application, published application, or other publication incorporated herein by reference, the definition set forth herein shall take precedence over the definition incorporated herein by reference.

[0055] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. I. Overview

[0056] Direct delivery of drugs and / or implants into the eye is a major approach for treating various ocular diseases. Among drug delivery methods, intravitreal injection is the mainstream and an effective route for achieving high intraocular concentrations of antibiotics, antivirals, antifungals, steroids, and anti-VEGF drugs (Peyman GA et al. Retina. 2009, 29(7), 875-912). Although intravitreal injection has a favorable safety profile, it can lead to ocular complications such as cataracts, glaucoma, choroidal hemorrhage, endophthalmitis, vitreous hemorrhage, and retinal detachment. Furthermore, the injected drugs may be absorbed and cause systemic side effects (Prasad AG et al., Compr Ophthalmol Update. 2007, 8(5), 259-269). Some drugs and gene therapy vectors may penetrate the posterior hyaloid membrane and inner retinal layers to reach the outer retina or retinal pigment epithelium, resulting in reduced efficacy. Furthermore, because the vitreous cavity is semi-open, drugs injected into the vitreous cavity can easily escape the eyeball via aqueous humor circulation, affecting the local drug concentration and pharmacokinetics and potentially causing side effects such as increased intraocular pressure and cataracts. Another common method for drug delivery is topical drug administration, which typically results in relatively low intravitreal drug concentrations and is generally not commonly used to treat ocular diseases, especially those that do not involve the ocular surface (Abdelkader H. et al., Curr Drug Deliv. 2012, 9(4), 421-430). Systemic treatment also has limitations, as the blood-retinal barrier limits the ability of drugs to reach the eye, and high doses can cause systemic side effects (Rai Udo J. et al., Drug Discov Today. 2015, 20(4), 491-495). Periocular (subconjunctival, sub-Tenon's fascia, or retrobulbar) injections can bypass the blood-retinal barrier without intraocular penetration. However, the injected drug still needs to cross the sclera, which has low permeability to large molecules and may not reach therapeutic concentrations at the retinal level (Geroski DH et. al., Adv Drug Deliv Rev. 2001, 52(1), 37-48).

[0057] In contrast, suprachoroidal space injections can achieve higher drug concentrations in the choroid / ciliary body, retinal pigment epithelium, and / or outer retina while lowering drug concentrations in the vitreous. Animal studies have shown that the SCS can accommodate up to 1 mL of fluid, which rapidly diffuses to the posterior segment (Seiler GS et al., Invest Ophthalmol Vis Sci. 2011, 52(8), 5730-5736). This volume is much larger than the volume required to achieve clinically relevant therapeutic drug levels. Injections of 10–50 μL into the SCS have been demonstrated to be well tolerated intraocularly with a low risk of complications (Gu B. et al., Invest Ophthalmol Vis Sci. 2015, 56(6), 3623-3634). Therefore, SCS is a promising route for drug delivery, as it allows for the administration of larger drug volumes and a longer duration of action with a safer procedure. Furthermore, drug delivery via the SCS bypasses the inner limiting membrane barrier and the blood-retinal barrier and may also be a preferred route for drug delivery targeted to the retinal pigment epithelium.

[0058] However, precise drug delivery to the suprachoroidal space (SCS) presents significant challenges. In some cases, targeted injection of therapeutic agents is desirable. However, due to the relatively small anatomical structures of the eye, positioning a needle at the target location using known instruments and methods, particularly positioning the distal tip of the needle at the desired depth within the eye, often presents significant challenges. Many known methods for injecting drugs directly into the eye involve inserting a needle or catheter at a small angle relative to the surface of the eye, which can make it difficult to control the depth of insertion. For example, some such methods involve controlling the angle and orientation of the needle so that the injected substance exits the needle at a specific location. Furthermore, some known methods for injecting substances into ocular tissues also involve the use of complex visualization systems and sensors to control the placement of the needle or catheter.

[0059] These deficiencies of known systems and methods are exacerbated because the size and thickness of each layer contained within the eye can vary from person to person. For example, the thickness of the conjunctiva and sclera can vary significantly, making their true values ​​difficult to determine in advance using standard techniques. Furthermore, the thickness of these layers can vary in different parts of the eye and even in the same eye and location at different times of the day. Therefore, using known systems and methods, it can be difficult to determine and / or adjust the length of a needle used to puncture the eye so that the needle tip reaches a desired depth, such as the SCS.

[0060] In some cases, such as choroidal melanoma, precise targeted injection of a therapeutic agent into the choroidal space can improve therapeutic efficacy and reduce side effects. However, due to the small structure of the eye, it is difficult to achieve puncture, dilation, injection, or catheter placement in the choroidal space using conventional devices or methods, especially when medical devices such as catheters need to be placed at specific locations in the choroidal space.

[0061] Some methods for puncturing the suprachoroidal space involve ensuring that the exposed length of the needle is equal to the thickness of the sclera. After the needle is fully inserted into the sclera, fluid is injected to achieve the suprachoroidal space injection. A technical drawback of this puncture method is that the exposed length of the needle may not be exactly the same as the thickness of the sclera. In practical applications, the above technical drawbacks are further exacerbated by differences in scleral thickness between different human groups, different eyes, and different parts of the same eye. A needle that is too short may not be able to penetrate the sclera, while a needle that is too long may penetrate the SCS and damage the retina. A convenient method is needed to detect the position of the needle tip within the eye.

[0062] Due to the sensitivity of intraocular injections (e.g., tissue sensitivity, potential effects on intraocular pressure, etc.), many known systems employ manual injection. More particularly, many known devices and methods involve a user manually applying force (e.g., by pressing a plunger with the user's thumb or finger) to inject a fluid (e.g., a medication) into the eye. Due to the relatively small size of the needle and / or the properties of the medication being injected, some such devices and methods involve using force levels that are beyond the user's comfort range, and in some cases, the user may be unable to adequately deliver the medication using known systems and methods.

[0063] Furthermore, injection into different target layers of the eye can result in variations in the amount of force required to insert the needle and / or inject the drug. Different tissue layers of the eye may have different densities. For example, the sclera is typically denser than the conjunctiva or SCS. The difference in density of the target area or tissue layer can create different backpressures against the needle exit (e.g., the tip of the needle through which the fluid flows). Therefore, injection into relatively dense ocular tissues, such as the sclera, requires a greater driving force to expel the drug from the needle than injection into the SCS. Furthermore, the injection force required to expel the drug also varies depending on the density and viscosity of the liquid drug, the needle length, and the needle diameter. Injecting a particular drug into the eye with a desired needle (e.g., 27-gauge, 30-gauge, or smaller) can require less predictable and / or controllable force to achieve a proper injection without risking ocular tissue damage in a particular subject.

[0064] Thus, there is a pressing need for improved devices and methods to help determine whether a needle is at the correct depth, to facilitate the injection of drugs into tissues such as ocular tissues, and / or to facilitate the implantation of specific structures into tissues such as ocular tissues.

[0065] Additional challenges to accurately delivering drugs and / or implants to the SCS include the high demands for sterility and precise dosing during intraocular injection. For example, it has been demonstrated that the risk of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) drugs is significantly affected by the sterility of the pharmaceutical composition and the drug-loading environment (VanderBeek BL, JAMA Ophthalmol., 2019, 137(4), 343-344). Injections prepared in outpatient settings have been shown to have a higher incidence of endophthalmitis compared with pre-loaded or pre-filled injection devices or systems. Eliminating drug transfer in outpatient settings eliminates a common source of contamination and significantly reduces contamination-related side effects. Accurate control of dose and volume is also crucial, especially for the small spaces and thin tissues within the eye. Therefore, there remains an urgent need for injection devices or systems that not only enable accurate injection into the SCS but also improve sterility, better control the dose, and minimize inconvenience to healthcare professionals.

[0066] To achieve one or more of the above objectives, in some embodiments, the present disclosure provides a medical puncture device for injecting a pre-filled drug of a pharmaceutical composition, comprising: a syringe barrel including a proximal end and a distal end; a floating seal member located within the syringe barrel; a needle hub located at the proximal end of the floating seal member, the floating seal member and the needle hub being resiliently engaged with each other; A needle for intraocular puncture, the needle comprising: (i) a needle proximal end engaged with a needle hub; (ii) needle distal end; (iii) needle distal end opening; (iv) a needle body opening located between the needle proximal end and the needle distal end, the needle body opening located at a proximal end of the needle distal end opening; and (v) a needle including a needle body passage connecting the needle distal end opening and the needle body opening; the needle hub is configured to advance the needle distally toward and / or through the floating seal member; and A medical puncture device is provided in which the pharmaceutical composition is contained within a chamber formed by the floating seal member and the distal end of the syringe barrel.

[0067] In other aspects, provided herein are adapter sets that, when combined with a syringe, can significantly improve the injection depth accuracy of the syringe, facilitating the injection of drugs into tissue, such as ocular tissue, and / or facilitating the implantation of specific structures into tissue, such as ocular tissue. In some aspects, the adapters described herein, when attached to a syringe, can improve the injection accuracy and safety of the syringe. In some embodiments, the adapters described herein, when attached to other syringes (e.g., syringes disclosed in U.S. Patent No. 2020 / 0069883), can improve the injection accuracy and safety of the syringe. In some aspects, the adapter sets include: a contact member extending from a proximal end to a distal end; a pressing unit including a first elastic element; the contact member may be assembled to the distal end of the injection needle such that the distal end of the contact member is located at the distal end of the needle distal end opening and the distal end of the contact member is in direct contact with the surface tissue of the target injection site; The pushing unit may be assembled to the syringe barrel and the push shaft such that the pushing unit is elastically engaged with the push shaft and / or the syringe barrel via a first elastic element.

[0068] In another aspect, provided herein is a method for improving syringe injection accuracy and safety, comprising: (1) providing a syringe including a syringe barrel extending from a proximal end to a distal end forming a chamber extending from the proximal end to the distal end, a push shaft extending from the proximal end to the distal end forming a seal between the distal end and the syringe barrel, and a needle extending from the proximal end to the distal end and including an end opening for allowing fluid to pass through the needle hub, through the distal end of the syringe barrel, and out of the chamber; (2) providing an adapter set including a contact member extending from a proximal end to a distal end and a pressing unit including a first elastic element; (3) attaching a contact member to the distal end of the needle; (4) attaching the pressing unit to the syringe; The distal end of the contact member is located at the distal end of the needle distal end opening, and the distal end of the contact member can directly contact the surface tissue of the target injection site; and A method is provided, wherein the pushing unit is resiliently engaged with the push shaft and / or the syringe barrel via a first resilient element.

[0069] In some embodiments, after injection into the suprachoroidal space (SCS), one or more structures, such as a permanent or semi-permanent stent, can be implanted in the SCS for extended periods, for example, at least 4 months, 6 months, 8 months, 10 months, 12 months, 24 months, or 36 months, or even longer. In some embodiments, a method disclosed herein includes: (a) inserting a needle into the eye at an injection site to inject into the suprachoroidal space (SCS) of the eye; (b) delivering a composition (e.g., a viscoelastic composition) through the needle to form an SCS; and (c) placing a stent (e.g., a microstent) in the SCS through the injection site or an enlarged insertion site (e.g., formed by enlarging the injection site, such as by surgical enlargement) to maintain the SCS in an expanded state and promote drainage of aqueous humor.

[0070] Some embodiments of the present disclosure will be described with reference to several figures of the accompanying drawings. II. Injection Device or System

[0071] An integrated device (e.g., a pre-filled syringe) containing a pharmaceutical preparation is disclosed. In some embodiments, the present specification provides a pre-filled injection device or system, which includes an injection device for assisting the penetration of a puncture member (e.g., a needle or microneedle) into the eye and / or for assisting the injection of a pre-filled drug in the device into a target eye tissue. In some embodiments, the present specification describes a pre-filled injection device or system, which includes an injection device for controlling the penetration depth of a puncture member (e.g., a microneedle) into the eye to deliver a therapeutic agent pre-filled in the device to, for example, the posterior region of the eye (e.g., via the suprachoroidal space). In some embodiments, the present specification describes a pre-filled injection device or system, which includes an injection device for introducing an implant pre-filled in the device into a tissue, such as an obvious or potential tissue void, chamber, or blood vessel.

[0072] In some embodiments, a prefilled injection device or system is provided herein, comprising: a syringe barrel having a proximal end and a distal end; a floating seal member located within the syringe barrel; and a needle hub located at the proximal end of the floating seal member (e.g., the needle hub is closer to the operator, while the floating seal member is closer to the subject), wherein the floating seal member and the needle hub are elastically engaged. In some embodiments, the prefilled injection device or system further comprises a needle having a needle proximal end and a needle distal end, the needle proximal end being engaged with the needle hub. In any embodiment herein, the needle proximal end may be fixed to the needle hub or releasably connected (e.g., inserted) to the needle hub. In any embodiment herein, the needle may comprise: (i) a needle distal end opening; (ii) a needle body opening located between the needle proximal end and the needle distal end; and (iii) a needle body passage connecting the needle distal end opening and the needle body opening. In any of the embodiments herein, the needle body opening can be located proximal to the needle distal opening. In any of the embodiments herein, the needle hub can be configured to advance the needle distally toward the floating seal member (e.g., when the needle distal end is located proximal to the floating seal member), through the floating seal member (e.g., when the needle distal end has already entered or penetrated the floating seal member), and / or through the distal end of the syringe barrel.

[0073] In any of the embodiments herein, the proximal and distal chambers within the syringe barrel may be located on different sides of the floating seal member. In some embodiments, the distal chamber contains a prefilled flowable composition (e.g., a drug, pharmaceutical, and / or a pharmaceutically acceptable carrier or excipient such as saline), while the proximal chamber does not contain a non-gaseous flowable composition. The proximal chamber may be prefilled with a gas, such as sterile air, and / or may be in communication with the external environment (e.g., atmosphere) as the needle advances within and / or passes through the syringe barrel.

[0074] In some embodiments, the needles included in the embodiments described herein have a bevel, which allows the needle to easily penetrate tissues such as the sclera and / or suprachoroidal space with minimal collateral damage. In some embodiments, the needles disclosed herein may define a narrow lumen (e.g., gauge sizes of 30 gauge, 32 gauge, 34 gauge, 36 gauge or larger, etc.) to deliver drugs to the suprachoroidal space while minimizing the diameter of the needle tract resulting from needle insertion. In some embodiments, the aspect ratio of the lumen to the bevel of the needles described herein is the same as or different from the standard 27 gauge and 30 gauge needles commonly used for intraocular injections.

[0075] In some embodiments, the prefilled injection device or system disclosed herein includes an injection device configured to include or be connected to a prefilled drug container containing a drug (e.g., a gel, etc.), which may be at least partially constituted by a syringe barrel.

[0076] In some embodiments, a needle is coupled to the distal end of the prefilled drug container (e.g., the needle is located at the distal end of the syringe), as described in, for example, U.S. Patent Nos. 9,180,047, 9,539,139, 9,572,800, 9,636,253, 9,636,332, 9,770,361, 9,937,075, 10,555,833, and 10,517,756, which are incorporated herein by reference for all purposes. In other embodiments, the needle employed in the present disclosure is coupled to a drive member within the syringe barrel. In some embodiments, the needle disclosed herein is at least partially located within the syringe barrel. In some embodiments, prior to use, the needle is not exposed or directly engaged at the distal end of the syringe barrel.

[0077] In some embodiments, the prefilled injection device or system disclosed herein includes an injection device including an energy storage member (e.g., one or more springs) configured to be engaged with a needle hub and a floating seal member. In some embodiments, a distal end portion of the energy storage member is located within the syringe barrel and configured to be directly or indirectly engaged with the floating seal member. In some embodiments, the energy storage member is configured to generate a force at a proximal end portion of the floating seal member. In some embodiments, when the distal tip of the needle is located within an apparent or potential tissue void, chamber, or blood vessel, this force is sufficient to move the floating seal member within the syringe barrel, thereby delivering at least a portion of the substance from the drug container (e.g., the flowable composition cavity) through the needle. Furthermore, when the distal tip of the needle is located within adjacent tissue (e.g., tissue above or below) of an apparent or potential tissue void, chamber, or blood vessel, this force is insufficient to move the floating seal member within the syringe barrel. In some embodiments, the apparent or potential tissue void, chamber, or vessel has a first density and the adjacent tissue has a second density that is higher than the first density. In some embodiments, a first backpressure is generated within the apparent or potential tissue void, chamber, or vessel and a second backpressure is generated by the adjacent tissue, the second backpressure being higher than the first backpressure.

[0078] In some embodiments, the needle is coupled to the floating seal member. In other embodiments, the needle employed in the present disclosure has its proximal end connected to a drive member within the syringe barrel, the drive member being separately provided and located at the proximal end of the floating seal member. In some embodiments, the proximal end of the needle disclosed herein is not coupled to the floating seal member. In some embodiments, prior to use, the needle may be located at the distal end of the floating seal member or may pass through the floating seal member, but the proximal end of the needle remains located at the distal end of the floating seal member and is not fixedly connected to the floating seal member.

[0079] In some embodiments, the prefilled injection device or system disclosed herein includes a prefilled drug container (e.g., containing a liquid) located between a proximal end seal member and a distal end seal member, both of which are movable within the syringe barrel, as described, for example, in U.S. Pat. No. 11,413,397 and U.S. Pat. No. 2020 / 0069883, which are incorporated herein by reference for all purposes. In some embodiments, provided herein is a system for delivering any one or more compositions disclosed herein (e.g., pharmaceutical formulations disclosed in Section III herein) into an actual or potential void, chamber, or blood vessel within a subject, the system comprising: a syringe barrel extending from a first end to a second end to form a chamber extending from the first end to the second end; a plunger disposed in the chamber proximate the first end, the plunger forming a seal between the plunger and the syringe barrel to prevent fluid (prefilled in the chamber) from exiting the chamber between the plunger and the syringe barrel; and a floating seal member disposed in the chamber proximate the second end, the floating seal member forming a seal between the floating seal member and the syringe barrel to prevent fluid from exiting the chamber between the floating seal member and the syringe barrel. and a hollow needle connected to the floating seal member and extending from a proximal end to a distal end, the hollow needle having an opening at the distal end to allow a fluid (e.g., comprising one or more compositions disclosed herein) to flow from the chamber through the floating seal member, through the hollow needle, and out the second end of the syringe barrel, wherein materials and sizes of the syringe barrel, plunger, and floating seal member are selected based on a threshold flow rate of the fluid contained in the chamber, and wherein when a force is applied to the fluid, a counter force is overcome, such that the floating seal member and hollow needle move from the second end of the syringe barrel and the distal end of the hollow needle extends into the tissue of the subject, and when the distal end of the hollow needle extends through the tissue of the subject and enters a void in the subject, the counter force causes the fluid to enter the void through the opening formed in the distal end of the hollow needle.Any of the adapters disclosed herein (e.g., those disclosed in Section VII of the present specification) can be used in combination with the system to further improve injection accuracy and / or safety.

[0080] In some embodiments described above, the force applied to the proximal end of the proximal seal member is transmitted to the distal seal member connected to the needle via a liquid. Because liquids are generally incompressible, if an operator applies excessive or sudden force to the proximal seal member (e.g., by applying force via a plunger coupled to the proximal seal member), the force is transmitted to the needle. In some embodiments, in devices such as those disclosed in U.S. Patent No. 2020 / 0069883, the liquid provides little compressibility to cushion the force, potentially causing the needle to be inserted too deeply or too forcefully, potentially damaging the target tissue (e.g., the suprachoroidal space) and / or surrounding tissue. While the positions of the proximal and distal seal members can be observed during injection, if a force is applied that could cause the needle to penetrate too deeply, it may be too late to prevent needle movement due to the lack of force cushioning. In contrast, in some embodiments, the prefilled injection device or system disclosed herein further includes a contact member located at the distal end of the syringe barrel, and the contact member is elastically connected to the distal end of the syringe barrel via an elastic element. The contact member can directly contact the surface tissue of the target injection site, and this elastic connection helps the operator apply the correct force when inserting the needle, cushioning the impact of the force and thereby preventing the needle from penetrating too deeply. In some embodiments, the elastic element is in the form of a spring, one side of the spring is connected to the contact member, and the other side of the spring is connected to the distal end seal member. In some embodiments, the elastic element is an elastic sleeve or sheath, and the needle is located inside the elastic sleeve or sheath and surrounded by the elastic sleeve or sheath. In some embodiments, the prefilled injection device or system disclosed herein may include any device disclosed in US Patent Publication No. 2020 / 0069883. In some embodiments, the prefilled injection device or system disclosed herein may include any of the devices disclosed in US 2020 / 0069883 and may further include any of the adapters described herein.

[0081] In other embodiments of the present disclosure, the prefilled injection device or system disclosed herein includes a prefilled drug container (e.g., a flowable composition cavity) located between a floating seal member and the distal end of the syringe barrel (wherein the distal end does not move relative to the syringe barrel). In some embodiments, the distal end of the syringe barrel includes a distal end seal member, and the flowable composition cavity is located between the floating seal member and the distal end seal member. In some embodiments, the needle hub is elastically connected to the floating seal member (and thus the flowable composition), which helps the operator apply the correct force and cushions the impact of that force. Furthermore, the operator can keep the needle hub fixed relative to the syringe barrel and observe the movement of the floating seal member to assess the needle insertion depth. Once fluid communication is established between the flowable composition and an apparent or potential tissue void, chamber, or blood vessel, and the pressure within the flowable composition is greater than the pressure within the apparent or potential tissue void, chamber, or blood vessel, the floating seal member may move when the flowable composition enters the tissue, but the needle and needle hub do not need to move, thereby achieving accurate needle placement and stable injection, and effectively reducing or eliminating the possibility of needle over-sticking.

[0082] In some embodiments, the pre-filled injection device or system disclosed herein comprises an injection device that is provided and / or packaged as an integrated device that includes interlocking parts. In some embodiments, the pre-filled injection device or system disclosed herein comprises an injection device that does not require the operator to assemble one or more parts before use. In some embodiments, the pre-filled injection device or system disclosed herein comprises a pre-filled drug container (e.g., a flowable composition cavity) that contains a flowable composition, such as a drug in the form of a liquid, solution, suspension, gel, oil, ointment, emulsion, cream, foam, lotion, and / or paste.

[0083] Flowable compositions include liquids (e.g., solutions, suspensions, etc.) or semi-solid compositions (e.g., gels) that are easy to manipulate and, upon solidification, can be injected, shaped, and / or molded at or near a target tissue site. "Flowable" encompasses formulations ranging from low viscosity or water-like consistency to high viscosity formulations (e.g., viscoelastic or paste-like substances). In some embodiments, the methods disclosed herein include injecting a viscoelastic substance (e.g., a viscoelastic fluid) into the eye, for example, between the sclera and the choroid / ciliary body of the eye, to form a suprachoroidal space containing the viscoelastic substance. In some embodiments, the viscoelastic fluid is a non-Newtonian fluid formed of a viscous component and an elastic component, such as, for example, a mixture of a solvent and a polymeric material. Examples of viscoelastic agents that can be used herein include sodium hyaluronate, Provisc (a 1% viscous transparent substance that is a specific component of sodium hyaluronate), Viscoat (a dispersive viscoelastic preparation consisting of sodium hyaluronate and chondroitin sulfate), Amvisc (a purified component of sodium hyaluronate), Amvisc Plus (a 1.6% sodium hyaluronate product derived from rooster comb), sodium chondroitin sulfate / sodium hyaluronate, or DisCoVisc (4% sodium chondroitin sulfate, 1.65% sodium hyaluronate).

[0084] In embodiments, the flowability of the formulation allows it to adhere to irregularities, cracks, crevices, and / or voids in a tissue site. For example, in embodiments, the formulation may be used to fill one or more voids, enlarge a tissue void (e.g., an apparent tissue void), and / or create a tissue void from a latent tissue void and, if necessary, enlarge the created void. In some embodiments, the flowable composition can harden upon contact with an aqueous medium (e.g., bodily fluid, water, etc.) to form a drug depot that controls drug release.

[0085] In some embodiments, the device is pre-filled with a therapeutic agent (e.g., a drug), for example, as part of a flowable composition. Non-limiting examples of specific drugs and drug classes include β-adrenergic receptor antagonists (e.g., carteolol, cetamolol, betaxolol, levobunolol, metipranolol, timolol), miotics (e.g., pilocarpine, carbachol, physostigmine), sympathomimetics (e.g., adrenaline, dipivefrine), carbonic anhydrase inhibitors (e.g., acetazolamide, dorzolamide), topoisomerase inhibitors (e.g., topotecan, irinotecan, carbamazepine), and benzodiazepines (e.g., benzodiazepine). antibacterial and antifungal agents such as chloramphenicol, chlortetracycline, ciprofloxacin, framycetin B, fusidic acid, gentamicin, neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline, tobramycin, and quinoline drugs; antiviral; compounds (e.g., acyclovir, cidofovir, iodoxuridine, interferon), aldose reductase inhibitors, anti-inflammatory and / or anti-allergic compounds (e.g., steroid compounds such as triamcinolone, betamethasone, clobetasone, dexamethasone, fluorometholone, hydrocortisone, prednisolone, and non-steroidal anti-inflammatory drugs such as antazoline, bromfenac, diclofenac, indomethacin, lodoxamide, sapropterin, sodium cromoglycate, etc. These include: steroid compounds, artificial tears / dry eye medications, local anesthetics (e.g., amethocaine, lidocaine, oxybuprocaine, proxymetacaine), cyclosporine, diclofenac, urogastrone and growth factors (e.g., epidermal growth factor), mydriatics and cycloplegics, mitomycin C, collagenase inhibitors, and drugs used to treat age-related macular degeneration (e.g., pegaptanib sodium, ranibizumab, aflibercept, and bevacizumab).

[0086] In one embodiment, the therapeutic agent is an integrin antagonist, a selectin antagonist, an adhesion molecule antagonist (e.g., intercellular adhesion molecule (ICAM)-1, ICAM-2, ICAM-3, platelet endothelial adhesion molecule (PCAM), vascular cell adhesion molecule (VCAM)), a cytokine or growth factor antagonist that guides leukocyte adhesion (e.g., tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1 / CCL2), or vascular endothelial growth factor (VEGF)). In some embodiments, a vascular endothelial growth factor (VEGF) inhibitor is administered using one of the microneedles described herein. In some embodiments, two drugs are delivered by the methods described herein. The compounds can be administered in the form of a single formulation or sequentially in two separate formulations. For example, both a VEGF inhibitor and a VEGF are provided. In some embodiments, the VEGF inhibitor is an antibody, such as a humanized monoclonal antibody. In a further embodiment, the VEGF antibody is bevacizumab. In another embodiment, the VEGF inhibitor is ranibizumab, aflibercept, or pegaptanib. In other embodiments, the devices and methods described herein can be used to deliver one or more of the following VEGF antagonists: AL8326, 2C3 antibody, AT001 antibody, HyBEV, bevacizumab (Avastin), ANG3070, APX003 antibody, APX004 antibody, ponatinib (AP24534), BDM-E, VGX100 antibody (VGX100CIRCADIAN), VGX200 (c-fos guide growth factor monoclonal antibody), VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, stent (sunitinib malate), INDUS815C, R84 antibody, KD019, NM3, allogeneic mesenchymal progenitor cells used in combination with anti-VEGF drugs or antibodies, MGCD265, MG516, VEGF receptor tyrosine kinase inhibitor, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, Palomid 529, BD0801 antibody, XV615, lucitanib (AL3810, E3810), AMG706 (motesanib diphosphate), AAV2 -sFLT01, soluble Flt1 receptor, cediranib (Resentin), AV-951 (tivozanib, KRN-951), Stivarga (regorafenib), volasertib (BI6727), CEP11981, KH903, lenvatinib (E7080), telameprocol (EM1421), ranibizumab (Lucentis), Votrient (pazopanib hydrochloride), PF00337210, PRS050, SP01 (curcumin), carboxyamidotriazole orotate, hydroxychloroquine, linifanib (ABT869, RG3635), Iluvien (fluocinonide), ALG1001, AGN150998, DARPinMP0112, AMG386, ponatinib (AP24534), AVA101, Vargatef (nintedanib), BMS690514, KH902, golvatinib (E7050), Afinitor (everolimus), dovitinib lactate (TKI258, CHIR258), ORA101, ORA102, axitinib (Inlyta, AG013736), plitidepsin (Aplidin), lenvatinib mesylate acid salt, PTC299, aflibercept (Zaltrap, Eylea), pegaptanib sodium (Macugen, LI900015), Visudyne (verteporfin), bucillamine (Rimatil, Lamin, Brimani, Lamit, Boomiq), R3 antibody, AT001 / r84 antibody, troponin (BLS0597), EG3306, vatalanib (PTK787), Bmab100, G SK2136773, anti-VEGFR allosteric enzyme, Avila, CEP7055, CLT009, ESBA903, HuMax-VEGF antibody, GW654652, HMPL010, GEM220, H YB676, JNJ17029259, TAK593, XtendVEGF antibody, Nova21012, Nova21013, CP564959, smart anti-VEGF antibody, AG028262, AG13958 , CVX241, SU14813, PRS055, PG501, PG545, PT1101, TG100948, ICS283, XL647, enzalutamide hydrochloride (LY317615), BC194, quinolines, COT601M06.1, COT604M06.2, MabionVEGF, SIR-Spheres-conjugated anti-VEGF or VEGF-R antibodies, apatinib (YN968D1), and AL3818. Additionally, delivery of VEGF inhibitors or VEGF antagonists using the microneedle devices and methods described herein can be used in combination with one or more agents listed herein, as well as in combination with other known agents.

[0087] In some embodiments, one or more components of the prefilled injection devices or systems described herein are configured to be assembled together. For example, the system or device may include one or more syringe barrels.

[0088] In some embodiments, a prefilled injection device or system may include two or more units, such as a first syringe unit including a first syringe barrel, a needle hub located within the first syringe barrel, and a needle including a proximal needle end and a distal needle end engaged with the needle hub. In some embodiments, a prefilled injection device or system may include a second syringe unit configured to be engaged with the distal end of the first syringe unit, the second syringe barrel, and a floating seal member located within the second syringe barrel, the floating seal member configured to resiliently engage with the needle hub when the first syringe unit and the second syringe unit are engaged. In some embodiments, a prefilled injection device or system may include a third syringe unit including a third syringe barrel containing a flowable composition, the third syringe unit configured to be engaged with the distal end of the second syringe unit, and the needle hub may be configured to advance the needle so that the proximal and / or distal ends of the needle enter the flowable composition. In any of the embodiments described herein, the prefilled injection device or system may include one or more syringe units, and may optionally include a fourth syringe unit configured to be engaged with the distal end of the third syringe unit.

[0089] In some embodiments, the prefilled injection device or system may include a first syringe unit including a first syringe barrel, a needle hub and a floating seal member located within the first syringe barrel and elastically engaged with each other, the needle hub located at the proximal end of the floating seal member, and a needle having a proximal end and a distal end engaged with the needle hub, the needle including: (i) a needle distal end opening, (ii) a needle body opening located between the needle proximal end and the needle distal end and located at the proximal end of the needle distal end opening, and (iii) a needle body passage connecting the needle distal end opening and the needle body opening. In some embodiments, the prefilled injection device or system may further include a second syringe unit configured to be engaged with the distal end of the first syringe unit, the second syringe barrel containing the flowable composition, and the needle hub may be configured to advance the needle so that the proximal and / or distal ends of the needle enter the flowable composition. In any of the embodiments described herein, the device may include one or more syringe units, and may optionally include a third syringe unit configured to be engaged with the distal end of the second syringe unit.

[0090] In some embodiments, a prefilled injection device or system may include a first syringe unit including: a first syringe barrel; a needle hub located within the first syringe barrel; and a needle having a proximal needle end and a distal needle end engaged with the needle hub, the needle including: (i) a needle distal end opening; (ii) a needle body opening located between the proximal needle end and the distal needle end and located at the proximal end of the needle distal end opening; and (iii) a needle body passage connecting the needle distal end opening and the needle body opening. In some embodiments, the system or device may further include a second syringe unit configured to be connected to the distal end of the first syringe unit, the second syringe barrel, a floating seal member located within the second syringe barrel, the floating seal member configured to resiliently engage the needle hub when the first and second syringe units are engaged, and a flowable composition, wherein the needle hub may be configured to advance the needle so that the proximal and / or distal needle ends enter the flowable composition. In any of the embodiments described herein, the prefilled injection device or system may include one or more syringe units, and may optionally include a third syringe unit configured to be engaged with the distal end of the second syringe unit.

[0091] In some embodiments, the present disclosure provides a syringe including a syringe barrel having a distal closed end and a proximal open end; an actuation unit (e.g., a resilient moving unit) including a drive member (e.g., a pushing element) and a floating seal member, the floating seal member located within the syringe barrel, the actuation unit (e.g., a resilient moving unit) being resiliently engageable with the drive member (e.g., the pushing element); and a hollow puncture needle connected to the drive member (e.g., the pushing element), the hollow puncture needle including a needle distal end opening and a needle body opening, the needle body opening being located at the proximal end of the floating seal member (the needle distal end opening is connected to the floating seal member). a hollow puncture needle (which may be located at the proximal end of the floating seal member, e.g., the entire length of the needle may be located at the proximal end of the floating seal member, or the needle may pass through the floating seal member such that the needle distal end opening is located at the distal end of the floating seal member), and a prefilled flowable composition cavity (e.g., for a liquid or gel) formed by the distal closed end of the syringe barrel, a cavity wall of the syringe barrel (e.g., a portion of the syringe barrel), and the floating seal member.

[0092] In some embodiments, the prefilled injection device or system is configured to advance the hollow puncture needle by pressing a drive member (e.g., a pressing element). In some embodiments, the hollow puncture needle sequentially pierces the floating seal member and the closed distal end of the syringe barrel, thereby connecting the flowable composition cavity, the needle body opening, and the needle distal end opening. In some embodiments, the hollow puncture needle is pre-inserted into the floating seal member. For example, the needle distal end opening may be located within and blocked by the floating seal member, and then the needle may pass through the flowable composition cavity and pierce the closed distal end of the syringe barrel. In some embodiments, the hollow puncture needle is pre-inserted into the floating seal member. For example, the needle distal opening may be located within the flowable composition cavity, while the needle body opening may be located at the proximal end of or within the floating seal member (e.g., the needle body opening may be blocked by the floating seal member, as shown in FIG. 3E), after which the needle may be advanced to pierce the closed distal end of the syringe barrel. In some embodiments, the hollow puncture needle pre-pierces and penetrates the floating seal member and is located at or passes through the closed distal end of the syringe barrel. For example, the needle distal opening may be located within a distal end seal member of the closed distal end of the syringe barrel (e.g., the needle distal opening may be blocked by the distal end seal member), or at the distal end of the distal end seal member and / or the closed distal end of the syringe barrel, while the needle body opening may be located at the proximal end of a floating seal member (e.g., as shown in FIG. 3D, 6b1), within a floating seal member (e.g., as shown in FIG. 3D, 6b2, the needle body opening may be blocked by a floating seal member), or within the flowable composition cavity (e.g., as shown in FIG. 3D, 6b3), and the needle may then be passed through the closed distal end of the syringe barrel to expose the needle distal opening and puncture tissue.

[0093] Optionally, the prefilled injection device or system may include a state in which the flowable composition cavity, the needle body opening, and the needle distal end opening are in fluid communication. For example, in the fluid communication state, the needle body opening may be located at the proximal end of the floating seal member, and the needle distal end opening may be located at the distal end of the floating seal member and be within the flowable composition cavity. In the fluid communication state, the needle and / or the floating seal member are movable. For example, the floating seal member can move under the action of an elastic restoring force between the floating seal member and the driving member (e.g., a pressing element), so that the floating seal member seals or closes the needle body opening, thereby preventing or stopping the flowable composition (e.g., gel) from being discharged from the needle body opening and / or the needle distal end opening.

[0094] Optionally, in the fluid communication state, the floating seal member can seal the needle body opening when it moves forward and contacts the closed distal end of the syringe barrel, thereby preventing or stopping the flowable composition (e.g., a gel) from being expelled from the needle body opening and / or the needle distal end opening.

[0095] Optionally, a stopper, such as an axial stopper, may be provided in the syringe cavity at the distal end of the floating seal member. In some embodiments, the stopper may be used to limit the forward movement of the floating seal member. In some embodiments, the prefilled injection device or system includes a fluid communication state in which the flowable composition cavity is connected to the needle body opening and the needle distal end opening. When the medical puncture device is in a fluid communication state, the needle body opening may be located at the distal end of the stopper (e.g., as shown in FIG. 2D), and the floating seal member moves forward due to elastic engagement with the drive member (e.g., a pressing element).

[0096] Optionally, the prefilled injection device or system includes a manual control element connected to the floating seal member and extending to the exterior of the syringe barrel.

[0097] Optionally, the pre-filled injection device or system includes a pre-puncture state after the hollow puncture needle pierces the distal closed end of the syringe barrel, a surface tissue puncture state, and a post-puncture fluid communication state. In the pre-puncture state, the superficial tissue puncture state, and the fluid communication state, the length ranges of the hollow puncture needle extending from the closed distal end of the syringe barrel may correspond to a pre-puncture length range, a superficial tissue puncture length range, and a fluid communication length range, respectively, wherein when the length of the hollow puncture needle extending from the closed distal end of the syringe barrel is within the pre-puncture length range, the needle body opening is maintained above the flowable composition cavity (e.g., the needle body opening may be located at the proximal end of and within the floating seal member), and / or when the length of the hollow puncture needle extending from the closed distal end of the syringe barrel is within the superficial tissue puncture length range, at least a portion of the needle body opening is connected to the flowable composition cavity, and / or when the length of the hollow puncture needle extending from the closed distal end of the syringe barrel is within the fluid communication length range, the needle body opening is located within the flowable composition cavity.

[0098] Optionally, an axially extending annular contact element is formed on the closed distal end of the syringe barrel, wherein the difference between the upper and lower limits of the pre-puncture length range is equal to the axial length of the annular contact element.

[0099] Optionally, the elastic moving unit includes an elastic sheath that covers the outside of the hollow puncture needle. The elastic sheath can seal the needle body opening when the needle body opening is located at the proximal end of the floating seal member. In some embodiments, when the flowable composition is a gel, it may not be necessary to seal the needle body opening when the needle body opening is located at the proximal end of the floating seal member.

[0100] Optionally, the prefilled injection device or system includes a catheter guide structure for inserting a catheter into the lumen of the hollow puncture needle (e.g., the needle body passage connected to the needle distal end opening and / or the needle body opening).

[0101] Optionally, the catheter guide structure includes an angled guide groove formed on the floating seal member and extending at an angle toward the hollow puncture needle.

[0102] Optionally, the angled guide groove is configured to pass through the floating seal member from front to rear. In some embodiments, the catheter guide structure further includes a one-way valve fitted into the angled guide groove and capable of being opened and closed, and / or a guide groove plug inserted into the angled guide groove.

[0103] Optionally, the angled guide groove is provided on the top surface of the floating seal member and is a non-through groove.

[0104] Optionally, the needle body opening is formed as a slanted opening that opens diagonally rearward.

[0105] Optionally, the catheter guide structure includes a beveled guide needle hole formed in the wall of the hollow puncture needle body, the hole opening obliquely backward. In some embodiments, the prefilled injection device or system includes a fluid communication state in which the flowable composition cavity is connected to the needle body opening and the needle distal end opening. In the fluid communication state, the beveled guide needle hole is located at the proximal end of the floating seal member.

[0106] Optionally, the catheter guide structure further includes a one-way valve fitted into the beveled guide needle hole and capable of being opened and closed, or a guide groove plug inserted into the beveled guide needle hole.

[0107] Optionally, the catheter guide structure includes a puncturable central guide groove formed in the center of the proximal end face of the drive member (e.g., the pushing element). In some embodiments, a needle proximal end opening is formed in the hollow puncture needle, and the needle proximal end opening is arranged to be axially aligned with the central guide groove.

[0108] Optionally, the prefilled injection device or system includes a puncture control module and a fluid storage module that are independently manufactured and formed, wherein the puncture control module includes a first syringe unit, an elastic movement unit and a hollow puncture needle provided in the first syringe unit, and the fluid storage module includes a second syringe unit, a flowable composition cavity formed in the second syringe barrel, a prefilled pharmaceutical composition or implant, and a module packaging assembly removably packaged at the proximal end of the second syringe unit, and a detachable connection structure is formed between the first syringe unit and the second syringe unit.

[0109] In a second aspect, the present disclosure provides a medical instrument assembly, hi some embodiments, the medical instrument assembly includes a catheter and a medical puncture device with a catheter guide structure.

[0110] Optionally, the medical device assembly further includes a hollow auxiliary guide needle for use in combination with the catheter guide structure. In some embodiments, when the hollow auxiliary guide needle is connected to the catheter guide structure, a catheter may be inserted into the needle body passage of the hollow puncture needle, passing sequentially through the needle body passage of the auxiliary guide needle and the catheter guide structure.

[0111] In some embodiments, when using the prefilled injection device or system of the present disclosure, a user may first apply pressure to a drive member (e.g., a pressing element) to drive the hollow puncture needle to pass through the floating seal member and the distal closed end of the syringe barrel in sequence. When the needle distal end opening of the hollow puncture needle reaches an apparent or potential tissue void, chamber system, and blood vessel, the needle body opening is already located within the flowable composition cavity, and the floating seal member has already formed an elastic engagement with the drive member (e.g., a pressing element). In some embodiments, the fluid pressure within the flowable composition cavity may be set to be higher than the pressure within the apparent or potential tissue void, chamber, or blood vessel.

[0112] At this time, the prefilled fluid in the flowable composition cavity may flow through the needle body opening and the needle distal tip opening into an apparent or potential tissue void, chamber, or blood vessel. During injection, by simply maintaining the position of the driving member (e.g., the pushing element) unchanged, the fluid in the flowable composition cavity can flow into the needle body opening (and then out of the needle distal tip opening through the needle body passage) under the action of the elastic engagement between the floating seal member and the driving member (e.g., the pushing element), thereby achieving injection, puncture, and / or dilation into an apparent or potential tissue void, chamber, or blood vessel. Furthermore, the medical instrument assembly described herein can realize the implantation of catheters and other medical devices through medical puncture devices, such as the catheter guide structures and needle lumens described herein.

[0113] In some embodiments, before the hollow puncture needle is inserted into an apparent or potential tissue void, chamber, or blood vessel, the external pressure on the needle distal end opening is higher than the fluid pressure in the flowable composition cavity, preventing fluid from flowing out of the needle distal end opening. Therefore, by observing whether the floating seal member moves forward due to its elastic engagement with the driving member (e.g., a pushing element), it is possible to determine whether the hollow puncture needle has been inserted into an apparent or potential tissue void, chamber, or blood vessel, thereby informing the operator of the current puncture depth and ensuring accurate puncture. Because the injection is controlled by changes in the fluid pressure in the flowable composition cavity, the operator does not need to manually apply thrust or force during injection, thereby preventing fluctuations in flow rate and achieving stable injection. III. Pharmaceutical Compositions for Prefilled Injection Devices or Systems

[0114] In some embodiments, provided herein is a preloaded or prefilled injection device or system comprising any of the injection devices and any of the pharmaceutical compositions described herein. In some embodiments, provided herein is a preloaded or prefilled injection device or system comprising any of the injection devices and any of the implants described herein. In some embodiments, provided herein is a preloaded or prefilled injection device or system comprising any of the injection devices, any of the pharmaceutical compositions, and any of the implants described herein.

[0115] It should be noted that the present disclosure encompasses any combination of any embodiment of the injection device described herein with any embodiment of the pharmaceutical composition and / or any embodiment of the implant. It should also be noted that the present disclosure encompasses any combination of any embodiment of the pharmaceutical composition described herein with any embodiment of the implant, so long as they are pharmaceutically compatible. For example, in some embodiments, a prefilled injection device or system of the present disclosure may include an injection device and a pharmaceutical composition described herein. As another example, in some embodiments, a prefilled injection device or system of the present disclosure may include an injection device, a pharmaceutical composition described herein, and an implant described herein. In some embodiments, the pharmaceutical composition is a fluid, and the implant is contained within the fluid. In some embodiments, the pharmaceutical composition is coated on or carried by the implant. In some embodiments, the implant is not coated with or carries any pharmaceutical composition.

[0116] In some embodiments, provided herein is a preloaded or prefilled injection device or system comprising any of the injection devices and pharmaceutical compositions described herein, wherein the pharmaceutical composition may be contained in any of the chambers of any of the injection devices described herein. In some embodiments, the pharmaceutical composition comprises only one drug. In some embodiments, the pharmaceutical composition comprises two or more drugs. In some embodiments, the pharmaceutical composition comprises only one drug, and the drug is contained in one chamber. In some embodiments, the pharmaceutical composition comprises only one drug, and the drug is contained in multiple chambers. In some embodiments, the pharmaceutical composition comprises two or more drugs, and the drugs are contained in one chamber. In some embodiments, the pharmaceutical composition comprises two or more drugs, and the drugs are contained in separate chambers.

[0117] In some embodiments, the pharmaceutical composition comprises a corticosteroid. Exemplary corticosteroids include, but are not limited to, dexamethasone, triamcinolone acetonide, triamcinolone, triamcinolone acetonide acetate, fluocinolone acetonide, prednisolone, loteprednol, difluprednate, fluorometholone, and any combination thereof. In some embodiments, the pharmaceutical composition comprises a corticosteroid. In some embodiments, the pharmaceutical composition comprises a combination of two or more corticosteroids.

[0118] In some embodiments, the pharmaceutical composition comprises a corticosteroid formulation comprising a corticosteroid or a pharmaceutically acceptable salt or solvate thereof and one or more pharmaceutically acceptable excipients. In some embodiments, the formulation comprises (1) triamcinolone, (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, (3) a buffering agent, and (4) a tonicity adjusting agent. In some embodiments, the formulation comprises (1) triamcinolone acetonide, (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, (3) a buffering agent, and (4) a tonicity adjusting agent. In some embodiments, the formulation comprises (1) triamcinolone acetonide acetate, (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, (3) a buffering agent, and (4) a tonicity adjusting agent. In some embodiments, the formulation comprises (1) dexamethasone, (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, (3) a buffering agent, and (4) a tonicity adjusting agent. In some embodiments, the formulation comprises (1) fluocinolone acetonide, (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, (3) a buffering agent, and (4) a tonicity adjusting agent. In some embodiments, the formulation comprises (1) prednisolone, (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, (3) a buffering agent, and (4) a tonicity adjusting agent. In some embodiments, the formulation comprises (1) loteprednol, (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, (3) a buffering agent, and (4) a tonicity adjusting agent. In some embodiments, the formulation comprises (1) difluprednate, (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, (3) a buffering agent, and (4) a tonicity adjusting agent. In some embodiments, the formulation comprises (1) fluorometholone, (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, (3) a buffering agent, and (4) a tonicity adjusting agent.

[0119] In some embodiments that may be combined with any of the above or below embodiments, the formulation comprises hyaluronic acid, or a pharmaceutically acceptable derivative, salt, or solvate thereof. In some embodiments, the formulation comprises a salt of hyaluronic acid. In some embodiments, the salt of hyaluronic acid is an alkali metal salt of hyaluronic acid, an alkaline earth metal salt of hyaluronic acid, or a combination thereof. In some embodiments, the salt of hyaluronic acid is a sodium salt of hyaluronic acid. In some embodiments, the molecular weight of the hyaluronic acid, or a pharmaceutically acceptable derivative, salt, or solvate thereof, ranges from about 50,000 daltons to about 2,000,000 daltons. For example, the molecular weight of the hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof is about 50,000, 60,000, 70,000, 80,000, 90,000, 100,000, 110,000, 120,000, 130,000, 140,000, 150,000, 160,000, 170,000, 180,000, 190,000, 200,000 daltons, or any intermediate value therebetween.

[0120] In some embodiments that may be combined with any of the above or below embodiments, the formulation comprises a buffer. In some embodiments, the buffer comprises an acetate buffer, a citrate buffer, a phosphate buffer, a borate buffer, or any mixture thereof. In some embodiments, the buffer comprises a phosphate buffer. In some embodiments, the buffer comprises disodium hydrogen phosphate, sodium dihydrogen phosphate, or a mixture thereof. In some embodiments, the buffer comprises sodium dihydrogen phosphate in the monohydrate form and disodium hydrogen phosphate in the dodecahydrate form. In some embodiments, the buffer is used in an amount sufficient to maintain the pH of the formulation in the range of about 5.5 to about 9.0. In some embodiments, the buffer is used in an amount sufficient to maintain the pH of the formulation in the range of about 6.0 to about 8.5. In some embodiments, the buffer is used in an amount sufficient to maintain the pH of the formulation in the range of about 6.5 to about 8.0. In some embodiments, the buffer is used in an amount sufficient to maintain the pH of the formulation in the range of about 7.0 to about 9.5. In some embodiments, the buffer is used in an amount sufficient to maintain the pH of the formulation at about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, or any intermediate value therebetween. In some embodiments, the formulation further comprises a pH adjuster. In some embodiments, the formulation further comprises a pH adjuster, wherein the pH adjuster is sodium hydroxide. In some embodiments, the pH adjuster is a sodium hydroxide solution, wherein the sodium hydroxide solution has a sodium hydroxide concentration of about 1.5 to 2.5 mol / L (e.g., 2.0 mol / L).

[0121] In some embodiments that may be combined with any of the above or below embodiments, the formulation comprises a osmolality adjuster. In some embodiments, the osmolality adjuster comprises sodium chloride, potassium chloride, magnesium chloride, calcium chloride, or any mixture thereof. In some embodiments, the osmolality adjuster comprises sodium chloride, potassium chloride, or any mixture thereof. In some embodiments, the osmolality adjuster comprises sodium chloride. In some embodiments, the osmolality adjuster is sodium chloride. In some embodiments, the osmolality adjuster is used in an amount sufficient to maintain an osmolality in the range of about 200 mOsm / kg to about 400 mOsm / kg. In some embodiments, the osmolality adjuster is used in an amount sufficient to maintain an osmolality in the range of about 250 mOsm / kg to about 300 mOsm / kg. In some embodiments, the osmolality adjusting agent is used in an amount sufficient to maintain an osmolality of about 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400 mOsm / kg or any intermediate value therebetween.

[0122] In some embodiments that may be combined with any of the above or below embodiments, the formulation comprises water. In some embodiments, the water is water for injection.

[0123] In some embodiments that may be combined with any of the above or below embodiments, the formulation comprises a corticosteroid, and the weight ratio of the corticosteroid to the total formulation is about 1.0-8.0% (w / w). In some embodiments, the formulation comprises triamcinolone acetonide, and the weight ratio of the triamcinolone acetonide to the total formulation is about 1.0-8.0% (w / w). For example, the weight ratio of triamcinolone acetonide to the total formulation is about 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0% (w / w), or any intermediate value thereof.

[0124] In some embodiments that may be combined with any of the above or below embodiments, the formulation comprises hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, wherein the weight ratio of the hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate to the total formulation is about 0.1-5.0% (w / w). In some embodiments, the formulation comprises triamcinolone acetonide and hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate thereof, wherein the weight ratio of the hyaluronic acid or a pharmaceutically acceptable derivative, salt, or solvate to the total formulation is about 0.1-5.0% (w / w). For example, the weight ratio of hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof to the entire formulation may be about 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.10, 1.20, 1.30, 1.40, 1.50, 1.60, 1.70, 1.80, 1.90, 2.00, 2.10, 2.20, 2.30, 2.40, 2.50, 2.60, 2.70, 2.80, 2.90, 3.00, 3.10, 3.20, 3.30, 3.40, 3.50, 3.60, 3.70, 3.80, 3.90, 4.00, 4.10, 4.20, 4.30, 4.40, 4.50, 4.60, 4.70, 4.80, 4.90, 5.00% (w / w) or any intermediate value therebetween.

[0125] In some embodiments that may be combined with any of the above or below embodiments, the formulation comprises a buffering agent, and the weight ratio of the buffering agent to the total formulation is about 0.05-0.8% (w / w). In some embodiments, the formulation comprises triamcinolone acetonide and a buffering agent, and the weight ratio of the buffering agent to the total formulation is about 0.05-0.8% (w / w). For example, the weight ratio of the buffering agent to the total formulation is about 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80% (w / w), or any intermediate value thereof. In some embodiments, the buffer comprises disodium hydrogen phosphate and sodium dihydrogen phosphate, and the weight ratio of the sodium dihydrogen phosphate to the total formulation is about 0.01-0.50% (w / w), and the weight ratio of the disodium hydrogen phosphate to the total formulation is about 0.05-0.20% (w / w). For example, the weight ratio of the sodium dihydrogen phosphate to the total formulation is about 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50% (w / w), or any intermediate value thereof. For example, the weight ratio of the disodium hydrogen phosphate to the total formulation is about 0.05, 0.10, 0.15, 0.20% (w / w), or any intermediate value thereof.

[0126] In some embodiments that can be combined with any of the above or below embodiments, the formulation includes an osmotic agent, and the weight ratio of the osmotic agent to the total formulation is about 5.0-10.0% (w / w). In some embodiments, the formulation includes triamcinolone acetonide and an osmotic agent, and the weight ratio of the osmotic agent to the total formulation is about 5.0-10.0% (w / w). For example, the weight ratio of the osmotic agent to the total formulation is about 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0% (w / w), or any intermediate value therebetween. Preferably, the weight ratio of the osmotic agent to the total formulation is about 6.0-9.0% (w / w).

[0127] In some embodiments, the formulation comprises: (1) 3.0-5.0% (w / w) triamcinolone acetonide; (2) 0.1-5.0% (w / w) hyaluronic acid sodium salt; (3) 0.6-0.8% (w / w) sodium chloride; (4) 0.2-0.4% (w / w) sodium dihydrogen phosphate; (5) 0.05-0.15% (w / w) disodium hydrogen phosphate; (6) sodium hydroxide in an amount sufficient to adjust the pH to about 6.5 to about 7.5; and (7) water. In some embodiments, the formulation contains the following ingredients: (1) 3.0-5.0% (w / w) triamcinolone acetonide, (2) 0.1-5.0% (w / w) hyaluronic acid sodium salt, (3) 0.6-0.8% (w / w) sodium chloride, (4) 0.2-0.4% (w / w) sodium dihydrogen phosphate, (5) 0.05-0.15% (w / w) disodium hydrogen phosphate, (6) sodium hydroxide in an amount sufficient to adjust the pH to about 6.5 to about 7.5, and (7) water.

[0128] In certain embodiments that may be combined with any of the above or below embodiments, the formulation is a suspension.

[0129] In some embodiments that may be combined with any of the above or below embodiments, the formulation comprises triamcinolone acetonide, and the triamcinolone acetonide in the formulation has a volume mean diameter (VMD) of about 0.5 to 3.5 μm. For example, the VMD of the triamcinolone acetonide in the formulation is about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5 μm, or any intermediate value thereof. In some embodiments, the VMD of the triamcinolone acetonide in the formulation is about 0.5 to 3.5 μm. 10 The D of triamcinolone acetonide in the formulation is approximately 0.4 to 1.0 μm. 10is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 μm, or any intermediate value therebetween. In some embodiments, the D of triamcinolone acetonide in the formulation 50 is approximately 1.0 to 2.0 μm. For example, the D 50 is about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 μm, or any intermediate value thereof. In some embodiments, the D of triamcinolone acetonide in the formulation 90 The D of triamcinolone acetonide in the formulation is approximately 2.0 to 3.8 μm. 90 is about 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8 μm, or any intermediate value therebetween.

[0130] In some embodiments, the pharmaceutical composition comprises a formulation of triamcinolone acetonide, wherein the formulation is a suspension of triamcinolone acetonide particles, and the D of triamcinolone acetonide in the formulation 10 is approximately 0.4 to 1.0 μm, and the D of triamcinolone acetonide in the formulation 50 is approximately 1.0-2.0 μm, and the D of triamcinolone acetonide in the formulation 90 In some embodiments, the formulation is a suspension of triamcinolone acetonide particles, and the D of triamcinolone acetonide in the formulation is 10 is approximately 0.6 to 0.85 μm, and the D of triamcinolone acetonide in the formulation 50 is approximately 1.5-1.8 μm, and the D of triamcinolone acetonide in the formulation 90 In some embodiments, the formulation is a suspension of triamcinolone acetonide particles, and the D of triamcinolone acetonide in the formulation is 10 is approximately 0.7-0.8 μm, and the D of triamcinolone acetonide in the formulation 50is approximately 1.6-1.8 μm, and the D of triamcinolone acetonide in the formulation 90 is approximately 3.1 to 3.5 μm.

[0131] In some embodiments, the pharmaceutical composition comprises a formulation of triamcinolone acetonide, the formulation being a suspension of triamcinolone acetonide particles, wherein about 10% of the triamcinolone acetonide particles have a volume mean diameter (VMD) of less than 0.4 to 1.0 μm, about 50% of the triamcinolone acetonide particles have a VMD of less than 1.0 to 2.0 μm, and about 90% of the triamcinolone acetonide particles have a VMD of less than 2.0 to 3.8 μm. For example, the D of triamcinolone acetonide in the formulation is 10 is approximately 0.4 μm, D 50 is approximately 1.0 μm, D 90 is about 2.0-3.8 μm, 10% of the triamcinolone acetonide particles in the formulation have a VMD of less than 0.4 μm, 50% of the triamcinolone acetonide particles have a VMD of less than 1.0 μm, and 90% of the triamcinolone acetonide particles have a VMD of less than 2.0 μm. 10 is approximately 1.0 μm, D 50 is approximately 2.0 μm, D 90is about 3.8 μm, 10% of the triamcinolone acetonide particles in the formulation have a VMD of less than 1.0 μm, 50% of the triamcinolone acetonide particles have a VMD of less than 2.0 μm, and 90% of the triamcinolone acetonide particles have a VMD of less than 3.8 μm. In some embodiments, about 10% of the triamcinolone acetonide particles in the formulation have a VMD of less than 0.6-0.85 μm, about 50% of the triamcinolone acetonide particles in the formulation have a VMD of less than 1.5-1.8 μm, about 90% of the triamcinolone acetonide particles in the formulation have a VMD of less than 3.0-3.5 μm, and the triamcinolone acetonide particles in the formulation have an average VMD of about 1.5-2.5 μm. In some embodiments, about 10% of the triamcinolone acetonide particles in the formulation have a VMD of less than 0.7-0.8 μm, about 50% of the triamcinolone acetonide particles in the formulation have a VMD of less than 1.6-1.8 μm, about 90% of the triamcinolone acetonide particles in the formulation have a VMD of less than 3.1-3.5 μm, and the triamcinolone acetonide particles in the formulation have a mean VMD of about 1.8-2.0 μm.

[0132] In some embodiments, the pharmaceutical composition comprises a formulation of triamcinolone acetonide, the formulation being a suspension of triamcinolone acetonide particles, wherein about 10% of the triamcinolone acetonide particles have a VMD of about 0.5 μm to less than about 0.85 μm, about 50% of the triamcinolone acetonide particles have a VMD of about 1.2 μm to less than about 1.9 μm, and about 90% of the triamcinolone acetonide particles have a VMD of about 2.5 μm to less than about 3.6 μm. In some embodiments, about 10% of the triamcinolone acetonide particles have a VMD of about 0.7 μm to less than about 0.8 μm, about 50% of the triamcinolone acetonide particles have a VMD of about 1.5 μm to less than about 1.8 μm, and about 90% of the triamcinolone acetonide particles have a VMD of about 3.0 μm to less than about 3.5 μm. In some embodiments, about 10% of the triamcinolone acetonide particles have a VMD of about 0.75 μm to less than about 0.78 μm, about 50% of the triamcinolone acetonide particles have a VMD of about 1.63 μm to less than about 1.79 μm, and about 90% of the triamcinolone acetonide particles have a VMD of about 3.15 μm to less than about 3.48 μm. In some embodiments, the triamcinolone acetonide particles in the formulation have a mean VMD of about 0.5 to 2.5 μm. In some embodiments, the triamcinolone acetonide particles in the formulation have a mean VMD of about 0.7 to 2.1 μm. In some embodiments, the triamcinolone acetonide particles in the formulation have a mean VMD of about 0.8 to 2.0 μm. In some embodiments, the triamcinolone acetonide particles in the formulation have a mean VMD of about 0.81 to 1.99 μm.

[0133] In some embodiments that can be combined with any of the above or below embodiments, the pharmaceutical composition comprises a formulation of triamcinolone acetonide, wherein the formulation is prepared by a method comprising wet milling. In some embodiments, the formulation is prepared by a method comprising ball milling. For example, the formulation is prepared by a method comprising adding hyaluronic acid (e.g., in the form of an aqueous solution) to a mixture comprising triamcinolone acetonide particles. As another example, the formulation is prepared by a method comprising adding triamcinolone acetonide particles to a mixture containing hyaluronic acid (e.g., an aqueous solution of hyaluronic acid) and milling the triamcinolone acetonide particles in the mixture containing hyaluronic acid until the VMD of the triamcinolone acetonide particles is in a desired range or value (e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5 μm, or any intermediate value thereof).

[0134] In some embodiments, the pharmaceutical composition comprises a formulation of triamcinolone acetonide, the formulation being substantially free of triamcinolone acetonide particles having a VMD of less than 0.2 μm. In some embodiments, the formulation is substantially free of triamcinolone acetonide particles having a VMD of 0.2-0.4 μm. In some embodiments, greater than 10%, greater than 50%, or greater than 90% of the triamcinolone acetonide particles in the formulation have a VMD greater than 0.2 μm, 0.3 μm, 0.4 μm, 0.5 μm, 0.6 μm, 0.7 μm, 0.8 μm, 0.9 μm, 1.0 μm, 1.5 μm, 2.0 μm, 2.5 μm, 3.0 μm, or 3.8 μm. In some embodiments, about 10% or more of the triamcinolone acetonide particles in the formulation have a VMD greater than 3.8 μm. In some embodiments, about 50% or more of the triamcinolone acetonide particles in the formulation have a VMD greater than 2.0 μm. In some embodiments, about 90% or more of the triamcinolone acetonide particles in the formulation have a VMD greater than 1.0 μm. In some embodiments, about 10% or more of the triamcinolone acetonide particles in the formulation have a VMD greater than 2.0 μm, about 50% or more of the triamcinolone acetonide particles have a VMD greater than 1.0 μm, and about 90% or more of the triamcinolone acetonide particles have a VMD greater than 0.4 μm.

[0135] In some embodiments, the wetting agent used herein includes polysorbate 80. In some embodiments, the wetting agent used herein is polysorbate 80. In some embodiments, the pharmaceutical composition comprises a formulation of triamcinolone acetonide, wherein the formulation does not include polysorbate 80 and any derivatives or analogs thereof.

[0136] In certain embodiments that may be combined with any of the above or below embodiments, the pharmaceutical composition comprises a formulation of triamcinolone acetonide, wherein the formulation further comprises one or more viscosity modifying agents.

[0137] In some embodiments, the present invention provides a preloaded or prefilled injection device or system, comprising any of the injection devices described herein and a pharmaceutical composition comprising a tyrosine kinase inhibitor. Exemplary tyrosine kinase inhibitors include, but are not limited to, axitinib, afatinib, erlotinib, gefitinib, crizotinib, dabrafenib, vemurafenib, dasatanib, imatinib, nilotinib, trametinib, or any combination thereof. In some embodiments, the pharmaceutical composition comprises axitinib.

[0138] In some aspects, provided herein are preloaded or prefilled injection devices or systems comprising any of the injection devices described herein and a pharmaceutical composition comprising a complement inhibitor, in some embodiments, the pharmaceutical composition comprises a plasma kallikrein inhibitor.

[0139] In some aspects, the present invention provides a preloaded or prefilled injection device or system, comprising any of the injection devices described herein and a pharmaceutical composition containing a neuroprotective agent. Exemplary neuroprotective agents include, but are not limited to, cholic acid, chenodeoxycholic acid, deoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, lithocholic acid, taurocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, ursodeoxycholic acid, or any combination thereof. In some embodiments, the pharmaceutical composition comprises a neuroprotective agent, and the neuroprotective agent is tauroursodeoxycholic acid.

[0140] In some embodiments, the present invention provides a preloaded or prefilled injection device or system comprising any of the injection devices described herein and a pharmaceutical composition comprising a hypoxia factor-induced inhibitor. Exemplary hypoxia factor-induced inhibitors include, but are not limited to, EZN-2698, aminoflavone, camptothecin (e.g., topotecan, EZN-2208, SN38, irinotecan, temsirolimus, everolimus, sirolimus, LY294002, wotomannin, cardiac glycosides, digoxin, ouabain, proscillaridin, 2ME2, romidepsin (KF228), trichostatin, LW6, acriflavine, echinomycin, anthracycline antibiotics (e.g., doxorubicin and daunorubicin), chetomin, bortezomib, or any combination thereof. In some embodiments, the pharmaceutical composition comprises a hypoxia factor-induced inhibitor, and the inhibitor is acriflavine.

[0141] In some embodiments, the present invention provides a preloaded or prefilled injection device or system, comprising any injection device described herein and a pharmaceutical composition comprising an adrenergic receptor agonist.Exemplary adrenergic receptor agonists include but are not limited to adrenaline, noradrenaline, isoproterenol, dopamine, phenylephrine, methoxamine, midodrine, oxymetazoline, α-methyldopa, clonidine, brimonidine, dobutamine, salbutamol / albuterol, terbutaline, salmeterol, formoterol, pirbuterol, clenbuterol, or any combination thereof.In some embodiments, the pharmaceutical composition comprises an adrenergic receptor agonist, and the agonist is brimonidine.

[0142] In some embodiments, the present disclosure provides a preloaded or prefilled injection device or system comprising any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more gene therapy agents, such as one or more viral vectors and / or non-viral gene therapy vectors. Exemplary gene therapy agents include, but are not limited to, gene therapy agents using AAV2, AAV5, AAV8, and AAV9 vectors, ET, liposome, or DNA nanoparticle vectored gene therapy agents, or any combination thereof. For example, electroporation or electropermeabilization is a physical method that can be used in gene therapy to introduce polar molecules (e.g., DNA) into eukaryotic cells through the cell membrane by exposing the cells to an electric pulse.

[0143] In some embodiments, the present disclosure provides a preloaded or prefilled injection device or system, comprising any of the injection devices described herein and pharmaceutical compositions, wherein the pharmaceutical compositions comprise one or more protein or polypeptide drugs.Exemplary protein or polypeptide drugs include but are not limited to anti-VEGF drugs (e.g., bevacizumab, ranibizumab, aflibercept, conbercept, etc.), bispecific antibody drugs (e.g., faricimab), vasoconstrictors (e.g., endothelin-1), TNF-α inhibitors (e.g., adalimumab), or any combination thereof.

[0144] In some embodiments, provided herein is a preloaded or prefilled injection device or system comprising any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more therapeutic cells or therapeutic components (e.g., cellular components) for cell therapy. Exemplary cells or therapeutic components include, but are not limited to, stem cells, regulatory T cells, exosomes, or any combination thereof.

[0145] In some embodiments, the present invention provides a preloaded or prefilled injection device or system, comprising any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises, for example, a gel or aqueous polymer solution, such as one or more viscoelastic substances. Examples of gels or aqueous polymer solutions that can be used herein include, but are not limited to, sodium hyaluronate, Provisc (a 1% viscous transparent substance that is a specific component of sodium hyaluronate), Viscoat (a dispersive viscoelastic preparation consisting of sodium hyaluronate and chondroitin sulfate), Amvisc (a purified component of sodium hyaluronate), Amvisc Plus (a 1.6% sodium hyaluronate product derived from rooster comb), sodium chondroitin sulfate / sodium hyaluronate, or DisCoVisc (4% sodium chondroitin sulfate, 1.65% sodium hyaluronate), sodium carboxymethylcellulose, poloxamer, or any combination thereof.

[0146] In some embodiments, the present invention provides a preloaded or prefilled injection device or system, comprising any injection device described herein and a pharmaceutical composition comprising one or more anti-tumor drugs.Exemplary anti-tumor drugs include but are not limited to paclitaxel, immunosuppressants (such as ipilimumab), or any combination thereof.

[0147] In some embodiments, the present invention provides a preloaded or prefilled injection device or system, comprising any injection device described herein and a pharmaceutical composition comprising one or more herbal medicines.Exemplary herbal medicines include but are not limited to artemisinin, curcumin, pilocarpine, or any combination thereof.

[0148] In some embodiments, the present invention provides a preloaded or prefilled injection device or system, comprising any of the injection devices described herein and a pharmaceutical composition comprising one or more H1 receptor antagonists. Exemplary H1 receptor antagonists include, but are not limited to, 0.3% pheniramine maleate (naproxen), emestine (imatinib), and 0.05% levocabastine hydrochloride (rivastine), or any combination thereof.

[0149] In some embodiments, the present invention provides a preloaded or prefilled injection device or system, comprising any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more mast cell stabilizers. Exemplary mast cell stabilizers include, but are not limited to, 4% sodium cromoglycate (Crolom), 2% nedocromil (Alocril), 0.1% pemirolast (Alamast), 0.1% lodoxamide (Alomide), or any combination thereof.

[0150] In some embodiments, the present invention provides a preloaded or prefilled injection device or system, comprising any of the injection devices described herein and a pharmaceutical composition comprising one or more nonsteroidal anti-inflammatory drugs (NSAIDs).Exemplary NSAIDs include but are not limited to aspirin, ibuprofen, naproxen, celecoxib, 0.5% ketorolac tromethamine (Acular), or any combination thereof.

[0151] In some embodiments, the present invention provides preloaded or prefilled injection device or system, comprising any injection device described herein and the pharmaceutical composition comprising one or more prostaglandin derivatives.Exemplary prostaglandin derivatives include but are not limited to latanoprost, travoprost, bimatoprost, or any combination thereof.

[0152] In some embodiments, the present invention provides a preloaded or prefilled injection device or system, comprising any of the injection devices described herein and a pharmaceutical composition comprising one or more anticholinergic drugs.Examples of anticholinergic drugs include but are not limited to atropine, homatropine, tropicamide, or any combination thereof.

[0153] In some embodiments, the present invention provides a preloaded or prefilled injection device or system, comprising any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more anesthetic agents. Exemplary anesthetic agents include, but are not limited to, tetracaine, oxybuprocaine, proparacaine, or any combination thereof. IV. Syringe adapter

[0154] In some aspects, provided herein are adapter sets that can be used in combination with syringes to significantly improve the injection depth accuracy of the syringe, facilitate injection of drugs into tissue (e.g., ocular tissue), and / or facilitate implantation of specific structures into tissue (e.g., ocular tissue). In some aspects, the adapters described herein, when attached to a syringe, can improve the injection accuracy and safety of the syringe. In some embodiments, the adapters described herein, when attached to other syringes (e.g., syringes disclosed in U.S. Patent No. 2020 / 0069883), can improve the injection accuracy and safety of the syringe.

[0155] In some embodiments, the adapter set comprises: a contact member extending from a proximal end to a distal end; a pressing unit including a first elastic element; The contact member may be attached to the distal end of the injection needle such that the distal end of the contact member is located at the distal end of the needle distal end opening and the distal end of the contact member can directly contact the surface tissue of the target injection site; and The pushing unit may be mounted to be engaged with the syringe barrel and the push shaft such that the pushing unit is resiliently engaged with the push shaft and / or the syringe barrel via the first resilient element.

[0156] In some embodiments, the pressing unit can be assembled to the syringe, and the pressing unit can be resiliently engaged with the push shaft and / or syringe barrel via a first resilient element. In some embodiments, the first resilient element is in the form of a spring (e.g., 31 in FIGS. 16A and 16B). In some embodiments, the first resilient element can apply a force to the push shaft, pushing the push shaft toward the distal end. In some embodiments, the pressing unit can limit movement of the syringe barrel of the syringe, particularly toward the distal end. In some embodiments, the pressing unit has a pair of stoppers (e.g., 32 in FIG. 16A) or locking elements (e.g., 33 in FIG. 16B), which can prevent the syringe barrel from moving toward the distal end after the pressing unit is assembled to the syringe.

[0157] In some embodiments, the adapter sets described herein include a contact member, and after the contact member is assembled to the syringe, the proximal end of the contact member directly contacts the distal end of the needle hub or syringe barrel. In some embodiments, as shown in FIG. 15A, after the contact member is assembled to the syringe, the proximal end of the contact member directly contacts the distal end of the syringe barrel. In some embodiments, after the contact member is assembled to the syringe, the proximal end of the contact member indirectly contacts the needle hub. In some embodiments, as shown in FIG. 15A, after the contact member is assembled to the syringe, the proximal end of the contact member indirectly contacts the needle hub or syringe barrel, and the contact member 25 is fabricated from one or more materials having a low modulus of elasticity (e.g., Young's modulus). In some embodiments, the Young's modulus of the contact member is about 0.001 GPa to about 15 GPa. In some embodiments, the Young's modulus of the contact member is about 0.01 GPa to about 10 GPa. In some embodiments, the Young's modulus of the contact member is from about 0.1 GPa to about 5 GPa.

[0158] In some embodiments, the adapter sets described herein further include a second elastic element (e.g., 26 in FIGS. 15C-15E ), which elastically connects the proximal end of the contact member to the distal end of the needle hub or syringe barrel of the syringe after the contact member and second elastic element are assembled to the syringe. In some of the aforementioned embodiments, as shown in FIG. 15B , the contact member 25 has a high elastic modulus (e.g., Young's modulus) and is elastically engaged with the distal end of the needle hub or syringe barrel via the second elastic element 26. In some embodiments, the Young's modulus of the contact member is greater than 10 GPa. In some embodiments, the elastic modulus of the contact member is greater than that of the second elastic element. In some embodiments, the contact member includes a first portion and a second portion, the first portion being located at the distal end of the second portion. In some embodiments, the first portion and the second portion have different elasticities. In some embodiments, the first portion has a higher elasticity than the second portion. In some embodiments, the first portion has a lower elasticity than the second portion. In some embodiments, as shown in FIG. 15D, the contact member 25 includes a first portion 25a and a second portion 25b, the first portion 25a being more elastic than the second portion 25b, the first portion 25a being located at the distal end of the second portion 25b, and the proximal end of the second portion 25b being connected to the needle hub or syringe barrel via a second elastic element 26.

[0159] In some embodiments, the adapter sets described herein further include a connector (e.g., 27 in FIG. 15F), which connects the proximal end of the contact member to the distal end of the needle hub or syringe barrel after the contact member is assembled to the syringe, and which is less elastic than the contact member. In some of the foregoing embodiments, the contact member has a low modulus of elasticity. In some embodiments, the Young's modulus of the contact member is about 0.001 GPa to about 10 GPa. In some embodiments, the connector has a high modulus of elasticity. In some embodiments, the Young's modulus of the connector is greater than 10 GPa.

[0160] In some embodiments, the contact member is in the form of a sleeve or sheath that surrounds the needle. In some embodiments, the contact member is an elastic sleeve or sheath that surrounds the needle (e.g., 25 in FIG. 15A). In some embodiments, the contact member is block-shaped (e.g., 25 in FIG. 15B). In some embodiments, the contact member is block-shaped, and the distal end of the needle can pierce this block. In some embodiments, the contact member is an elastic block, and the distal end of the contact member has a surface shape that conforms to the surface tissue of the target injection site. For example, the distal end of the contact member may have a particular pattern (e.g., FIG. 15G). As another example, the distal end of the contact member may be beveled (e.g., FIG. 15H). In some embodiments, the second elastic element is in the form of a spring (e.g., 26 in FIGS. 15B and 15D). In some embodiments, the second elastic element is in the form of a sleeve or sheath that surrounds the needle (e.g., 26 in FIGS. 15C and 15E). In some embodiments, the second elastic element is an elastic sheath that surrounds the needle. In some embodiments, the connector is in the form of a sleeve or sheath that surrounds the needle (e.g., 27 in Figure 15F). V. Medical Puncture and Implantation Methods

[0161] In some embodiments, methods are described herein for performing a medical puncture, for example, in an eye or other organ or tissue.

[0162] As shown in FIGS. 1-11B, in some embodiments, the present disclosure provides a prefilled injection device or system including a syringe barrel 1, an actuation unit (e.g., an elastic movement unit for pushing the needle), a hollow puncture needle 6, and a flowable composition cavity 7.

[0163] In some embodiments, syringe barrel 1 includes a closed distal end and an open proximal end. In some embodiments, syringe barrel 1 may be designed to have two open ends in the axial direction, and distal end sealing may be achieved by attaching distal end sealing member 8 to the distal end opening of syringe barrel 1. In some embodiments, distal end sealing member 8 may be made of a material that can be punctured by hollow puncture needle 6, such as rubber.

[0164] In some embodiments, the actuation unit (e.g., a resilient displacement unit) includes a drive member (e.g., a pushing element) 2 and a floating seal member 3, where the floating seal member 3 is sealingly engaged with the inner wall of the syringe barrel and configured to move axially, e.g., toward the distal or proximal end of the syringe barrel. In some embodiments, the drive member (e.g., pushing element) 2, or a portion thereof, is located outside the proximal end opening of the syringe barrel, allowing an operator to manually push the drive member (e.g., pushing element) or a portion thereof. In some embodiments, the floating seal member 3 is resiliently engaged with the drive member 2, and when pressure is applied to the drive member 2, the floating seal member 3 can move forward or backward relative to the drive member (e.g., pushing element). In some embodiments, the floating seal member 3 is configured to move toward the distal end of the syringe barrel. In some embodiments, the floating seal member 3 is configured to move toward the proximal end of the syringe barrel. In some embodiments, the position of the drive member (e.g., the pushing element) relative to the syringe barrel remains unchanged, and the floating seal member 3 is configured to move forward (e.g., toward the distal end) due to an elastic restoring force generated by elastic engagement with the drive member (e.g., the pushing element).

[0165] In some embodiments, the hollow puncture needle 6 is fixedly connected to the drive member 2. When no pressure is applied to the drive member 2, the hollow puncture needle 6 is maintained at the proximal end of the floating seal member 3, and the two do not contact each other. In some embodiments, the hollow puncture needle 6 itself includes a needle distal end opening 6a and a needle body opening 6b. In some embodiments, the needle distal end opening 6a and the needle body opening 6b are connected via a needle lumen or a needle body passage of the hollow puncture needle 6.

[0166] In some embodiments, the flowable composition cavity 7 is used to store, for example, medications and other flowable compositions, such as liquids or gels. In some embodiments, the flowable composition cavity is surrounded by the closed distal end of the syringe barrel, the cavity wall of the syringe barrel, and the floating seal member 3; that is, the flowable composition cavity occupies the distal end portion of the syringe barrel cavity. In some embodiments, the floating seal member 3 is axially movable, and the flowable composition cavity 7 is configured to have a variable volume, such that the fluid pressure within the flowable composition cavity 7 can be changed by axial movement of the floating seal member 3. In some embodiments, the flowable composition cavity contains a prefilled pharmaceutical composition. In some embodiments, the flowable composition cavity contains a prefilled fluid and / or one or more structures to be implanted in the eye, for example, in the suprachoroidal space (SCS).

[0167] In some embodiments, using the prefilled injection device or system disclosed herein includes applying pressure to the drive member 2 to push the hollow puncture needle 6 to advance to the distal end and pass through the floating seal member 3 (e.g., by puncturing the floating seal member or piercing an existing hole or slit in the floating seal member) and the closed distal end of the syringe barrel (e.g., by puncturing the closed distal end or piercing an existing hole or slit in the closed distal end). The existing hole or slit may, for example, penetrate the floating seal member from its proximal end face to its distal end face, thereby forming a through-hole in the floating seal member. The existing hole or slit may not penetrate the entire floating seal member, and advancing the needle distal end through the floating seal member may include any suitable combination of passing through an existing hole or slit and piercing a portion of the floating seal member. For example, the needle distal end may first be advanced through an existing hole or slit in the proximal end face, then puncture the floating seal member, and then exit the distal end face of the floating seal member, or vice versa. In some embodiments, the hollow puncture needle 6 is inserted into an apparent or potential tissue void, chamber, or blood vessel, such that the needle distal end opening 6a is located within the apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the needle body opening 6b is located within the flowable composition cavity 7, and the floating seal member 3 is resiliently engaged with the drive member 2. In some embodiments, the fluid pressure within the flowable composition cavity 7 is higher than the pressure within the apparent or potential tissue void, chamber, or blood vessel.

[0168] At this time, the flowable composition within the flowable composition cavity 7 can flow through the needle body opening 6b and the needle distal tip opening 6a into an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, during injection, the user may simply maintain pressure on the drive member 2, for example, without further increasing the pressure. The elastic engagement between the floating seal member 3 and the drive member 2 allows the flowable composition (e.g., a solution, suspension, or gel) within the flowable composition cavity 7 to enter the needle body opening 6b and pass through the needle body passage, thereby achieving injection, penetration, and / or expansion into an apparent or potential tissue void, chamber, or blood vessel.

[0169] In some embodiments, before the hollow puncture needle 6 is inserted into an apparent or potential tissue void, chamber, or blood vessel, the external pressure on the needle distal end opening 6a may be higher than the fluid pressure in the flowable composition cavity 7. This is because, for example, the needle distal end opening is located in tissue that is denser, harder, and / or less deformable than the apparent or potential tissue void, chamber, or blood vessel. Therefore, the flowable composition in the flowable composition cavity cannot flow out of the needle distal end opening 6a and enter the surrounding tissue. Taking the puncture process of the SCS of the eye as an example, if the hollow puncture needle 6 has punctured the sclera 13 but has not yet punctured the SCS 14, the flowable composition will not flow out of the needle distal end opening 6a regardless of whether the needle body opening 6b is in fluid communication with the flowable composition cavity 7. This is because the sclera 13 is relatively dense, and the needle distal end opening 6a is subjected to a high external pressure when it is located within the sclera 13. The external pressure is greater than the fluid pressure within the flowable composition cavity 7, and dense tissue such as the sclera actually acts as a plunger to prevent the flowable composition from flowing out.

[0170] In some embodiments, by observing whether the floating seal member 3 moves forward due to the elastic engagement while the drive member 2 remains stationary under pressure, the operator can determine whether the hollow puncture needle 6 has penetrated into an apparent or potential tissue void, chamber, or blood vessel, thereby informing the operator of the current needle depth and / or the location of the needle distal end opening and ensuring accurate needle placement. In some embodiments, the injection process is controlled by changes in fluid pressure within the flowable composition cavity 7, eliminating the need for manual application of force transmitted through a relatively rigid medium (e.g., a solid or liquid) to advance the needle tip and accurately position it within an apparent or potential tissue void, chamber, or blood vessel. Meanwhile, the elastic engagement between the drive member 2 and the floating seal member 3 can buffer sudden forces applied to the drive member 2, thereby enabling more controllable and stable movement of the floating seal member. In some embodiments, the use of the devices disclosed herein can prevent or reduce fluctuations in flow rate and achieve stable injection.

[0171] In some embodiments, when the hollow puncture needle 6 pierces the closed distal end of the syringe barrel, the medical puncture device may assume at least three states: a pre-puncture state, a superficial tissue puncture state, and a fluid communication state.

[0172] In some embodiments, in the pre-puncture state, the length range of the hollow puncture needle 6 extending from the closed distal end of the syringe barrel is a pre-puncture length range, in which the hollow puncture needle 6 has not yet begun to puncture the living body or its tissue.

[0173] In some embodiments, a system or device of the present disclosure includes a flowable composition cavity prefilled with a flowable composition. In some embodiments, a needle has already passed through the floating seal member prior to use of the system or device. In some embodiments, a needle has already passed through the floating seal member and the distal end of the syringe barrel, e.g., a distal seal member used to seal the distal end of the syringe barrel, prior to use of the system or device.

[0174] In some embodiments, the flowable composition has a relatively high viscosity, e.g., a consistency greater than watery, such as a gel or paste-like substance. The elastic sheath or sleeve 4 shown in the figures of the present disclosure is optional, particularly if the viscosity of the flowable composition is sufficient to prevent the needle body opening and / or needle distal tip opening from being within the flowable composition cavity. For example, as shown in FIG. 3A, the needle may pass through the floating seal member such that the needle body opening 6b is located at the proximal end of the floating seal member and the needle distal tip opening 6a is located within the flowable composition cavity. The viscosity of the composition may prevent the flowable composition from exiting the needle body opening, and the elastic sheath is optional. Alternatively, as shown in FIG. 3B, the needle body opening 6b may be located within the flowable composition cavity and the needle distal tip opening 6a may be located outside the flowable composition cavity. The viscosity of the composition can prevent the flowable composition from exiting the needle distal tip opening until the needle distal tip opening reaches the target tissue, such as an apparent or potential tissue void, chamber, or blood vessel.

[0175] In some embodiments, for example, before or during use of the system or device, needle distal tip opening 6a may be located outside the flowable composition cavity, and needle body opening 6b may be at the proximal end of the floating seal member (e.g., as shown at 6b1 in FIG. 3C) or within the floating seal member (e.g., as shown at 6b2 in FIG. 3C). The viscosity of the composition may prevent the flowable composition from exiting the needle distal tip opening until it reaches the target tissue, such as an apparent or potential tissue void, chamber, or blood vessel.

[0176] In some embodiments, for example, before or during use of the system or device, the needle distal end opening 6a may be located within a distal end seal member at the closed distal end of the syringe barrel (e.g., the needle distal end opening may be blocked by the distal end seal member), and the needle body opening 6b may be located at the proximal end of a floating seal member (e.g., as shown in 6b1 in FIG. 3D ), within a floating seal member (e.g., as shown in 6b2 in FIG. 3D ), or within a flowable composition cavity (e.g., as shown in 6b3 in FIG. 3D ). Discharge of the flowable composition from the needle distal end opening and the needle body opening can be prevented.

[0177] In some embodiments, for example, before or during use of the system or device, needle distal end opening 6a may be located within the flowable composition cavity, and needle body opening 6b may be located within a floating seal member (e.g., as shown at 6b1 in FIG. 3E) or within the flowable composition cavity (e.g., as shown at 6b2 in FIG. 3E), preventing the flowable composition from exiting the needle body opening.

[0178] In some embodiments, for example, before or during use of the system or device, the needle distal end opening 6a may be located within the floating seal member and the needle body opening 6b may be located at the proximal end of the floating seal member (e.g., as shown at 6b in FIG. 3F), preventing the flowable composition from exiting the needle body opening.

[0179] In some embodiments, in the superficial tissue puncture state, the length range of the hollow puncture needle 6 extending from the closed distal end of the syringe barrel is the superficial tissue puncture length range. Within this range, the distal end of the hollow puncture needle 6 has already entered the superficial tissue (e.g., penetrated the sclera 13) but has not yet entered any apparent or potential tissue void, chamber, or blood vessel (e.g., has not yet penetrated the SCS 14). In some embodiments, due to the relatively dense superficial tissue, the external pressure at the needle distal end opening 6a is higher than the fluid pressure within the flowable composition cavity 7, and therefore, the flowable composition does not enter the needle body opening 6b and / or exit the needle distal end opening 6a, regardless of whether the needle body opening 6b is connected to the flowable composition cavity 7.

[0180] In some embodiments, in the fluid communication state, the length range of the hollow puncture needle 6 extending from the closed distal end of the syringe barrel is the fluid communication length range. Within this range, the distal end of the hollow puncture needle 6 has already been inserted into an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the device may be designed such that, in the fluid communication state, the fluid pressure within the flowable composition cavity 7 is higher than the pressure within the apparent or potential tissue void, chamber, or blood vessel. In some embodiments, in the fluid communication state, the needle body opening 6b is already located within the flowable composition cavity 7, and the pressure difference between the interior (e.g., the apparent or potential tissue void, chamber, or blood vessel) and the exterior (e.g., within the flowable composition cavity 7) allows the flowable composition within the flowable composition cavity 7 to pass through the needle body opening 6b, the needle body passage, and then flow into the apparent or potential tissue void, chamber, or blood vessel via the needle distal end opening 6a.

[0181] In some embodiments, due to the resilient engagement between the floating seal member 3 and the drive member 2 (e.g., because the pressure in the flowable composition cavity is greater than the backpressure at the needle distal end opening in the apparent or potential tissue void, chamber, or vessel), the floating seal member 3 moves distally until it seals the needle body opening 6b (e.g., as shown in Figures 4A-4B). In some embodiments, the axial size of the needle body opening is equal to or less than the thickness of the floating seal member. In some embodiments, the needle body opening may be completely sealed or blocked by the floating seal member, in which case the flowable composition will not flow into the tissue void from the needle distal end opening 6a. In some embodiments, when the floating seal member blocks the needle body opening, only a portion of the total volume of the flowable composition flows out of the needle distal end opening 6a (e.g., as shown in Figure 4A). In some embodiments, when the floating seal member blocks the needle body opening, the entire volume of the flowable composition in the chamber is expelled from the needle distal end opening 6a of the needle (e.g., as shown in Figure 4B).

[0182] In some embodiments, the needle body opening may be located within the distal end seal member or within the subject's tissue, and the flowable composition stops flowing out of the needle distal end opening 6a (e.g., as shown in FIG. 4C). In some embodiments, the distance between the needle distal end opening 6a and the needle body opening 6b may remain constant. In some embodiments, the distance between the needle distal end opening 6a and the needle body opening 6b may vary. For example, a needle having an appropriate distance between the needle distal end opening 6a and the needle body opening 6b may be selected based on a known or estimated depth of the tissue to be reached. In some embodiments, a stopper 1a may be provided in the syringe chamber and used to limit the forward movement of the floating seal member 3 to achieve a precise injection, e.g., a predetermined volume.

[0183] In some embodiments, when the floating seal member 3 contacts the stopper 1a, further movement of the floating seal member toward the distal end is restricted, thereby stabilizing the floating seal member 3 for subsequent manipulation, as shown, for example, in FIGS. 6-11B.

[0184] In some embodiments, a system or device disclosed herein includes two or more floating seal members. For example, as shown in FIG. 5A, a first cavity is formed between floating seal member 3b and the syringe barrel distal end seal member, and a second cavity is formed between floating seal member 3a and floating seal member 3b. In some embodiments, the first and second cavities contain the same flowable composition. In some embodiments, the first and second cavities contain different flowable compositions. In some embodiments, the first and second cavities contain the same drug (e.g., active pharmaceutical ingredient) in the same or different flowable carrier or excipient. In some embodiments, the first and second cavities contain different drugs (e.g., active pharmaceutical ingredients) in the same or different flowable carrier or excipient. In some embodiments, the first cavity contains a drug and the second cavity contains a pharmaceutically acceptable carrier or excipient, such as saline, or vice versa. In some embodiments that can be combined with any of the preceding embodiments, the first cavity is prefilled with a first flowable composition. In some embodiments that can be combined with any of the preceding embodiments, the second cavity is prefilled with a second flowable composition. The first and second flowable compositions can be the same or different. For example, the first and second flowable compositions can contain the same active pharmaceutical ingredient (but in, e.g., different carriers or excipients), or they can contain different active pharmaceutical ingredients. In some embodiments that can be combined with any of the preceding embodiments, both the first and second cavities are prefilled with the same flowable material (e.g., the same pharmaceutical formulation) or different flowable materials (e.g., different pharmaceutical formulations).

[0185] In some embodiments, the flowable compositions in the first and second cavities may be sequentially delivered into an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the flowable compositions in the first and second cavities may be mixed within an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the flowable composition in the first cavity enters an apparent or potential tissue void, chamber, or blood vessel, reaches the tissue void, chamber, or blood vessel, and / or dilates the tissue void, chamber, or blood vessel. Next, the drug-containing flowable composition in the second cavity can enter an apparent or potential tissue void, chamber, or blood vessel. For example, as shown in FIG. 5A, when the needle distal end opening 6a of the hollow puncture needle 6 is located within an apparent or potential tissue void, chamber, or blood vessel and the needle body opening 6b is located within the first cavity (between the floating seal member 3b and the distal end seal member of the syringe barrel), the flowable composition in the first cavity is delivered to the tissue. In FIG. 5B, when floating seal member 3b moves distally and needle body opening 6b contacts the second cavity (between floating seal member 3a and floating seal member 3b), needle distal opening 6a may remain stationary within an apparent or potential tissue void, chamber, or vessel. In this manner, the flowable composition within the second cavity begins to be delivered into the tissue, as shown in FIG. 5C, until a specific volume is delivered and / or until floating seal member 3a (or both floating seal member 3a and floating seal member 3b) occludes needle body opening 6b. In some embodiments, a set (e.g., preset) volume of the flowable composition within the first cavity and / or a set (e.g., preset) volume of the flowable composition within the second cavity may be delivered into an apparent or potential tissue void, chamber, or vessel.In some embodiments, the size of the needle body opening 6b along the needle shaft is greater than the thickness of the floating seal member 3b, so that the first flowable composition (between the floating seal member 3b and the syringe distal end seal member) and the second flowable composition (between the floating seal member 3b and the floating seal member 3a) may be sequentially and continuously delivered through the needle distal end opening into an apparent or potential tissue void, chamber, or vessel. In some embodiments, the size of the needle body opening 6b along the needle shaft is less than or equal to the sum of the thicknesses of the floating seal member 3a and the floating seal member 3b. In some embodiments, the size of the needle body opening 6b along the needle shaft is greater than the thickness of the floating seal member 3b but less than the sum of the thicknesses of the floating seal member 3a and the floating seal member 3b. In some embodiments, a system or device disclosed herein includes one or more additional floating seal members (e.g., third floating seal member 3c) positioned at the proximal end of floating seal member 3a, the distal end of floating seal member 3b, and / or between floating seal member 3a and floating seal member 3b to form a third cavity, and the third flowable composition may be delivered before the first flowable composition, after the second flowable composition, or between the first and second flowable compositions. In some embodiments, the third cavity is prefilled with a flowable material.

[0186] In some embodiments, the prefilled injection device or system disclosed herein includes two or more needle body openings. In some embodiments, the prefilled injection device or system disclosed herein includes two or more needle body openings and two or more floating seal members. For example, as shown in FIG. 5D, when the needle distal end opening 6a is in an apparent or potential tissue space, chamber, or blood vessel, the needle body opening 6b1 is in the first cavity (between the floating seal member 3b and the distal end seal member of the syringe barrel), and the needle body opening 6b2 is blocked by the floating seal member 3b, the flowable composition in the first cavity is delivered to the tissue. In FIG. 5E, when the floating seal member 3b moves distally to block the needle body opening 6b1 and the needle body opening 6b2 contacts the second cavity (between the floating seal member 3a and the floating seal member 3b), the needle distal end opening 6a remains stationary in the apparent or potential tissue space, chamber, or blood vessel. In this manner, the flowable composition in the second cavity begins to be delivered into the tissue, as shown in FIG. 5F, until a specific volume is delivered and / or until floating seal member 3a (or both floating seal member 3a and floating seal member 3b) occludes needle body opening 6b2 (and / or needle body opening 6b1). In some embodiments, a set (e.g., preset) volume of the flowable composition in the first cavity and / or a set (e.g., preset) volume of the flowable composition in the second cavity may be delivered into an apparent or potential tissue void, chamber, or vessel. In some embodiments, the first cavity is prefilled with a set (e.g., preset) volume of the flowable composition. In some embodiments, the second cavity is prefilled with a set (e.g., preset) volume of the flowable composition.In some embodiments, the distance between needle body opening 6b1 and needle body opening 6b2 along the needle shaft is greater than the thickness of floating seal member 3b, so that the first flowable composition (between floating seal member 3b and the syringe distal end seal member) and the second flowable composition (between floating seal member 3b and floating seal member 3a) may be sequentially and continuously delivered through the needle distal end opening into an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the distance between needle body opening 6b1 and needle body opening 6b2 along the needle shaft is less than or equal to the sum of the thicknesses of floating seal member 3a and floating seal member 3b. In some embodiments, the distance between needle body opening 6b1 and needle body opening 6b2 along the needle shaft is greater than the thickness of floating seal member 3b but less than the sum of the thicknesses of floating seal member 3a and floating seal member 3b. In some embodiments, the systems or devices disclosed herein include one or more additional needle body openings (e.g., third needle body opening 6b3) located at the proximal end of needle body opening 6b2, the distal end of needle body opening 6b1, and / or between needle body openings 6b1 and 6b2 to form a third cavity, and the third flowable composition may be delivered before the first flowable composition, after the second flowable composition, or between the first and second flowable compositions.

[0187] Below, several embodiments are described in which the medical lancing devices disclosed herein are used to control the end of an injection.

[0188] In some embodiments, when the prefilled injection device or system is in fluid communication, the floating seal member 3 moves forward due to its elastic engagement with the drive member 2 until it seals the needle body opening 6b. Once the needle body opening 6b is sealed, the injection process is terminated. In some embodiments, the axial position of the needle body opening 6b within the flowable composition cavity 7 limits the maximum injection volume of the medical puncture device. In some embodiments, when the needle body opening 6b is closed or sealed by the floating seal member 3, the floating seal member 3 does not yet contact the wall of the distal closed end of the syringe barrel. In some embodiments, the flowable composition cavity 7 is not completely emptied, and the flowable composition still exists between the floating seal member 3 and the wall of the distal closed end of the syringe barrel.

[0189] In some embodiments, when it is necessary to empty the flowable composition cavity 7, the floating seal member 3 may be designed to seal the needle body opening 6b when the floating seal member contacts the wall of the closed distal end of the syringe barrel. In some embodiments, the needle body opening 6b is located at the distal end of the flowable composition cavity 7. In some embodiments, the floating seal member 3 contacts the wall of the closed distal end of the syringe barrel, and the needle body opening 6b is blocked or sealed by the floating seal member 3 and / or the wall of the closed distal end of the syringe barrel. In some embodiments, the flowable composition cavity 7 is emptied and there is little or no flowable composition between the floating seal member 3 and the wall of the closed distal end of the syringe barrel.

[0190] In some embodiments, as the flowable composition within flowable composition cavity 7 gradually enters the apparent or potential tissue void, chamber, or vessel, a condition may occur in which the fluid pressure within flowable composition cavity 7 balances with the pressure within the apparent or potential tissue void, chamber, or vessel. At this point, the balance of forces prevents the floating seal member 3 from moving. To continue injecting and / or emptying flowable composition cavity 7, additional force must be applied to the floating seal member 3, moving it forward toward the closed distal end of the syringe barrel.

[0191] For example, as shown in FIGS. 2A-2E, the body wall of the syringe barrel 1 may be provided with one, two, or more axially extending slide grooves (not shown). A slider aligned with the slide groove may be provided on the drive member 2 (e.g., the slider may comprise a portion of the drive member 2 extending outside the syringe barrel 1), thereby increasing the upper limit of the travel distance or stroke of the drive member 2 since the movement is no longer limited by the proximal end of the drive member 2. When the floating seal member 3 is no longer able to move due to a balance of forces (e.g., the balance between the pressure within the flowable composition cavity 7 and the pressure within an actual or potential tissue void, chamber, or vessel), greater pressure can be applied to the slider of the drive member 2, driving the drive member 2 forward toward the distal end. This increases the elastic restoring force between the floating seal member 3 and the drive member 2, upsetting the force balance and causing the floating seal member 3 to move forward toward the distal end of the syringe barrel. In this manner, more flowable composition is expelled from flowable composition cavity 7, and in some embodiments, flowable composition cavity 7 becomes empty.

[0192] In some embodiments, other drive structures may be used to move the floating seal member 3 further until it contacts the wall of the closed distal end of the syringe barrel. Some exemplary drive structures are described below.

[0193] In some embodiments, the prefilled injection device or system includes an element configured to allow an operator to manually control the movement of the floating seal member 3 with one or both hands. In some embodiments, the manual control element can be moved using one or more fingers, for example, one finger of the same hand that holds the syringe barrel. In some embodiments, the manual control element is fixed to the floating seal member 3 and extends partially outside the syringe barrel. In some embodiments, if the volume of the flowable composition injected into an apparent or potential tissue void, chamber, or blood vessel does not reach the target volume and the floating seal member 3 no longer moves due to a balance of forces, the operator may drive the floating seal member 3 to move further forward by moving the portion of the manual control element that extends outside the syringe barrel until the volume of the expelled flowable composition reaches the target volume. In some embodiments, the use of the manual control element is useful for emptying the flowable composition cavity 7. These embodiments are not limited to situations where the flowable composition cavity 7 needs to be emptied.

[0194] In some embodiments, the prefilled injection device or system can achieve precise delivery (e.g., via injection) of a specific volume of the flowable composition and / or control the delivered volume. In some embodiments, the specific volume is a preset volume before delivery. In some embodiments, the specific volume is a prefilled volume before delivery. In some embodiments, the specific volume is one of multiple volumes that the operator can select during the delivery process, and the delivered volume may differ from the preset volume. In some embodiments, as shown in FIGS. 1A-1E, 2A-2E, and 11A-11B, an axial stopper 1a is provided in the syringe cavity and located at the distal end of the floating seal member 3, and is used to limit the forward movement of the floating seal member 3. In some embodiments, when the medical puncture device is in fluid communication, the needle body opening 6b may be located at the distal end of the axial stopper 1a, and the floating seal member 3 may move forward due to elastic engagement with the drive member 2.

[0195] In some embodiments, the floating seal member 3 moves to a position limited by the axial stop 1 a. In some embodiments, when the floating seal member 3 moves to a position limited by the axial stop 1 a, the pressure within the flowable composition cavity 7 is still not lower than the pressure within the apparent or potential tissue void, chamber, or vessel. In some embodiments, the floating seal member 3 may be advanced forward to a position limited by the axial stop 1 a by the elastic restoring force between the floating seal member 3 and the drive member 2 without relying on an additional drive structure or force to move the floating seal member 3 to a position limited by the axial stop 1 a.

[0196] In some embodiments, the pressure within the flowable composition cavity 7 has already equalized with the pressure within the apparent or potential tissue void, chamber, or vessel before the floating seal member 3 moves to a position limited by the axial stop 1a due to the elastic restoring force between the floating seal member 3 and the drive member 2 (i.e., the balance of forces prevents the floating seal member 3 from moving further until it reaches the axial stop 1a). At this point, the floating seal member 3 is prevented from advancing forward to a position limited by the axial stop 1a solely by the elastic restoring force between the floating seal member 3 and the drive member 2. Therefore, in some embodiments, one or more additional drive structures or mechanisms may be used to further advance and move the floating seal member 3 forward. For example, the additional drive structures or mechanisms may include manual control elements described herein (e.g., shown in FIGS. 2A-2E). In some embodiments, the axial stop 1a provides a mechanism for achieving the injection of a set volume of fluid.

[0197] Below are several embodiments relating to the timing of puncturing and injection of the medical puncturing device disclosed herein.

[0198] In some embodiments, when the prefilled injection device or system is in a pre-puncture state, i.e., when the length of the hollow puncture needle 6 extending from the closed distal end of the syringe barrel is within a pre-puncture length range (or when the hollow puncture needle 6 has already pierced the closed distal end of the syringe barrel but has not yet begun to puncture a living body or its tissue), the needle body opening 6b is maintained above (e.g., at its proximal end) the flowable composition cavity 7. In this way, premature leakage from the needle distal end opening 6a can be prevented, and the reliability of the medical puncture device can be improved.

[0199] In some embodiments, a corresponding structure can be provided on the prefilled injection device or system to prevent premature leakage before the hollow puncture needle 6 punctures tissue and / or before the needle distal end opening 6a reaches an obvious or potential tissue cavity, chamber, or blood vessel. For example, an axially extending annular contact element 1b (this element is optional) can be formed on the closed distal end of the syringe barrel. In some embodiments, the axial length of the annular contact element 1b is set to be equal to the difference between the upper and lower limits of the pre-puncture length range of the hollow puncture needle 6 (i.e., the difference between the pre-puncture length of the hollow puncture needle 6 when it pierces the closed distal end of the syringe barrel and when it begins to puncture the living body or tissue). With this configuration, premature leakage will not occur at the needle distal end opening 6a as long as the distal end of the hollow puncture needle 6 remains within the axial length range of the annular contact element 1b. During puncture, the annular contact element 1b can first contact the surface of the living body or tissue to stabilize the medical puncture device. Pressure can then be applied to the drive member 2 to initiate the lancing operation.

[0200] In some embodiments, when the prefilled injection device or system is in a superficial tissue puncture state, i.e., when the length of the hollow puncture needle 6 extending from the closed distal end of the syringe barrel is within the superficial tissue puncture length range (or when the distal end of the hollow puncture needle 6 has already pierced the superficial tissue but has not yet entered an apparent or potential tissue void, chamber, or blood vessel), the needle body opening 6b is at least partially connected to the flowable composition cavity 7. In some embodiments, fluid communication is already established between the flowable composition cavity 7, the needle distal end opening 6a, and the needle body opening 6b before the distal end of the hollow puncture needle 6 is inserted into an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the flowable composition in the chamber 7 can pre-enter the needle body passage of the hollow puncture needle 6 (via the needle body opening 6b), thereby removing at least a portion of the air that may be present in the needle body passage and thereby reducing the amount of air that enters an apparent or potential tissue void, chamber, or blood vessel.

[0201] In some embodiments, as the distal end of hollow puncture needle 6 begins to penetrate the superficial tissue, needle body opening 6b begins to connect with flowable composition cavity 7. In some embodiments, as the distal end of hollow puncture needle 6 penetrates an apparent or potential tissue void, chamber, or blood vessel, the needle body passage of hollow puncture needle 6 is already filled with flowable composition, thereby eliminating or reducing the possibility of air getting into the apparent or potential tissue void, chamber, or blood vessel.

[0202] In some embodiments, when the prefilled injection device or system is in fluid communication, i.e., when the length of the hollow puncture needle 6 extending from the closed distal end of the syringe barrel is within the fluid communication length range (or when the distal end of the hollow puncture needle 6 has already been inserted into an apparent or potential tissue void, chamber, or blood vessel), the needle body opening 6b is already located within the flowable composition cavity 7, thereby achieving a maximum flow rate at the needle body opening 6b, thereby increasing the injection speed.

[0203] The embodiments described herein may be implemented singly or in any suitable combination.

[0204] In some embodiments, the devices disclosed herein can prevent backflow and / or back leakage of fluid through the needle body opening 6b.

[0205] In some embodiments, when the needle distal end opening 6a is connected to the flowable composition cavity 7 and the needle body opening 6b is still located at the proximal end of the floating seal member 3, there is a risk of backflow and / or back leakage of fluid from the needle body opening 6b. In some embodiments, when the needle distal end opening 6a is located within an apparent or potential tissue void, chamber, or blood vessel and the needle body opening 6b is still located at the proximal end of the floating seal member 3, there is a risk of backflow and / or back leakage of fluid from the needle body opening 6b. In some embodiments, an elastic sheath 4 covering the outside of the hollow puncture needle 6 may be provided within the actuation unit (e.g., elastic movement unit), for example, between the needle hub and the floating seal member 3. In some embodiments, when the needle body opening 6b is located at the proximal end of the floating seal member 3 (e.g., when the needle body opening 6b is not yet connected to the flowable composition cavity 7), the elastic sheath 4 can maintain the seal of the needle body opening 6b, thereby effectively avoiding backflow and / or back leakage of the flowable composition, preventing contamination of the area near the floating seal member 3, reducing fluid loss, and improving product reliability.

[0206] In some embodiments, the elastic sheath 4 is not used to seal the needle body opening 6b, but simply functions as an elastic engagement element between the floating seal member 3 and the drive member 2. In some embodiments, advancing the drive member 2 forward can compress the elastic sheath 4 between the floating seal member 3 and the drive member 2, thereby generating an elastic restoring force between the floating seal member 3 and the drive member 2 and driving the floating seal member 3 to move forward. In some embodiments, the elastic engagement element between the floating seal member 3 and the drive member 2 can include or be a spring 5, which is connected at two axial ends to the floating seal member 3 and the drive member 2, respectively. Such connection at one or both ends of the spring can be direct or indirect. Such connection at one or both ends of the spring can be releasable or non-releasable. The spring, floating seal member, and drive member (e.g., a pressing element) can be manufactured separately and then assembled in any suitable order. Alternatively, any two or more of the spring 5, the floating seal member 3, and the drive member (e.g., the pressing element) may be integrated, e.g., manufactured as a whole. The spring 5 and the elastic sheath 4 may be used alone or in combination.

[0207] In some embodiments, the elastic engagement between the floating seal member 3 and the drive member 2 may be achieved by methods other than providing one or more elastic engagement members. For example, the floating seal member 3 and the drive member 2 may be provided as an integrated actuation unit (e.g., an elastic movement unit).

[0208] In some embodiments, the present disclosure provides devices and methods for implanting the medical puncture device disclosed herein into obvious or potential tissue voids, chamber systems, and blood vessels. For ease of understanding, a stent will be used as an example to describe the implanted medical device. In some embodiments, the disclosed methods include guiding a stent 11 into the needle body passage of a hollow puncture needle 6 using a stent guide structure. In some embodiments, the stent guide structure is provided in a prefilled injection device or system disclosed herein.

[0209] In some embodiments, as shown in FIGS. 6-8 , the stent guide structure is disposed within or engaged with the floating seal member 3 and includes an inclined guide groove 3a extending at an angle toward the hollow puncture needle 6. In some embodiments, when the flowable composition cavity 7, the needle body opening 6b, and the needle distal end opening 6a are connected, the flowable composition can enter and expand an obvious or potential tissue void, chamber, or blood vessel. In some embodiments, the stent 11 may be implanted into an obvious or potential tissue void, chamber, or blood vessel after expansion through the inclined guide groove 3a, the needle body opening 6b, the needle body passage of the hollow puncture needle 6, and the needle distal end opening 6a.

[0210] The inclined guide groove 3a may be provided as a groove that penetrates the floating seal member 3 in the direction of the proximal end / distal end, or may be provided as a non-penetrating groove formed on the proximal end surface of the floating seal member 3.

[0211] In some embodiments, the inclined guide groove 3a is a through groove. In some embodiments, the catheter guide structure further includes a valve 9 disposed within or engaged with the inclined guide groove 3a. The valve may be a one-way valve configured to open and close. In some embodiments, the valve includes multiple flaps configured to open and close the valve. In some embodiments, in the absence of an external force, the one-way valve 9 is closed, preventing the flowable composition in the flowable composition chamber 7 from leaking through the valve. In some embodiments, in the presence of an opening force, the multiple flaps of the valve may be opened, thereby allowing the catheter 11 to be inserted through the open valve into the needle body opening 6b. In some embodiments, the catheter guide structure further includes a guide groove stopper configured to be removably inserted into the inclined guide groove 3a. The guide groove stopper can be withdrawn when the catheter 11 needs to be implanted.

[0212] In some embodiments, the inclined guide groove 3a is a non-through groove. In some embodiments, the catheter 11 to be implanted is directly punctured into the inclined guide groove. In some embodiments, the inclined guide groove may be punctured by a puncturing member other than a catheter, and then the catheter 11 may enter the needle body opening 6b through the punctured opening.

[0213] In some embodiments, the needle body opening 6b can be provided in the form of a rearwardly inclined inclined opening to match the guide direction of the inclined guide groove 3a, so that the needle body opening 6b can be aligned with the inclined guide groove 3a, and the catheter 11 can be accurately guided through the inclined guide groove and into the needle body opening.

[0214] 9 and 10, the catheter guide structure includes a rearwardly inclined, angled guide needle hole 6c formed or provided in the body wall of the hollow puncture needle 6. In some embodiments, for example, when the medical puncture device is in fluid communication, the angled guide needle hole 6c is maintained at the proximal end of the floating seal member 3. In some embodiments, the catheter 11 may be inserted into the needle body passage of the hollow puncture needle 6 through the angled guide needle hole 6c. In some embodiments, the catheter 11 may be implanted into an apparent or potential tissue void, chamber, or blood vessel (or an apparent or potential tissue void, chamber, or blood vessel dilated with the flowable composition) through the needle distal end opening 6a.

[0215] In some embodiments, the catheter guide structure further includes a valve 9 disposed within or engaged with the beveled guide needle lumen 6c. The valve may be a one-way valve configured to open and close. In some embodiments, the valve includes multiple flaps configured to open and close the valve. In some embodiments, in the absence of an external force, the one-way valve 9 is closed, preventing the flowable composition in the flowable composition chamber 7 from leaking through the valve. In some embodiments, in the presence of an opening force, the multiple flaps of the valve are opened, thereby allowing the catheter 11 to be inserted through the open valve and the beveled guide needle lumen 6c into the needle body passage (which may be connected to or separate from the needle body passage connecting the needle body opening 6b and the needle distal end opening 6a). In some embodiments, the catheter guide structure may further include a needle lumen stopper 10 configured to be removably inserted into the beveled guide needle lumen 6c, and the needle lumen stopper 10 can be withdrawn to begin the implantation procedure of the catheter 11. In some embodiments, the guide needle lumen 6c is connected to the needle distal end opening 6a. The needle body passage connecting the needle distal end opening 6a and the needle body opening 6b may be the same as or separate from the needle body passage connecting the needle distal end opening 6a and the guide needle lumen 6c. In some embodiments, the guide needle lumen 6c is connected to a needle distal end opening other than the needle distal end opening 6a connected to the needle body opening 6b. The needle body passage connecting the needle body opening 6b to the needle distal end may be completely separate from the needle body passage connecting the guide needle lumen 6c to the needle distal end. The needle body passage connecting the needle body opening 6b to the needle distal end may at least partially overlap or be in fluid communication with the needle body passage connecting the guide needle lumen 6c to the needle distal end.

[0216] In some embodiments, as shown in FIGS. 11A-11B, the catheter guide structure includes a central guide groove 2c formed or provided on the proximal end surface of the drive member 2. In some embodiments, the central guide groove 2c may include a hole, or a hole may be provided in the center of the proximal end surface of the drive member 2. In some embodiments, the central guide groove 2c may be punctured to form a hole. In some embodiments, the hollow puncture needle 6 is provided with a needle proximal end opening that is axially aligned with the central guide groove 2c. In some embodiments, when it is necessary to implant the catheter 11, the central guide groove 2c may be punctured, and the catheter 11 may be inserted into the needle body passage through the opening of the central guide groove 2c after puncture and the needle proximal end opening of the hollow puncture needle 6 (this passage may be connected to or separate from the needle body passage connecting the needle body opening 6b and the needle distal end opening 6a). In some embodiments, catheter 11 may be implanted through a needle distal end opening (e.g., needle distal end opening 6a or another needle distal end opening) into an apparent or potential tissue void, chamber, or vessel (or an apparent or potential tissue void, chamber, or vessel dilated by the flowable composition).

[0217] In some embodiments, disclosed herein are kits that include components configured to be assembled to form the prefilled injection devices or systems disclosed herein.

[0218] In some embodiments, a kit for assembling a prefilled injection device or system includes a puncture control module and a prefilled flowable composition storage module (e.g., a fluid storage module). In some embodiments, the puncture control module and the flowable composition storage module are independently manufactured and / or provided. In some embodiments, the puncture control module includes a first syringe unit, an actuation unit (e.g., an elastic movement unit) and a hollow puncture needle 6 provided in the syringe barrel of the first syringe unit. Based on the embodiments disclosed herein, it has been found that the puncture control module may further include other components or members, such as an elastic sheath 4 and a spring 5. In some embodiments, the prefilled fluid storage module includes a second syringe unit, a flowable composition cavity 7 formed in the syringe barrel of the second syringe unit, and a module packaging member removably provided at the proximal end of the second syringe unit. In some embodiments, a detachable connection structure is formed between the first syringe unit and the second syringe unit. In some embodiments, the first syringe unit and the second syringe unit are connected to each other to form the syringe barrel 1. Based on the embodiments disclosed herein, it has been found that the fluid storage module can further include other components, such as a distal end seal member 8.

[0219] In some embodiments, the puncture control module and the fluid storage module may be manufactured, assembled, and / or packaged separately and then assembled with each other (and optionally with other modules, members, and / or components) to form the medical puncture device disclosed herein. In some embodiments, the module packaging member is used to seal the proximal end of the flowable composition cavity 7. In some embodiments, the module packaging assembly may be removed when assembling the puncture control module and the fluid storage module.

[0220] In some embodiments, the present specification provides a pre-filled medical device assembly and a system including the same. As shown in Figures 7 and 11A-11B, in some embodiments, the medical device assembly includes a stent 11 and a medical puncture device including a stent guide structure disclosed herein. In some embodiments, the stent 11 may be implanted into an obvious or hidden tissue void, chamber, or blood vessel via a pre-filled injection device or system. The medical device assembly described herein may have all the technical effects provided by a pre-filled injection device or system.

[0221] In some embodiments, the medical device assembly includes a hollow auxiliary guide needle 12 that is used in conjunction with the stent guide structure. In some embodiments, the diameter of the needle body passage of the auxiliary guide needle 12 is large enough to accommodate the stent 11 and allow for insertion of the stent. In some embodiments, during the operation of implanting the stent 11, the auxiliary guide needle 12 is connected to the stent guide structure, allowing the stent 11 to pass through the needle body passage of the auxiliary guide needle 12, the stent guide structure, and the needle body passage of the hollow puncture needle 6, in that order, and then through the needle distal end opening 6a into an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, prior to implanting the stent, the apparent or potential tissue void, chamber, or blood vessel is dilated with a flowable composition using a prefilled injection device or system disclosed herein. In some embodiments, the stent is implanted while the apparent or potential tissue void, chamber, or blood vessel is dilated with the prefilled flowable composition using a prefilled injection device or system disclosed herein. In some embodiments, a stent is implanted prior to dilating an apparent or potential tissue void, chamber, or vessel with a flowable composition using a prefilled injection device or system disclosed herein.

[0222] In some embodiments, as shown in FIG. 7 , the stent guide structure includes a through-hole inclined guide groove 3a and a one-way valve 9. The one-way valve 9 is fitted into the inclined guide groove 3a and can be opened and closed. In some embodiments, the needle body opening 6b is provided in the form of an inclined opening that opens diagonally backward. In some embodiments, when implanting the stent 11, the auxiliary guide needle 12 is used to open the one-way valve 9, thereby allowing the auxiliary guide needle to be positioned within the inclined guide groove 3a. In some embodiments, the distal end of the auxiliary guide needle 12 is advanced into the needle body opening 6b, and the stent 11 is passed through the needle body passage of the auxiliary guide needle 12, the needle body passage of the hollow puncture needle 6, and the needle distal end opening 6a in that order before being implanted into an obvious or potential tissue void, chamber, or blood vessel.

[0223] 11A-11B, the stent guide structure includes a central guide groove 2c. In some embodiments, a proximal needle end opening is formed in the hollow puncture needle 6 and is axially aligned with the central guide groove 2c. In some embodiments, when implanting the stent 11, the auxiliary guide needle 12 may pierce the central guide groove 2c so as to be axially aligned with the proximal end opening of the hollow puncture needle 6. In some embodiments, the stent 11 is inserted into the needle body passage of the hollow puncture needle 6 by passing through the needle body passage of the auxiliary guide needle 12 and the proximal end opening of the hollow puncture needle 6 in that order, and then passed through the needle distal end opening (e.g., needle distal end opening 6a) and implanted into an apparent or potential tissue void, chamber, or blood vessel.

[0224] In some embodiments, a prefilling system is disclosed herein, the prefilling system including: a syringe barrel including a proximal end and a distal end; a floating seal member located within the syringe barrel; a needle hub located at the proximal end of the floating seal member; and a plunger rod between the floating seal member and the needle hub, the needle hub and the plunger rod being resiliently engaged with each other; and a needle including a needle proximal end and a needle distal end engaged with the needle hub and located within the plunger rod, the needle including: (i) a needle distal end opening; (ii) a needle body opening located between the needle proximal end and the needle distal end, the needle body opening being located at the proximal end of the needle distal end opening; and (iii) a needle body passage connecting the needle distal end opening and the needle body opening, wherein the needle hub is configured to advance the needle distally toward and / or through the floating seal member by the plunger rod.

[0225] In some embodiments, the floating seal member may be fixedly connected to the distal end of the plunger rod and form a sliding and sealing engagement with the interior surface of the syringe barrel. In any of the embodiments herein, the needle hub may be fixedly engaged to the drive member (e.g., a pushing element), and a spring may be engaged to the drive member and the plunger rod, thereby providing a resilient engagement between the needle hub and the plunger rod.

[0226] In some embodiments, when the needle distal end opening is within tissue, a known or potential tissue void, chamber, or blood vessel, and a pressure at the needle distal end opening greater than the pressure at the needle body opening is provided, the needle can be advanced distally by the plunger rod and pass through the floating seal member, but the floating seal member does not move distally. In some embodiments, tissue resistance or pressure prevents the flowable composition from being injected through the needle distal end opening into the tissue, and the floating seal member (and the plunger rod in embodiments with a plunger rod) does not move distally under the force of the spring, even though the needle can be advanced distally under the force of the push shaft. For example, if tissue pressure prevents injection, the needle distal end opening may be within the tissue, and the needle body opening is located at the distal end of the floating seal member and in contact with the flowable composition. The floating seal member can maintain its axial position while the needle is further advanced until the needle distal end opening reaches a known or potential tissue void, chamber, or blood vessel.

[0227] In some embodiments, the floating seal member may move distally when the needle distal opening is within tissue, or within an apparent or potential tissue void, chamber, or blood vessel, providing a pressure at the needle distal opening that is lower than the pressure at the needle body opening. In some embodiments, tissue resistance or pressure allows the flowable composition to be injected through the needle distal opening and into the tissue, and the floating seal member (and plunger rod in embodiments comprising a plunger rod) moves distally under spring force without the need to further advance the needle distally. For example, when tissue pressure allows injection, the needle distal opening may be within an apparent or potential tissue void, chamber, or blood vessel, and the needle body opening is located at the distal end of the floating seal member and in contact with the flowable composition. The floating seal member may move distally, allowing the flowable composition to be expelled through the needle distal opening without further advancing the needle distally.

[0228] In some embodiments, provided herein are methods for performing a medical puncture using a prefilled injection device or system described herein. In some embodiments, a prefilled injection device or system is provided that is preassembled, as shown in FIG. 17A. In some embodiments, the housing of the preassembled device may be rotated to separate the syringe from the device body. In some embodiments, the proximal end portion of the syringe may be threaded onto the distal end portion of the housing. For example, as shown in FIG. 17B, the proximal end portion of the syringe may have a thread on its inner surface configured to mate with a thread on the outer surface of the distal end portion of the housing.

[0229] In some embodiments, after the syringe is separated, the proximal end of the plunger rod is exposed. The handle may be connected to the plunger rod by being threaded onto the proximal end of the plunger rod, for example, as shown in FIG. 17C. In some embodiments, an adapter including a built-in adapter needle may be connected to the syringe. In some embodiments, the adapter includes a distal end opening and a proximal end opening. In some embodiments, the distal end of the syringe (e.g., having a distal end seal member connected thereto) is inserted into the proximal end opening of the adapter, whereby the adapter needle contacts the distal end seal member connected to the syringe. In some embodiments, the proximal end of the adapter needle passes through the distal end seal member connected to the syringe such that the proximal end opening of the adapter needle is located within the chamber of the syringe. In some embodiments, a container or portion thereof containing a prefilled flowable composition (e.g., a pharmaceutical composition) is inserted into the distal end opening of the adapter, whereby the adapter needle contacts the container. In some embodiments, the distal end of the adapter needle is inserted into the container so that the distal opening of the adapter needle is positioned within the container, establishing fluid communication between the flowable composition and the lumen of the syringe. In some embodiments, pulling the handle moves the plunger rod to the proximal end, allowing the flowable composition to be drawn into the lumen of the syringe by the adapter needle, and pushing the handle moves the plunger rod to the distal end, allowing undesired gas to be expelled. Pulling and / or pushing the handle can position the distal end of the plunger rod and the seal member within the syringe to set the appropriate volume of flowable composition in the syringe, e.g., 0.1 mL or 0.05 mL, as shown in FIG. 17D , after which the handle and adapter can be removed from the plunger rod and syringe, respectively.The syringe with the flowable composition therein may be connected to the device body, for example, by inserting the injection needle (e.g., 6 shown in FIG. 17B ) into the plunger rod (e.g., 15 shown in FIG. 17D ), inserting the plunger rod into a guide tube in the housing, and rethreading the proximal end of the syringe into the distal end of the housing, as shown in FIG. 17E . In some embodiments, the control knob can be rotated to advance the push shaft distally, thereby advancing the injection needle connected to the push shaft distally toward and / or through a seal member in the syringe. As shown in FIG. 17F , the injection needle can be further advanced through the sealed tip and into the sclera of the eye. In some embodiments, because the sclera is a dense tissue, the pressure at the distal end opening of the injection needle is greater than the pressure at the needle body opening of the injection needle, which may be in fluid communication with the flowable composition in the syringe, allowing the injection needle to be advanced further into the sclera without changing the position of the floating seal member in the syringe. In some embodiments, the operator monitors the position of the floating seal member within the syringe as they push the push shaft to advance the injection needle. When the distal end opening of the injection needle is outside the sclera and enters the choroid / ciliary body, the pressure at the distal end opening of the injection needle decreases, and the pressure at the needle body opening of the syringe drives the flowable composition through the needle body passage and out of the distal end opening of the injection needle, thereby creating and expanding a suprachoroidal space containing the flowable composition. As a portion of the flowable composition in the syringe is expelled, the seal member (along with the plunger rod) moves to a more distal position within the syringe. Thus, by observing the movement of the seal member, the operator can determine whether the distal end opening of the injection needle has exited the first tissue and reached a second tissue with a relatively lower density, for example, from the sclera into the choroid / ciliary body. In some embodiments, when the seal member moves past a preset volume mark or indicator line (e.g., 0.1 mL or 0.05 mL), the advancement of the injection needle toward the distal end is stopped.

[0230] As shown in Figures 17A-17F, in some examples, some fluid chambers in a prefilled injection device or system are not prefilled with a flowable substance or composition, but rather the flowable substance or composition is aspirated from a container into a syringe and then delivered into a tissue, or into an apparent or potential tissue void, chamber, or blood vessel.

[0231] In some examples, the prefilled injection device or system disclosed herein is prefilled with a fluid substance or composition. In some embodiments, the syringe (e.g., syringe barrel 1 shown in FIG. 16) may be provided in the form of one or more parts. In some embodiments, the container (e.g., syringe unit) may include a cylindrical wall and a floating seal member (movable within the container and passable through a needle) sealingly engaged with a fixed seal member (fixed to the container at the distal end of the container and passable through a needle), and the space enclosed by the cylindrical wall, the fixed seal member, and the floating seal member may be prefilled with a fluid substance or composition. In some embodiments, the prefilled injection device or system may include a first syringe unit, and the container may be a second syringe unit configured to be engaged with the distal end of the first syringe unit. The container (e.g., syringe unit) may be inserted into or connected to the device body (e.g., first syringe unit) before or after the flowable substance or composition is filled into the container (e.g., syringe unit). In some embodiments, a floating seal member in the container (e.g., syringe unit) can contact the distal end of the plunger rod, thereby establishing engagement between the plunger rod and the floating seal member and transmitting spring force to the floating seal member. A fixed seal member at the distal end of the container (e.g., syringe unit) may contact a contact element at the distal end of the device, which may be the distal end seal member of the syringe. In some embodiments, the fixed seal member of the container (e.g., syringe unit) also functions as the distal end seal member and / or contact element of the syringe. In some embodiments, the container (e.g., syringe unit) may be configured to be at least partially inserted into a syringe barrel. In some embodiments, the stationary seal member is sealingly engaged to the container (eg, syringe unit), and the container is engaged to the inner wall of the syringe barrel.In some embodiments, the stationary sealing member is sealingly engaged with the interior walls of both the container (e.g., syringe unit) and the syringe barrel. Engagement between the container (e.g., syringe unit) and the syringe barrel, and engagement between the stationary sealing member and the container wall, may include any suitable engagement means, such as, for example, insert, threaded, non-threaded, clip-fit ​​engagement, compression-fit engagement, or any combination thereof. VI. METHODS AND DEVICES FOR EYE DRAINAGE

[0232] Glaucoma is a leading cause of irreversible blindness. Current treatments involve lowering intraocular pressure (IOP) through medication or surgery. While drug-free approaches have been used (see, e.g., Chae et al., Adv. Sci. 2021, 8, 2001908), drug-free, non-surgical approaches can only reduce IOP for approximately 4 months.

[0233] In some embodiments, methods, compositions, and devices for reducing intraocular pressure for the treatment of glaucoma in a subject in need thereof are disclosed herein. In some embodiments, the methods, compositions, and devices and uses may include expanding the suprachoroidal space (SCS) of the eye using one or more viscoelastic agents. In some embodiments, the SCS is expanded by forming an in situ depot (which may or may not contain one or more drugs) within the SCS. In some embodiments, the SCS is expanded by forming a hydrogel in situ, for example, by injecting it into the SCS using a microneedle. In some embodiments, the SCS is expanded with one or more viscoelastic agents configured to form a permanent or semi-permanent structure within the SCS, thereby achieving long-term expansion of the SCS. In some embodiments, the SCS is expanded with one or more viscoelastic agents, followed by implanting a permanent or semi-permanent structure into the SCS, thereby achieving long-term expansion of the SCS. In some embodiments, the SCS is expanded with a composition comprising hyaluronic acid (HA) hydrogel. In some embodiments, the SCS expands (e.g., relative to its natural state as a potential tissue void) for at least or about 4 months, at least or about 6 months, at least or about 8 months, at least or about 1 year, at least or about 2 years, at least or about 3 years, at least or about 4 years, at least or about 8 years, at least or about 12 years, or more.

[0234] Aqueous humor drains from the eye primarily through traditional outflow pathways, including the trabecular meshwork and Schlemm canal. However, some aqueous humor drains through alternative or "non-traditional" pathways, including the ciliary muscle, the supraciliary space, and the suprachoroidal space. In some embodiments, dilating the SCS increases the amount of aqueous humor draining from the eye through non-traditional pathways, thereby reducing intraocular pressure (IOP). In some embodiments, a reduction in IOP is associated with SCS dilation. In some embodiments, there is no difference in pressure-dependent aqueous humor outflow through traditional pathways between SCS-dilated and untreated eyes. In some embodiments, the methods, compositions, and devices provided herein can treat elevated intraocular pressure and / or glaucoma by continuously reducing IOP without the need for drugs or surgery.

[0235] Any of the systems and devices disclosed herein can be used to implant a permanent or semi-permanent structure, such as a stent, in the eye to reduce intraocular pressure, for example, to treat glaucoma, and include: (a) inserting a needle into the eye at an injection site to inject into the suprachoroidal space (SCS) of the eye; (b) delivering a composition (e.g., a viscoelastic composition) through the needle to form the SCS; and (c) placing a stent (e.g., a microstent) within the SCS, thereby implanting the stent in the eye, maintaining the SCS in an expanded state, and promoting drainage of aqueous humor.

[0236] In some embodiments, the methods disclosed herein include: (a) inserting a needle into the eye to form a delivery channel within the eye that terminates in a region between the sclera and choroid of the eye; (b) delivering a composition (e.g., a viscoelastic composition) through the needle to form an SCS; (c) placing a stent (e.g., a microstent) within the expanded SCS, the stent being releasably coupled to the needle; and (d) releasing the needle from the stent, thereby positioning the stent within the eye to maintain the SCS and promote drainage of fluid (e.g., fluid from the anterior chamber) through the SCS. Prior to releasing the stent from the needle, the stent may be at least partially within the needle and / or at least partially outside the needle (e.g., in the form of a hollow tube through which a portion of the needle can pass).

[0237] In some embodiments, the methods disclosed herein include: (a) inserting a needle into the eye at an injection site to inject into the suprachoroidal space (SCS) of the eye; (b) delivering a composition (e.g., a viscoelastic composition) through the needle to form the SCS; and (c) placing a stent (e.g., a microstent) into the SCS through the injection site or an expanded insertion site (e.g., formed (e.g., surgically) by expanding the injection site), thereby maintaining the expanded state of the SCS and promoting drainage of aqueous humor. The stent can be inserted through the injection site or the expanded insertion site to further expand the SCS formed by the injection of the viscoelastic composition. During stent insertion, the presence of the viscoelastic composition promotes separation of the sclera and choroid and provides lubrication for movement of the stent tip between the sclera and choroid (e.g., in the equator-parallel plane), minimizing tissue damage during implantation.

[0238] Figure 18A illustrates the ab externo method, in which a viscoelastic agent is injected between the sclera and choroid to form an SCS, followed by the implantation of a permanent or semi-permanent structure (e.g., a stent) to maintain the SCS in an expanded state for extended periods. As shown in Figure 18B, the implant may form a ring-shaped or partially ring-shaped structure in the equator-parallel plane of the eyeball. Compared to the ab interno aqueous humor drainage method, the ab externo method does not rely on puncturing intraocular muscles with a stent or drainage tube, causing less tissue damage and potentially scarring, and does not rely on inserting a stent or drainage tube into the anterior chamber (e.g., by puncturing the anterior chamber angle).

[0239] In some embodiments, the stents disclosed herein may comprise any suitable material. Materials used to manufacture the stent include, but are not limited to, medical-grade stainless steel, titanium or titanium alloys, nickel-titanium alloys, TPU (thermoplastic polyurethane), e-PTFE (expanded polytetrafluoroethylene), silica gel, hydrogel, PES (polyethersulfone), SIBS (styrene-isobutylene-styrene block copolymer), or any combination thereof. In some embodiments, the stent material is highly biocompatible, matches the mechanical properties of ocular tissue, and does not damage or cause adverse effects. In some embodiments, the stents disclosed herein may be coated, but this is not required. In some embodiments, the stents disclosed herein may be coated with a drug, but this is not required. In some embodiments, the stents disclosed herein may comprise one or more pharmaceutical compositions.

[0240] In some embodiments, the stents disclosed herein may have any suitable shape. In some embodiments, the stent is a circular tube. In some embodiments, the stent comprises a single chamber. In some embodiments, the stent comprises multiple chambers, e.g., parallel chambers, each extending from one end of the stent to the other. In some embodiments, one or more pharmaceutical compositions may be housed in a single or multiple chambers within the stent. In some embodiments, the cross-sectional shape of the stent may be circular, oval, square, or any other suitable shape. In some embodiments, any one or more surfaces of the stent may be flat or curved.

[0241] In some embodiments, the stents disclosed herein include a marker ring and / or a retaining ring surrounding the stent. In some embodiments, an annular structure surrounding the stent, such as a retaining ring, may be configured to prevent displacement of the stent. The shape of the retaining ring may include, but is not limited to, annular, barbed, finned, or any combination thereof. The structure and size of the stent, including the marker ring and retaining ring, can be tailored to the anatomy of ocular tissue, thereby effectively draining aqueous humor and reducing intraocular pressure without causing tissue damage or scarring.

[0242] In some embodiments, the stents disclosed herein have a length of about 1.5 mm to about 12 mm, e.g., about 3 mm, about 4 mm, about 5 mm, or about 6 mm. In some embodiments, the stents disclosed herein have a diameter of about 0.1 mm to 1 mm, e.g., an outer diameter of about 0.25 mm, about 0.3 mm, about 0.35 mm, about 0.4 mm, about 0.45 mm, or about 0.5 mm. In some embodiments, the stents disclosed herein have an inner diameter of about 0.025 mm to 0.25 mm, e.g., a diameter of about 0.05 mm, about 0.08 mm, about 0.1 mm, about 0.12 mm, or about 0.15 mm. In some embodiments, a marker ring is located about 0.25 mm to 2.5 mm from one end of the stent, thereby facilitating accurate placement of the stent, e.g., for alignment within the SCS.

[0243] In some embodiments, the stents disclosed herein may include a solid structure, a porous structure, a multilayer composite structure, a membrane stent structure, or any combination thereof. A solid structure (e.g., a uniform solid structure) is simple and effective, establishing a framework for maintaining the SCS expanded by the viscoelastic agent. In some embodiments, to avoid or reduce the risk of fibrosis and scarring, a microporous material may be used to promote biocompatibility with the surrounding tissue material, thereby reducing fibrosis and scarring after implantation. In some embodiments, the pore size may be less than 20 microns to prevent tissue or cell overgrowth within the pores while allowing water to pass freely through the pores. In some embodiments, the core or inner layer of the multilayer composite structure may be designed to provide radial support. The outer layer of the multilayer composite structure may be a porous or woven layer with a pore size less than 20 microns to prevent tissue or cell overgrowth within the pores. In some embodiments, the stent is a hollow support structure that can provide sufficient support and flexibility.

[0244] In some embodiments, the present disclosure provides a method for delivering a stent disclosed herein using a device disclosed herein. In some embodiments, the stent is preloaded into the needle of a delivery system (e.g., a suprachoroidal space syringe) and implanted into the suprachoroidal space using the ab-externo method described herein. When the needle tip of the delivery system pierces the sclera and reaches the choroid / ciliary body layer, a viscoelastic agent is automatically injected to open the suprachoroidal space, and the stent within the needle is then pushed to the target location, for example, by wire pushing. The delivery system may be withdrawn to complete stent implantation. The methods disclosed herein can be used for minimally invasive glaucoma surgery (MIGS). In some embodiments, the stent may be inserted into the needle (or may be pre-inserted into the needle before inserting the needle and injecting the viscoelastic material) and deployed at the distal end of the needle.

[0245] In some embodiments, a method for delivering a stent disclosed herein using a device disclosed herein is provided. In some embodiments, a flowable substance or composition (e.g., a viscoelastic substance) is first injected into the choroidal space to form the choroidal space. The injection needle can then be removed from the injection site, leaving the choroidal space filled with the viscoelastic substance. In some embodiments, the injection site and path formed by the needle can be further enlarged to create a larger incision from the injection site and / or a larger path from the injection site to the choroidal space, and a linear element, such as a cannula, can be inserted, where the stent is releasably coupled to the linear element. In some embodiments, the stent can be a linear element inserted from the injection site through the larger incision. In some embodiments, the injection site can be further enlarged to create a larger incision from the injection site and / or a larger path from the injection site to the choroidal space, and the stent can be inserted into the choroidal space. In some embodiments, the injection site and tract need not be further enlarged and a linear member, such as a cannula, may be inserted, where the stent is releasably coupled to the linear member. In some embodiments, the injection site and tract need not be further enlarged and a stent may be inserted.

[0246] In some embodiments, the flowable composition, such as a viscoelastic composition, provides lubricity to the stent or a linear member releasably coupled to the stent, allowing the stent or linear member to slide over the interface between the sclera and the choroid / ciliary body, thereby reducing resistance during stent insertion and / or reducing the risk of choroidal puncture or the risk of the stent and / or linear member penetrating the vitreous, ciliary body, or other tissues. In some embodiments, the viscoelastic composition forms a protective layer around the stent or a linear member releasably coupled to the stent, which can provide lubricity and guide the direction of stent insertion.

[0247] In some embodiments, provided herein are minimally invasive methods for placing a stent in the eye using a needle without the need for surgically cutting the full thickness of the sclera, surgically separating the sclera from the choroid / ciliary body, or post-operatively suturing the cut sclera or conjunctiva. Thus, the methods disclosed herein can reduce tissue invasion, lower surgical skill requirements, and shorten surgical procedure time.

[0248] It should be understood that any suitable injection device or injection system can be used in the ocular drainage methods disclosed herein, including, but not limited to, those described with reference to the drawings herein. For example, the injection device or system shown in FIG. 12A can be used. The injection device or system can be prefilled with one or more drugs or other substances, such as a viscoelastic agent. In some embodiments, the injection device or system includes a syringe barrel having a proximal end and a distal end, a floating seal member located within the syringe barrel, a puncture member, such as a needle, located at the distal end of the syringe barrel, where the puncture member is not connected to the floating seal member, and a drive member configured to be resiliently engaged with the floating seal member via an energy storage member (e.g., a spring and / or other suitable resilient member). In some embodiments, the puncture member includes a distal end opening configured to establish fluid communication with a chamber within the syringe barrel containing the flowable composition. In some embodiments, the injection device or system further includes a stopper located within the syringe barrel between the floating seal member and the distal end of the syringe barrel. As shown in step 1 of FIG. 12A , the injection device or system is in an initial state, where the distal end opening of the puncture member has not yet entered the subject's tissue and the distance between the drive member and the floating seal member is x1. In step 2 of FIG. 12A , the distal end opening of the puncture member has already entered relatively dense tissue (e.g., the sclera, the anterior chamber angle, or the ciliary body), where the distance between the drive member and the floating seal member remains constant (x1). In step 3 of FIG. 12A , the energy storage member is compressed, e.g., when the distance between the drive member and the floating seal member decreases from x1 to x2, the distal end opening of the puncture member is still within the relatively dense tissue. In this manner, the energy storage member applies and maintains a force on the floating seal member. Pressure is further applied to the relatively dense tissue via the flowable composition and the distal end opening of the puncture member.Due to tissue density, relatively dense tissue applies backpressure to the distal opening of the puncture member, thereby preventing the flowable composition from being expelled into the tissue. In step 4 of FIG. 12A , the puncture member is advanced distally toward less dense tissue, such as an apparent or potential tissue void, chamber, or blood vessel (e.g., the SCS or subconjunctival space). In some embodiments, the decreased tissue density causes the backpressure at the distal opening of the puncture member to be lower than the pressure of the flowable composition, thereby allowing the flowable composition to be expelled into less dense tissue, such as an apparent or potential tissue void, chamber, or blood vessel. As the flowable composition is expelled from the distal opening of the puncture member, energy is released from the energy storage member, thereby increasing the distance between the drive member and the floating seal member from x2 to x3, as shown in step 5 of FIG. 12A . Distal movement of the floating seal member within the syringe barrel can be stopped, for example, by a stopper to control the volume of flowable composition delivered to the less dense tissue.

[0249] Another example is shown in step 1 of FIG. 12B , where the medical puncture device is in an initial state and the distal end opening of the puncture member has not yet entered the subject's tissue. In step 2 of FIG. 12B , the energy storage member can be compressed while the distal end opening of the puncture member is still outside the tissue, and the floating seal member has not yet advanced to the distal end so that the flowable composition can be expelled from the distal end opening. In step 3 of FIG. 12B , the distal end opening of the puncture member has already entered relatively dense tissue (e.g., the sclera, the anterior chamber angle, or the ciliary body). The energy storage member applies and maintains a force against the floating seal member. Pressure is then applied to the dense tissue via the flowable composition and the distal end opening of the puncture member. Due to the density of the tissue, the dense tissue applies back pressure to the distal end opening of the puncture member, thereby preventing the flowable composition from being expelled into the tissue. In step 4 of FIG. 12B, while the energy storage member remains compressed, the distal opening of the puncture member begins to enter the less dense tissue, such as an obvious or potential tissue void, chamber, or vessel (e.g., the SCS or subconjunctival space). In step 5 of FIG. 12B, as the tissue density decreases, the backpressure at the distal opening of the puncture member becomes lower than the pressure of the flowable composition, thereby allowing the flowable composition to be expelled into the less dense tissue. As the flowable composition is expelled from the distal opening of the puncture member, the energy within the energy storage member is released. In some embodiments, a stopper may be provided to stop the distal movement of the floating seal member within the syringe barrel to stop the flow of the flowable composition. In this manner, the volume of the flowable composition delivered to the less dense tissue can be controlled. As shown in step 6 of FIG. 12B, the force applied to the drive member may be released.

[0250] Another example is shown in Figure 12C. In some embodiments, the injection device or system includes a syringe barrel having a proximal end and a distal end, a floating seal member located within the syringe barrel, a puncture member such as a needle located at the distal end of the syringe barrel, where the puncture member is not connected to the floating seal member, and an energy storage member configured to be resiliently engaged with the floating seal member and the proximal end of the syringe barrel. In some embodiments, the injection device or system further includes a stopper located within the syringe barrel between the floating seal member and the distal end of the syringe barrel. In some embodiments, the medical puncture device includes a contact member. In step 1 of Figure 12C, the medical puncture device is in an initial state, where the distal end opening of the puncture member is within the contact member, and the contact member prevents the flowable composition from being discharged from the distal end opening. The energy storage member applies a force to the floating seal member, which in turn applies pressure to the contact member via the flowable composition and the distal end opening of the puncture member. Due to the density of the contact member, the backpressure at the distal opening of the puncture member prevents the flowable composition from leaking out of the syringe barrel. In step 2 of FIG. 12C, the distal opening of the puncture member has already entered dense tissue (e.g., the sclera, the anterior chamber angle, or the ciliary body), and the backpressure at the distal opening of the dense tissue prevents the flowable composition from leaking into the tissue. In step 3 of FIG. 12C, the distal opening of the puncture member begins to enter less dense tissue, such as an apparent or potential tissue void, chamber, or vessel (e.g., the SCS or subconjunctival space). In step 4 of FIG. 12C, the density of the tissue decreases, so the backpressure at the distal opening of the puncture member becomes lower than the pressure of the flowable composition, thereby allowing the flowable composition to be released into the less dense tissue. As the flowable composition is expelled from the distal opening of the puncture member, energy within the energy storage member is released. In some embodiments, a stopper may be used to stop the distal movement of the floating seal member within the syringe barrel to stop the flow of the flowable composition. In this manner, the volume of flowable composition delivered to the less dense tissue can be controlled. VII. Methods for Improving Injection Accuracy and Safety

[0251] Any of the adapters described herein can be incorporated into a syringe to improve syringe injection accuracy and safety. In some embodiments, provided herein is a method for improving syringe injection accuracy and safety, comprising: (1) providing a syringe including a syringe barrel extending from a proximal end to a distal end forming a chamber extending from the proximal end to the distal end, a push shaft extending from the proximal end to the distal end forming a seal between the distal end and the syringe barrel, and a needle extending from the proximal end to the distal end and including an end opening for allowing fluid to pass through the needle hub, through the distal end of the syringe barrel, and out of the chamber; (2) providing an adapter set including a contact member extending from a proximal end to a distal end and a pressing unit including a first elastic element; (3) attaching a contact member to the distal end of the needle; (4) attaching the pressing unit to the syringe; The distal end of the contact member is located at the distal end of the needle distal end opening, and the distal end of the contact member can directly contact the surface tissue of the target injection site; and A method is provided, wherein the pushing unit is resiliently engaged with the push shaft and / or the syringe barrel via a first resilient element.

[0252] In some embodiments, the contact member is attached to the distal end of the injection needle, where the distal end of the contact member is located at the distal end of the needle distal end opening, and the needle distal end opening is located entirely within the contact member. In some embodiments, as shown in Figure 15A, the contact member 25 is a long elastic sheath that can contact the needle hub of the syringe when attached, thereby establishing an elastic engagement between the syringe barrel 1 and the superficial tissue of the target injection site.

[0253] In some embodiments, the adapter set further includes a second elastic element, and when attached, the proximal end of the second elastic element contacts the needle hub. At the same time as the second elastic element is attached, a contact member is also attached to the distal end of the injection needle, with the distal end opening of the needle positioned completely within the contact member. In some embodiments, as shown in FIG. 15B, the contact member 25 is a non-elastic block, and a second elastic element 26 (e.g., a spring) can establish an elastic connection between the proximal end of the contact member and the needle hub. In some embodiments, as shown in FIG. 15C, the contact member 25 is a non-elastic block, and a second elastic element 26 (e.g., an elastic sheath) can establish an elastic connection between the proximal end of the contact member and the needle hub. In some embodiments, as shown in Figure 15D, the contact member 25 includes a resilient portion 25a and a non-resilient portion 25b, where the resilient portion 25a is located at the distal end of the non-resilient portion 25b, and a second resilient element 26 (e.g., a spring) can establish a resilient connection between the proximal end of the contact member (e.g., the proximal end of the non-resilient portion of the contact member) and the needle hub. In some embodiments, as shown in Figure 15E, the contact member includes a resilient portion 25a and a non-resilient portion 25b, where the resilient portion is located at the distal end of the non-resilient portion, and a second resilient element 26 (e.g., a resilient sheath) can establish a resilient connection between the proximal end of the contact member (e.g., the proximal end of the non-resilient portion of the contact member) and the needle hub.

[0254] In some embodiments, the adapter set further includes a connector, which is inelastic and, when attached, contacts the needle hub at its proximal end. At the same time as the connector is attached, a contact member is also attached to the distal end of the injection needle, with the distal end of the needle being located entirely within the contact member. In some embodiments, as shown in FIG. 15F, the contact member 25 is an elastic sheath, thereby establishing an elastic connection between the distal end of the connector 27 and the distal end of the surface tissue at the target injection site.

[0255] In some embodiments, the flowable composition may be drawn into the syringe chamber first, then the contact member is attached, optionally the second elastic element is attached, optionally the connector is attached, and then the pressing unit is attached. In some embodiments, the pressing unit is attached first, then the flowable composition is drawn into the syringe chamber, then the contact member is attached, optionally the second elastic element is attached, and optionally the connector is attached.

[0256] In some embodiments, as shown in FIG. 16A , the pressing unit 30 includes a proximal end and a distal end, and a first elastic element 31 is connected to the proximal end of the pressing unit. As shown in the left diagram of FIG. 16A , before being assembled to a syringe, the pressing unit is in an initial state, and the first elastic element 31 (e.g., a spring) is in a resting state, neither stretched nor compressed. The pressing unit 30 further includes a pair of stoppers 32 at its distal end, which can be non-elastically engaged with the syringe barrel of the syringe to prevent the syringe barrel from moving toward the distal end. As shown in the right diagram of FIG. 16A , the pressing unit 30 can be assembled to the proximal end of a syringe barrel 1 and a push shaft 2, where the push shaft 2 is engaged with the pressing unit via the first elastic element 31 (e.g., a spring), and the syringe barrel 1 is non-elastically engaged with the pressing unit 30 via the pair of stoppers 32, thereby elastically engaging the push shaft and the syringe barrel. In this state, the first elastic element 31 is compressed. The compressed first elastic element 31 applies a force to the push shaft 2, but the contact member at the needle distal end prevents the flowable composition from being expelled from the distal end opening.

[0257] In some embodiments, as shown in FIG. 16B , the pressing unit 30 includes a proximal end and a distal end connected by a first elastic element 31. As shown in the left diagram of FIG. 16B , before being assembled to a syringe, the pressing unit 30 is in an initial state, with the first elastic element 31 (e.g., a spring) in a resting state, neither stretched nor compressed. The pressing unit 30 further includes a locking element 33 at its distal end, which can prevent the pressing unit 30 from moving toward the distal end of the syringe barrel. As shown in the right diagram of FIG. 16B , the pressing unit 30 may be assembled to the proximal end of the syringe barrel 1 and the push shaft 2, with the push shaft 2 elastically engaged with the syringe barrel 1 via the first elastic element 31 (e.g., a spring), and the first elastic element 31 being stretched. Because the first elastic element 31 is in an extended state, the proximal end of the pushing unit applies force to the push shaft 2, but the contact member at the needle distal end prevents the flowable composition from being expelled from the distal end opening.

[0258] As shown in steps a-c of FIG. 17A, the adapter is attached to the syringe, and the flowable composition is aspirated into the chamber. In steps d and e of FIG. 17A, the syringe with the adapter is in an initial state, where the distal end opening of the needle is within the contact member, thereby preventing the flowable composition from being expelled from the distal end opening. A first elastic element (not shown in FIG. 17A) of the pushing unit applies force to the push shaft, which further applies pressure to the contact member through the flowable composition and the distal end opening of the needle. Due to the density of the contact member 25, back pressure at the distal end opening of the needle prevents the flowable composition from leaking from the syringe barrel. In steps f and g of FIG. 17A, the distal end opening of the needle has already entered dense tissue A (e.g., the sclera, the anterior chamber angle, or the ciliary body), and back pressure of the dense tissue against the distal end opening prevents the flowable composition from leaking into the tissue. The contact member, optional second elastic element, and optional connector can also increase resistance to distal advancement of the needle, thereby reducing the risk of needle over-penetration. In step h of FIG. 17A, the distal opening of the needle begins to enter low-density tissue B, such as an apparent or potential tissue void, chamber, or vessel (e.g., the SCS or subconjunctival space). In step i of FIG. 17A, as the tissue density decreases, the backpressure at the distal opening of the puncture member becomes lower than the pressure of the flowable composition, thereby allowing the flowable composition to be expelled into the low-density tissue. As the flowable composition is expelled from the distal opening of the puncture member, the energy stored in the first elastic element is released. In some embodiments, a stopper can be used to stop the distal movement of the push shaft within the syringe barrel to stop the flow of the flowable composition. In this manner, the volume of the flowable composition delivered to the low-density tissue can be controlled.

[0259] In some embodiments, the adapter sets described herein can also be used to improve the injection accuracy and safety of other syringes, such as the syringe disclosed in U.S. Patent No. 2020 / 0069883, which is incorporated herein by reference for all purposes. The contact member, optional second elastic element, and optional connector can be attached to the injection needle in the same manner as described above. The pressing unit can also be attached to the push shaft of the syringe in the same manner as described above.

[0260] As shown in steps a-c of FIG. 17B, an adapter is attached to the syringe disclosed in U.S. Patent No. 2020 / 0069883, and the flowable composition is aspirated into the chamber. As shown in steps d and e of FIG. 17B, the syringe with the adapter is in an initial state, where the distal end opening of the needle is within the contact member, thereby preventing the flowable composition from being expelled from the distal end opening. The first elastic element applies force to the push shaft, which applies pressure to the contact member through the flowable composition and the distal end opening of the needle. Due to the density of the contact member 25, backpressure at the distal end opening of the needle prevents the flowable composition from leaking from the syringe barrel. In steps f and g of FIG. 17B, the distal end opening of the needle has already entered dense tissue A (e.g., the sclera, the anterior chamber angle, or the ciliary body), and the backpressure of this dense tissue against the distal end opening prevents the flowable composition from leaking into the tissue. The contact member, optional second elastic element, and optional connector can also increase resistance to distal advancement of the needle, thereby reducing the risk of needle over-penetration. In step h of FIG. 17B, the distal opening of the needle begins to enter low-density tissue B, such as an apparent or potential tissue void, chamber, or blood vessel (e.g., the SCS or subconjunctival space). In step i of FIG. 17B, as the tissue density decreases, the backpressure at the needle distal opening becomes lower than the pressure of the flowable composition, thereby allowing the flowable composition to be expelled into the low-density tissue. The energy stored in the first elastic element is released, pushing the push shaft distally while the contact member blocks the floating seal member 3 from moving distally. This allows the flowable composition to be expelled from the distal opening of the puncture member. In some embodiments, a stopper can be used to stop the distal movement of the push shaft within the syringe barrel to stop the flow of the flowable composition. In this manner, the volume of flowable composition delivered to the low-density tissue can be controlled.

[0261] The exemplary embodiments and optional implementation methods of the present disclosure have been described in detail above with reference to the drawings. However, the present disclosure is not limited to the details described in the above embodiments. Simple modifications can be made to the embodiments of the present disclosure, all of which are within the scope of the present invention.

[0262] It should be noted that the technical features described in the above embodiments can be combined in any reasonable manner as long as they are not contradictory, and in order to avoid unnecessary repetition, the possible combinations will not be described individually in the embodiments.

[0263] Furthermore, different implementations of the embodiments of the present disclosure can be freely combined, and these combinations should be considered as part of the present disclosure as long as they do not violate the concept of the present disclosure. [Brief explanation of the drawings]

[0264] [Figure 1A] FIG. 1A shows a schematic diagram of the various stages of operation of an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. [Figure 1B] FIG. 1B shows a schematic diagram of the various stages of operating an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. [Figure 1C] FIG. 1C shows a schematic diagram of each stage of operation of an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. [Figure 1D] FIG. 1D shows a schematic diagram of each stage of operation of an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. [Figure 1E] FIG. 1E shows a schematic diagram of the various stages of operating an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. [Figure 1F] FIG. 1F illustrates steps for operating an exemplary medical lancing device without a contact member (eg, 1b shown in FIGS. 1A-1E). [Figure 2A]FIG. 2A shows a schematic diagram of the various stages of operation of an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. [Figure 2B] FIG. 2B shows a schematic diagram of the various stages of operation of an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. [Figure 2C] FIG. 2C shows a schematic diagram of each stage of operation of an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. [Figure 2D] 2A-2E show schematic diagrams of various stages of operation of an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. [Figure 2E] FIG. 2E shows a schematic diagram of the various stages of operating an exemplary medical puncture device, such as during puncture and injection of the suprachoroidal space (SCS) 14. [Figure 2F] FIG. 2F illustrates steps for operating an exemplary medical lancing device without a contact member (eg, 1b shown in FIGS. 2A-2E). [Figure 2G] FIG. 2G shows steps for operating an exemplary medical puncture device that includes an additional drive member 2′ engaged to a floating seal member 3 via another spring 4′, with the drive member 2 engaged to the floating seal member 3 via a spring 4. [Figure 3A] FIG. 3A is a partial structural view of an exemplary medical puncture device including a floating seal member 3, one or more needle body openings (6b or 6b1, 6b2 and / or 6b3), and a needle distal end opening 6a. [Figure 3B] FIG. 3B is a partial structural view of an exemplary medical puncture device including a floating seal member 3, one or more needle body openings (6b or 6b1, 6b2 and / or 6b3), and a needle distal end opening 6a. [Figure 3C] 3A-3F are partial structural diagrams of an exemplary medical puncture device including a floating seal member 3, one or more needle body openings (6b or 6b1, 6b2 and / or 6b3), and a needle distal end opening 6a. [Figure 3D] FIG. 3D is a partial structural view of an exemplary medical puncture device including a floating seal member 3, one or more needle body openings (6b or 6b1, 6b2 and / or 6b3), and a needle distal end opening 6a. [Figure 3E] 3A-3F are partial structural diagrams of an exemplary medical puncture device including a floating seal member 3, one or more needle body openings (6b or 6b1, 6b2 and / or 6b3), and a needle distal end opening 6a. [Figure 3F] FIG. 3F is a partial structural view of an exemplary medical puncture device including a floating seal member 3, one or more needle body openings (6b or 6b1, 6b2 and / or 6b3), and a needle distal end opening 6a. [Figure 4A] FIG. 4A is a partial structural view of an exemplary medical puncture device including a floating seal member 3 and a needle body opening 6b. [Figure 4B] FIG. 4B is a partial structural view of an exemplary medical puncture device including a floating seal member 3 and a needle body opening 6b. [Figure 4C] FIG. 4C is a partial structural view of an exemplary medical puncture device including a floating seal member 3 and a needle body opening 6b. [Figure 5A] FIG. 5A is a partial structural view of an exemplary medical puncture device including floating seal members 3a and 3b and one or more needle body openings (6b or 6b1 and / or 6b2). [Figure 5B] FIG. 5B is a partial structural view of an exemplary medical puncture device including floating seal members 3a and 3b and one or more needle body openings (6b or 6b1 and / or 6b2). [Figure 5C] FIG. 5C is a partial structural view of an exemplary medical puncture device including floating seal members 3a and 3b and one or more needle body openings (6b or 6b1 and / or 6b2). [Figure 5D]FIG. 5D is a partial structural view of an exemplary medical puncture device including floating seal members 3a and 3b and one or more needle body openings (6b or 6b1 and / or 6b2). [Figure 5E] FIG. 5E is a partial structural view of an exemplary medical puncture device including floating seal members 3a and 3b and one or more needle body openings (6b or 6b1 and / or 6b2). [Figure 5F] FIG. 5F is a partial structural view of an exemplary medical puncture device including floating seal members 3a and 3b and one or more needle body openings (6b or 6b1 and / or 6b2). [Figure 6] FIG. 6 shows a partial structural view of an exemplary medical puncture device including a through-sloped guide groove 3 a and a one-way valve 9 . [Figure 7] FIG. 7 shows a partial structural view of an exemplary medical puncture device including a through-sloped guide groove 3 a and a one-way valve 9 . [Figure 8] FIG. 8 shows a partial structural view of an exemplary medical puncture device including a non-penetrating inclined guide groove 3a. [Figure 9] FIG. 9 shows a partial structural view of an exemplary medical puncture device including an angled guide needle hole 6c and a one-way valve 9. [Figure 10] FIG. 10 shows a partial structural view of an exemplary medical puncture device including an inclined guide needle hole 6c and a needle hole plug 10. [Figure 11A] FIG. 11A shows a schematic diagram of implanting a catheter 11 into an SCS 14 using an exemplary medical device assembly including a central guide channel 2c. [Figure 11B] FIG. 11B shows a schematic diagram of implanting a catheter 11 into an SCS 14 using an exemplary medical device assembly including a central guide channel 2c. [Figure 12A] FIG. 12A shows a schematic diagram of the operational stages of operating an exemplary medical lancing device. [Figure 12B] FIG. 12B shows a schematic diagram of the operational stages of operating an exemplary medical lancing device. [Figure 12C]FIG. 12C shows a schematic diagram of the operational stages of operating an exemplary medical lancing device. [Figure 13] FIG. 13 shows a schematic diagram of the elements and features of an exemplary medical lancing device. [Figure 14A] FIG. 14A shows a schematic diagram of the operational stages of operating an exemplary medical lancing device. [Figure 14B] FIG. 14B shows a schematic diagram of the operational stages of operating an exemplary medical lancing device. [Figure 14C] FIG. 14C shows a schematic diagram of the operational stages of operating an exemplary medical lancing device. [Figure 14D] FIG. 14D shows a schematic diagram of the operational stages of operating an exemplary medical lancing device. [Figure 14E] FIG. 14E shows a schematic diagram of the operational stages of operating an exemplary medical lancing device. [Figure 14F] FIG. 14F shows a schematic diagram of the operational stages of operating an exemplary medical lancing device. [Figure 15A] FIG. 15A shows a schematic diagram of an exemplary contact member, second resilient element, and connector as part of an adapter. [Figure 15B] FIG. 15B shows a schematic diagram of an exemplary contact member, second resilient element, and connector as part of an adapter. [Figure 15C] FIG. 15C shows a schematic diagram of an exemplary contact member, second resilient element, and connector as part of an adapter. [Figure 15D] FIG. 15D shows a schematic diagram of an exemplary contact member, second resilient element, and connector as part of an adapter. [Figure 15E] FIG. 15E shows a schematic diagram of an exemplary contact member, second resilient element, and connector as part of an adapter. [Figure 15F] FIG. 15F shows a schematic diagram of an exemplary contact member, second resilient element, and connector as part of an adapter. [Figure 15G] FIG. 15G shows a schematic diagram of an exemplary contact member, second resilient element, and connector as part of an adapter. [Figure 15H] FIG. 15H shows a schematic diagram of an exemplary contact member, second resilient element, and connector as part of an adapter. [Figure 16A] FIG. 16A shows a schematic diagram of an exemplary pressing element as part of an adapter (e.g., for use with a suitable syringe, such as a syringe with or without a floating seal member) for applying pressure to the plunger of a syringe (e.g., after liquid has been drawn into the syringe and before the needle is inserted into tissue). [Figure 16B] FIG. 16B shows a schematic diagram of an exemplary pressing element as part of an adapter (e.g., for use with a suitable syringe, such as a syringe with or without a floating seal member) for applying pressure to the plunger of a syringe (e.g., after liquid has been drawn into the syringe and before the needle is inserted into tissue). [Figure 17A] FIG. 17A shows a schematic diagram of the various operational steps for operating a syringe fitted with an adapter as described herein. [Figure 17B] FIG. 17B shows a schematic diagram of the various operational steps for operating a syringe fitted with an adapter as described herein. [Figure 18A] FIG. 18A shows a schematic diagram of exemplary methods and compositions for drainage via the SCS. [Figure 18B] FIG. 18B shows a schematic diagram of exemplary methods and compositions for drainage via the SCS.

Claims

1. A pre-filled syringe for injecting a pharmaceutical composition into the eye, comprising: a syringe barrel including a proximal end and a distal end; a floating seal member located within the syringe barrel; a needle hub located at the proximal end of the floating seal member, the floating seal member and the needle hub being resiliently engaged with each other; a pharmaceutical composition contained within a chamber formed by the floating seal member and the distal end of the syringe barrel; A needle for intraocular puncture, the needle comprising: (i) a needle proximal end engaged with a needle hub; (ii) needle distal end; (iii) needle distal end opening; (iv) a needle body opening located between the needle proximal end and the needle distal end, the needle body opening located at the proximal end of the needle distal end opening; and (v) a needle including a needle body passage connecting the needle distal end opening and the needle body opening; A pre-filled syringe, wherein the needle hub is configured to advance the needle distally toward and / or through the floating seal member.

2. 10. The pre-filled syringe of claim 1, wherein the pharmaceutical composition comprises a triamcinolone formulation.

3. The triamcinolone formulation (i) triamcinolone or a pharmaceutically acceptable salt thereof; (ii) hyaluronic acid or a pharmaceutically acceptable derivative, analog, salt, or solvate thereof; (iii) one or more buffering agents; and (iv) one or more osmolality adjusting agents. The pre-filled syringe of claim 2,

4. The pre-filled syringe according to claim 3, wherein the pharmaceutically acceptable salt of hyaluronic acid comprises a pharmaceutically acceptable metal salt of hyaluronic acid, preferably an alkali metal salt or alkaline earth metal salt, more preferably a sodium salt, particularly preferably a pharmaceutically acceptable salt of hyaluronic acid having a molecular weight of about 50,000 to about 2,000,000 daltons.

5. 5. The pre-filled syringe according to claim 3 or 4, wherein the buffer comprises one or more reagents selected from the group consisting of acetate buffers, citrate buffers, phosphate buffers and borate buffers, preferably the buffer comprises a phosphate buffer, more preferably the buffer comprises disodium hydrogen phosphate, sodium dihydrogen phosphate or a mixture thereof, wherein the sodium dihydrogen phosphate is in the form of a monohydrate and the disodium hydrogen phosphate is in the form of a dodecahydrate.

6. The pre-filled syringe according to any one of claims 3 to 5, wherein the osmotic pressure adjusting agent comprises sodium chloride, potassium chloride, or a mixture thereof.

7. 7. The pre-filled syringe according to any one of claims 3 to 6, wherein the triamcinolone formulation further comprises water, preferably water for injection.

8. (i) the weight ratio of triamcinolone in the entire formulation is 1.0% (w / w) to 8.0% (w / w); (ii) the weight ratio of hyaluronic acid or a pharmaceutically acceptable salt thereof in the entire preparation is 0.1% (w / w) to 5.0% (w / w); (iii) the weight ratio of said one or more buffering agents in the total formulation is 0.05% (w / w) to 0.8% (w / w); (iv) The weight ratio of the one or more osmotic agents in the entire formulation is 5.0% (w / w) to 10.0% (w / w). A pre-filled syringe according to any one of claims 3 to 7.

9. The preparation contains, as ingredients: (i) triamcinolone in a weight ratio of 3.0% (w / w) to 5.0% (w / w) in the total formulation; (ii) sodium hyaluronate in a weight ratio of 0.1% (w / w) to 5.0% (w / w) in the total formulation; (iii) sodium chloride in a weight ratio of 0.6% (w / w) to 0.8% (w / w) in the total formulation; (iv) sodium dihydrogen phosphate in a weight ratio of 0.2% (w / w) to 0.4% (w / w) in the whole formulation; (v) disodium hydrogen phosphate in a weight ratio of 0.05% (w / w) to 0.15% (w / w) in the whole formulation; (vi) sodium hydroxide in an amount sufficient to adjust the pH of the formulation to about 6.5 to about 7.5; (vii) water. The pre-filled syringe according to any one of claims 3 to 8.

10. The pre-filled syringe according to any one of claims 3 to 9, wherein the pH of the formulation is about 6.0 to about 8.0, and preferably the formulation further comprises a pH adjuster, and the pH adjuster is sodium hydroxide.

11. The pre-filled syringe according to any one of claims 3 to 10, wherein the osmolality of the formulation is from about 200 mOsm / kg to about 400 mOsm / kg, and the average particle size of triamcinolone particles in the formulation is from about 0.5 μm to about 3.5 μm.

12. The formulation comprises: (a) adding hyaluronic acid or a pharmaceutically acceptable salt thereof, a buffer, an osmolality adjusting agent, and an optional pH adjusting agent to water and mixing; and step (b) dispersing triamcinolone in the mixture of step (a), Preferably, in step (b), the dispersion is promoted by stirring, and Preferably, the method further comprises the step (c) of wet-grinding the mixture of step (b).

13. 10. The pre-filled syringe of claim 1, wherein the pharmaceutical composition comprises one or more corticosteroids.

14. 14. The pre-filled syringe of claim 13, wherein the one or more corticosteroids are selected from dexamethasone, triamcinolone acetonide, triamcinolone, triamcinolone acetonide acetate, fluocinolone acetonide, prednisolone, loteprednol, difluprednate, fluorometholone, and any combination thereof.

15. 2. The pre-filled syringe of claim 1, wherein the pharmaceutical composition comprises one or more tyrosine kinase inhibitors.

16. 16. The pre-filled syringe of claim 15, wherein the one or more tyrosine kinase inhibitors are selected from axitinib, afatinib, erlotinib, gefitinib, crizotinib, dabrafenib, vemurafenib, dasatinib, imatinib, nilotinib, trametinib, and any combination thereof.

17. 10. The pre-filled syringe of claim 1, wherein the pharmaceutical composition comprises one or more complement inhibitors.

18. 18. The pre-filled syringe of claim 17, wherein the one or more complement inhibitors include a plasma kallikrein inhibitor.

19. 10. The pre-filled syringe of claim 1, wherein the pharmaceutical composition comprises one or more neuroprotective agents.

20. 20. The pre-filled syringe of claim 19, wherein the one or more neuroprotective agents are selected from cholic acid, chenodeoxycholic acid, deoxycholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid, lithocholic acid, taurocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, ursodeoxycholic acid, and any combination thereof.

21. The pre-filled syringe of claim 1, wherein the pharmaceutical composition comprises one or more hypoxia factor-induced inhibitors.

22. 16. The pre-filled syringe of claim 15, wherein the one or more hypoxic factor-induced inhibitors are selected from EZN-2698, aminoflavone, camptothecin (e.g., topotecan, EZN-2208, SN38, irinotecan, temsirolimus, everolimus, sirolimus, LY294002, wotomannin, cardiac glycosides, digoxin, ouabain, proscillaridin, 2ME2, romidepsin (KF228), trichostatin, LW6, acriflavine, echinomycin, anthracycline antibiotics (e.g., doxorubicin and daunorubicin), chetomin, bortezomib, and any combination thereof.

23. 2. The pre-filled syringe of claim 1, wherein the pharmaceutical composition comprises one or more adrenergic receptor agonists, gene therapy drugs, protein and polypeptide drugs, therapeutic cells or cell components for cell therapy, or any combination thereof.

24. 24. The pre-filled syringe of claim 23, wherein the one or more adrenergic receptor agonists are selected from adrenaline, noradrenaline, isoproterenol, dopamine, phenylephrine, methoxamine, midodrine, oxymetazoline, alpha-methyldopa, clonidine, brimonidine, dobutamine, salbutamol / albuterol, terbutaline, salmeterol, formoterol, pirbuterol, clenbuterol, and any combination thereof.

25. 24. The pre-filled syringe of claim 23, wherein the one or more gene therapy agents are selected from AAV2, AAV5, AAV8 and AAV9 vectored drugs, electrotransfer (ET), liposome and DNA nanoparticle vectored gene therapy agents, and any combination thereof.

26. 24. The pre-filled syringe of claim 23, wherein the one or more protein and polypeptide drugs are selected from anti-VEGF drugs (e.g., bevacizumab, ranibizumab, aflibercept, conbercept, etc.), bispecific antibody drugs (e.g., faricimab), vasoconstrictors (e.g., endothelin-1), TNF-α inhibitors (e.g., adalimumab), and any combination thereof.

27. 24. The pre-filled syringe of claim 23, wherein the one or more therapeutic cells or cellular components are selected from stem cells, regulatory T cells, exosomes, and any combination thereof.

28. 10. The pre-filled syringe of claim 1, wherein the pharmaceutical composition comprises one or more gels or aqueous polymer solutions.

29. 29. The pre-filled syringe of claim 28, wherein the one or more gels or aqueous polymer solutions comprise one or more viscoelastic materials.

30. 30. The prefilled syringe of claim 28 or 29, wherein the one or more gels or aqueous polymer solutions are selected from sodium hyaluronate, Provisc (a 1% viscous transparent substance that is a specific component of sodium hyaluronate), Viscoat (a dispersive viscoelastic preparation consisting of sodium hyaluronate and chondroitin sulfate), Amvisc (a purified component of sodium hyaluronate), Amvisc Plus (a 1.6% sodium hyaluronate product derived from rooster comb), sodium chondroitin sulfate / sodium hyaluronate, or DisCoVisc (4% sodium chondroitin sulfate, 1.65% sodium hyaluronate), sodium carboxymethylcellulose, poloxamer, and any combination thereof.

31. 10. The pre-filled syringe of claim 1, wherein the pharmaceutical composition comprises one or more anti-tumor drugs, herbal medicines, H1 receptor antagonists, mast cell stabilizers, or any combination thereof.

32. 10. The pre-filled syringe of claim 1, wherein the pharmaceutical composition comprises one or more nonsteroidal anti-inflammatory drugs, prostaglandin derivatives, anticholinergic drugs, anesthetic agents, or any combination thereof.

33. 1. A method of placing a stent in an eye, comprising: (a) inserting a needle into an injection site of the eye between the sclera and choroid of the eye; (b) delivering a flowable composition through the needle to form a suprachoroidal space; (c) removing the needle from the eye; (d) placing a stent into the suprachoroidal space through the injection site.

34. The method of claim 33 , wherein the flowable composition comprises a viscoelastic material.

35. 35. The method of claim 33 or 34, wherein the injection site is first dilated before the stent is placed in the suprachoroidal space.

36. The method according to any one of claims 33 to 35, wherein the stent is placed in the suprachoroidal space in a plane parallel to the equator of the eye.

37. The method according to any one of claims 33 to 36, wherein the anterior chamber angle is not punctured.

38. The method of any one of claims 33 to 37, wherein the stent is coated with or loaded with one or more drugs.

39. 39. The method of claim 38, wherein the one or more drugs are selected from corticosteroids, tyrosine kinase inhibitors, complement inhibitors, neuroprotective agents, hypoxia factor-induced inhibitors, adrenergic receptor agonists, gene therapy drugs, protein and polypeptide drugs, therapeutic cells or cell components for cell therapy, anti-tumor drugs, herbal medicines, H1 receptor antagonists, mast cell stabilizers, non-steroidal anti-inflammatory drugs, prostaglandin derivatives, anticholinergic drugs, and anesthetics.

40. using a device comprising: a syringe barrel including a proximal end and a distal end; a floating seal member located within the syringe barrel; a needle hub located at the proximal end of the floating seal member, the floating seal member and the needle hub being resiliently engaged with each other; A needle, the needle comprising: (i) a needle proximal end engaged with a needle hub; (ii) needle distal end; (iii) needle distal end opening; (iv) a needle body opening located between the needle proximal end and the needle distal end, the needle body opening located at the proximal end of the needle distal end opening; and (v) a needle including a needle body passage connecting the needle distal end opening and the needle body opening; 40. The method of any one of claims 33 to 39, wherein the needle hub is configured to advance the needle distally towards and / or through the floating seal member.

41. 1. A method for improving syringe injection accuracy and safety, comprising: (1) providing a syringe including a syringe barrel extending from a proximal end to a distal end forming a chamber extending from the proximal end to the distal end, a push shaft extending from the proximal end to the distal end forming a seal between the distal end and the syringe barrel, and a needle extending from the proximal end to the distal end including an end opening for allowing fluid to pass from the chamber through the needle hub to the distal end of the syringe barrel; (2) providing an adapter set including a contact member extending from a proximal end to a distal end and a pressing unit including a first elastic element; (3) attaching a contact member to the distal end of the needle; (4) attaching the pressing unit to the syringe; The distal end of the contact member is located at the distal end of the needle distal end opening, and the distal end of the contact member can directly contact the surface tissue of the target injection site; and The pressing unit is resiliently engaged with the push shaft and the syringe barrel via a first resilient element.

42. 42. The method of claim 41, wherein the proximal end of the contact member directly contacts the needle hub, and the contact member has a Young's modulus of about 0.001 GPa to about 10 GPa.

43. 42. The method of claim 41, wherein the adapter set further includes a second elastic element, and the method further includes step (3a) performed between steps (3) and (4), wherein step (3a) includes attaching the second elastic element between the contact member and the needle hub, the second elastic element elastically connecting the proximal end of the contact member and the needle hub.

44. 44. The method of claim 43, wherein the Young's modulus of the contact member is greater than the Young's modulus of the second elastic element.

45. 45. The method of claim 43 or 44, wherein the second elastic element is a spring or an elastic sheath.

46. 46. ​​The method of any one of claims 43 to 45, wherein the contact member comprises a first portion and a second portion, the first portion being located at a distal end of the second portion, and the first portion being more elastic than the second portion.

47. 42. The method of claim 41, wherein the adapter set further includes a connector, and the method further includes step (3a') performed between step (3) and step (4), wherein step (3a') includes attaching the connector between the contact member and the needle hub, and the elasticity of the connector is less than the elasticity of the contact member.

48. A method according to any one of claims 41 to 47, wherein the first elastic element is a spring.

49. An adapter set for a syringe, a contact member extending from a proximal end to a distal end; a pressing unit including a first elastic element; the syringe includes a barrel extending from a proximal end to a distal end and forming a chamber extending from the proximal end to the distal end; a push shaft extending from the proximal end to the distal end and forming a seal between the distal end and the barrel; and a needle extending from the proximal end to the distal end and including an end opening for allowing fluid to pass through the needle hub, through the distal end of the barrel, and out of the chamber; The contact member may be attached to the distal end of the injection needle such that the distal end of the contact member is located at the distal end of the needle distal end opening, and the distal end of the contact member can directly contact the surface tissue of the target injection site; and The adapter set for a syringe, wherein the pushing unit can be attached to the syringe barrel and / or the push shaft of the syringe such that the pushing unit is elastically engaged with the push shaft and / or the syringe barrel of the syringe via a first elastic element.

50. 50. The adapter set of claim 49, wherein the contact member is attachable to the distal end of the injection needle such that the proximal end of the contact member can directly contact the needle hub, and the Young's modulus of the contact member is from about 0.001 GPa to about 10 GPa.

51. 50. The adapter set of claim 49, further comprising a second elastic element, the second elastic element being attachable between the contact member and the needle hub, the second elastic element elastically connecting the proximal end of the contact member and the needle hub.

52. 52. The adapter set of claim 51, wherein the Young's modulus of the contact member is greater than the Young's modulus of the second elastic element.

53. 53. An adapter set according to claim 51 or 52, wherein the second elastic element is a spring or an elastic sheath.

54. An adapter set as described in any one of claims 51 to 53, wherein the contact member includes a first portion and a second portion, the first portion being located at a distal end of the second portion, and the first portion being more elastic than the second portion.

55. 50. The adapter set of claim 49, further comprising a connector, the connector being mountable between the contact members and the hub, the connector being less elastic than the contact members.

56. An adapter set according to any one of claims 49 to 55, wherein the first elastic element is a spring.

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