Medicated device, suprachoroidal implant and injection adapter

Abstract

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

Description

Cross - Reference to Related Applications

[0001] This application claims priority to International Application No. PCT / CN2022131454, filed on November 11, 2022, the entire content of which is incorporated herein by reference. Technical Field

[0002] In some aspects, the present disclosure relates to the field of medical devices and equipment, and more particularly to devices, kits, components, or systems for medical puncture and drainage. Background Art

[0003] In existing treatment methods involving the suprachoroidal space (SCS), a syringe is typically used to inject drugs into the SCS. When performing the puncture, the puncture depth of the syringe needle needs to be manually controlled, and medical staff must rely on his or her experience to determine whether the needle has entered the SCS. However, the eye structures of different patients are usually different from each other, and the determination of the needle depth by medical staff may not be precise. Therefore, the precise placement of the needle relative to the SCS cannot be guaranteed. In addition, when injecting drugs, the piston of the syringe must be continuously manually pressed. To stabilize the injection speed and prevent fluctuations in the flow rate, skilled operation by medical staff is required. However, in practice, it is challenging to ensure a stable injection each time. Therefore, improved devices and methods for medical puncture, such as injecting into the SCS, are needed.

[0004] At the same time, the medicaments used to treat the SCS need to reach a high level of sterility and need to be injected with minimal dosage error. Therefore, it is necessary to develop an injection device or system that not only achieves precise injection into the SCS but also minimizes contamination from the environment, eliminates dosage errors, and provides convenience for medical staff.

[0005] The present disclosure addresses these and other needs by providing a pre - loaded or pre - filled injection device that includes an apparatus suitable for precise injection into the SCS and one or more therapeutic agents. Summary

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

[0007] In some embodiments, provided herein is a prefilled syringe for injecting a pharmaceutical composition into an eye, comprising: a barrel including a proximal end and a distal end; a floating seal located within the barrel; a needle hub located proximal to the floating seal, wherein the floating seal and the needle hub are elastically engaged with each other; a pharmaceutical composition contained within a chamber formed by the floating seal and the distal end of the barrel; a needle for intraocular puncture, the needle comprising: (i) a proximal needle end engaged with the needle hub; (ii) a distal needle end; (iii) a distal needle opening; (iv) a needle body opening located between the proximal needle end and the distal needle end, wherein the needle body opening is close to the distal needle opening; and (v) a needle body channel connecting the distal needle opening and the needle body opening, wherein the needle hub is configured to advance the needle distally towards and / or through the floating seal.

[0008] In any embodiment herein, the pharmaceutical composition may comprise a triamcinolone formulation. In some embodiments, the triamcinolone formulation comprises: (i) triamcinolone or a pharmaceutically acceptable salt thereof; (ii) hyaluronic acid or a pharmaceutically acceptable derivative, analogue, salt or solvate thereof; (iii) one or more buffering agents; and (iv) one or more osmotic pressure regulators.

[0009] In some embodiments, provided herein is a method for intraocular placement of a stent, comprising: (a) inserting a needle at an ocular injection site between the sclera and the 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 into the suprachoroidal space through the injection site. In some embodiments, the flowable composition comprises a viscoelastic substance. In some embodiments, the injection site is dilated and then the stent is implanted into the suprachoroidal space through the dilated injection site. In some embodiments, the stent is placed in the suprachoroidal space on a plane parallel to the equator of the eyeball. In some embodiments, the stent implanted into the suprachoroidal space is configured to maintain the suprachoroidal space in a dilated state as compared to the state before the flowable composition is delivered to the eye, and the dilated state is maintained for at least 4 months, 8 months, 12 months, 18 months, 24 months, 30 months, 36 months or longer.

[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 pressing unit including a first elastic element; wherein 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 plunger shaft extending from the proximal end to the distal end and forming a seal between the distal end of the plunger shaft and the barrel; and a needle extending from the proximal end to the distal end, including an end opening for allowing fluid to flow out of the distal end of the barrel from the chamber and through the needle hub; wherein the contact member can be mounted to the distal end of the syringe needle such that the distal end of the contact member is located distal to the distal end opening of the needle, and the distal end of the contact member can directly contact the surface tissue of the target injection site; and wherein the pressing unit can be mounted to the barrel and / or the plunger shaft of the syringe such that the pressing unit elastically engages the plunger shaft and / or the barrel of the syringe through the first elastic element.

[0011] In some embodiments, the adapter set further includes a second elastic element configured to be mounted between the contact member and the needle hub, wherein the second elastic element elastically connects the proximal end of the contact member and the needle hub. In some embodiments, the second elastic element is a spring or an elastic sheath.

[0012] In some embodiments, the adapter set can be used in combination with any syringe disclosed herein (including any pre-filled syringe disclosed herein). Brief Introduction of Drawings

[0013] The drawings illustrate certain embodiments of 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] Figure 1A - 1E A schematic diagram showing different operating stages of operating an exemplary medical puncture device, such as during puncturing and injecting into the suprachoroidal space (SCS) 14. Figure 1F Shows the steps of operating an exemplary medical puncture device in the absence of a contact member (e.g., Figure 1A - 1E as shown in 1b), where the distal seal (e.g., Figure 1A - 1E as shown in 8) can directly contact the tissue.

[0015] Figure 2A - 2E A schematic diagram showing different operating stages of operating an exemplary medical puncture device, such as during puncturing and injecting into the suprachoroidal space (SCS) 14. Figure 2F Shows the steps of operating an exemplary medical puncture device in the absence of a contact member (e.g., Figure 2A - 2E as shown in 1b), where the distal seal (e.g., Figure 2A - 2E as shown in 8) can directly contact the tissue. Figure 2GShows the steps of operating an exemplary medical puncture device, which includes an additional drive member 2' that engages a floating seal 3 via another spring 4', while the drive member 2 engages the floating seal 3 via a spring 4.

[0017] Figure 3A - 3F Is a partial structural view of an exemplary medical puncture device, which includes a floating seal 3 and one or more needle body openings (6b or 6b1, 6b2, and / or 6b3) and a needle distal opening 6a.

[0018] Figure 4A - 4C Is a partial structural view of an exemplary medical puncture device, which includes a floating seal 3 and a needle body opening 6b.

[0019] Figure 5A - 5F Is a partial structural view of an exemplary medical puncture device, which includes floating seals 3a and 3b and one or more needle body openings (6b or 6b1 and / or 6b2).

[0020] Figure 6 Shows a partial structural view of an exemplary medical puncture device, which includes a through-going inclined guide groove 3a and a one-way valve 9.

[0021] Figure 7 Shows a partial structural view of an exemplary medical puncture device, which includes a through-going inclined guide groove 3a and a one-way valve 9.

[0022] Figure 8 Shows a partial structural view of an exemplary medical puncture device, which includes a non-through-going inclined guide groove 3a.

[0023] Figure 9 Shows a partial structural view of an exemplary medical puncture device, which includes an inclined guide needle hole 6c and a one-way valve 9.

[0024] Figure 10 Shows a partial structural view of an exemplary medical puncture device, which includes an inclined guide needle hole 6c and a needle hole plug 10.

[0025] Figure 11A - 11B Shows a schematic diagram of implanting a catheter 11 into an SCS 14 using an exemplary medical device assembly including a central guide groove 2c. Figure 11A Shows a contact member 1b that contacts tissue, while Figure 11B Shows a distal seal 8 that contacts tissue, without an intermediate contact member.

[0026] Figure 12A - 12C Shows a schematic diagram of different operating stages of operating an exemplary medical puncture device.

[0027] The reference numerals and exemplary corresponding structures provided below are for illustration only, for example, Figure 1A - 1E to Figure 11A - 11B , and should not be considered as limiting: 1-syringe barrel; 1a-axial stopper; 1b-annular contact element; 2-pressing element; 2c-central guide groove; 3-floating seal; 3a-inclined guide groove; 4-elastic sheath; 5-spring; 6-hollow puncture needle; 6a-distal needle opening; 6b-needle body opening; 6c-inclined guide needle hole; 7-flowable composition cavity; 8-distal seal; 9-one-way valve; 10-needle hole plug; 11-catheter; 12-auxiliary guide needle; 13-sclera; 14-suprachoroidal space (SCS).

[0028] Figure 13 A schematic diagram of various elements and features of an exemplary medical puncture device is shown. For example, the device may include a hollow housing 22 that engages with a proximal control knob 17. A push / push shaft 2 slidably passes through the control knob and engages with a guide tube 16 in the housing. The push / push shaft 2 is configured to apply a distal force to a compression spring 5, which in turn serves as a force element to apply a distal force to a piston rod 15. A bevel needle 6 is connected and fixed to a needle seat or base that is fixed to the push / push shaft. When a force is applied to the push / push shaft to move it distally, the distal end of the needle 6 may be located in a chamber of the piston rod 15 and move distally. The distal end of the needle may be advanced forward, passing through a seal 3 at the distal end of the piston rod 15, and entering a chamber formed by a syringe barrel 1 and a distal seal 8 of the syringe. A compression member 23 may engage with the syringe 1 and the distal seal 8 simultaneously, thereby facilitating a sealed engagement. The distal seal 8 can be in contact with the tissue, and the needle 6 can be advanced through the distal seal 8 to puncture the tissue. The needle 6 may include a needle distal opening and a needle body opening, similar to 6a and 6b, respectively. Figure 1A - 1E to Figure 11A - 11B As shown and Figure 1A - 1E to Figure 11A - 11B Used as described.

[0029] In some embodiments, the devices disclosed herein include a stopper, e.g. Figure 13Limiter 18 therein. In some embodiments, the limiter can be used to limit the maximum length of the axial movement of the pressing shaft, for example, to achieve precise injection. In some embodiments, the limiter can be used to limit the rotation and / or radial movement of the pressing shaft, for example, to prevent or minimize the deviation of the pressing shaft (and the needle hub and syringe needle coupled thereto) from the central axis of the assembled device. In some embodiments, the limiter can engage the guide tube. In some embodiments, the limiter can fixedly or removably engage the proximal end of the guide tube. In some embodiments, the guide tube can be used to guide the movement of the pressing shaft and the piston rod, for example, through corresponding structures on the components, so as to achieve the accuracy of the axial movement of the pressing shaft and the piston rod and the accuracy of the movement of the syringe needle. In some embodiments, the device, through combined features (such as the limiter and the guide tube), prevents or minimizes the rotation and / or deviation (e.g., from the central axis) of the pressing shaft, the piston rod, the needle hub or the base and / or the syringe needle during the transportation and storage of the assembled device and during the use of the device for medical puncture.

[0030] In some embodiments, the devices disclosed herein include a scale, such as Figure 13 scale 19 therein. In some embodiments, the scale can be used to measure or otherwise determine the distance between the puncture site (e.g., the site to be punctured by the syringe needle) and the limbus, which is the boundary between the cornea and the sclera. In some embodiments, the distal end of the scale can be configured to contact a part of the eye at the injection site. In some embodiments, the protrusion of the scale can be configured to leave a mark on a part of the eye, such as at the injection site. For example, the mark can indicate the injection site. For example, the mark can be manifested as parallel marking lines on the conjunctiva of the eye, indicating to the user that the injection should be performed in the area between the parallel marking lines. In some embodiments, the scale can be removably coupled to the delivery device, for example, at the distal end of the delivery device (e.g., coupled to Figure 13 distal seal 8 therein or coupled to Figure 1A contact element 1b therein). In such embodiments, after marking the injection site on the target tissue, the scale can be removed from the delivery device.

[0031] Figure 14A - 14F Schematic diagrams showing different operating stages of operating an exemplary medical puncture device are shown.

[0032] The following provides reference numerals and exemplary corresponding structures for illustration only, for example, referring to FIG. 14 Figure 14A - 14F, and should not be considered restrictive: 1 - a syringe having a barrel forming a chamber; 2 - a pressing element (e.g., a pressing shaft); 3 - a floating seal (e.g., a piston seal); 5 - an elastic element (e.g., a spring); 6 - a hollow puncture needle (the needle distal opening and the needle body opening are not shown); 8 - a distal seal; 15 - a piston rod (e.g., a push shaft); 16 - a guide tube; 17 - a control knob; 18 - a limiter; 19 - a scale; 20 - an adapter; 21 - a handle; 22 - a housing; 23 - a pressing member.

[0033] Figure 15A - 15H A schematic diagram showing an exemplary contact member, a second elastic element, and a connector as parts of an adapter is shown. The distal seal can serve as the contact member and contact the tissue surface at the start of the puncture operation. The distal seal can be rigid or substantially incompressible, or can include a combination of rigid, semi-rigid, soft, and / or elastic materials. The needle hub can be connected to the distal seal by one or more springs or other elastic materials, which are configured to control the pressure during puncture and / or injection, thereby enhancing safety. A sandwich structure (e.g., as shown in Figure 15D and Figure 15E ) can be provided between the needle hub and the tissue surface, and the sandwich structure includes a rigid or substantially incompressible material (e.g., in the distal seal), which is clamped by a first soft and / or elastic material (e.g., in the distal seal) on the distal side and a second soft and / or elastic material (e.g., a spring or an elastic sheath around the needle) on the proximal side. The first and second soft and / or elastic materials can be the same or different. The distal seal, the spring, and / or the elastic sheath around the needle can help reduce the risk of axial movement (e.g., axial deviation) and / or sliding of the needle during puncture. The soft and / or elastic materials used distally can improve the tight or sealed engagement between the contact member (e.g., the distal seal) and the tissue, especially when the tissue surface is uneven and / or when the needle is not perpendicular to the tissue surface, e.g., as shown in Figure 15G and Figure 15H .

[0034] The following provides reference numerals and exemplary corresponding structures for illustration only, e.g., referring to Figure 15A - 15H of Figure 15, and should not be considered restrictive: 1 - a barrel; 6 - a hollow puncture needle (the needle distal opening is not shown); 25 - a contact member; 25a - the first part of the contact member; 25b - the second part of the contact member; 26 - a second elastic element; 27 - a connector.

[0035] Figure 16A - 16BSchematic illustration of an exemplary pressing element forming part of an adapter (for a suitable syringe, such as a syringe with or without a floating seal) for applying pressure to the piston of the syringe (e.g., after liquid has been drawn into the syringe but before the needle pierces the tissue).

[0036] The following reference numerals and exemplary corresponding structures are provided for illustrative purposes only, e.g., with reference to FIG. 16 of Figure 16A - 16B , and should not be considered limiting: 1 - syringe barrel; 2 - push rod; 30 - pressing element; 31 - elastic element; 32 - limiter or locking element.

[0037] Figure 17A - 17B Schematic illustration of different operating stages of a syringe fitted with the adapter described herein.

[0038] The following reference numerals and exemplary corresponding structures are provided for illustrative purposes only, e.g., with reference to FIG. 17 of Figure 17A - 17B , and should not be considered limiting: 1 - syringe barrel; 2 - push rod; 3 - floating seal; 25 - contact member; A - denser tissue; B - less dense tissue.

[0039] In Figure 17AIn this case, step a shows the initial state of a syringe (e.g., a conventional syringe), and step b shows the state of the syringe after drawing in liquid. At this time, if the needle of the syringe is inserted into a contact member (e.g., a distal seal) that seals the opening of the needle, the liquid in the syringe can be retained within the sealed space, as shown in step c. Tissue A can be high-resistance tissue (e.g., high-density tissue), and tissue B is low-resistance tissue (e.g., low-density tissue) or a potential or apparent void, chamber, or blood vessel. To inject the liquid into tissue B, pressure can be applied to the surface of tissue A in step d so that the distal seal contacts the surface of tissue A. As the needle advances, the tip of the needle first advances within the distal seal (as shown in step e), and then reaches the interface between the distal seal and tissue A (as shown in step f). Then, the tip of the needle enters tissue A (as shown in step g), and subsequently the tip of the needle advances to the interface between tissue A and tissue B (as shown in step h). If an appropriate force is applied to the piston of the syringe in steps e - h, when the tip of the needle is in the positions shown in steps e - g, due to the relatively high pressing resistance in the distal seal and tissue A, the fluid cannot be discharged within the distal seal or tissue A. When the tip of the needle reaches the interface between tissue A and tissue B in step h, since the liquid pressure at the tip of the needle is greater than the pressure within tissue B (e.g., a potential or apparent void, chamber, or blood vessel), the liquid can automatically drain into tissue B, and the piston seal moves distally towards the tissue, indicating to the operator that the tip of the needle is at the interface between tissue A and tissue B. If the needle stops advancing but pressure is still applied to the piston, as long as the liquid pressure at the tip of the needle is still greater than the pressure within tissue B, the liquid can continue to drain into tissue B (in step i) until the pressure reaches equilibrium or the piston seal reaches its limit (e.g., blocked by a limiter that can be set in the syringe), thereby achieving precise positioning of the tip of the needle at the interface between tissue A and tissue B and automatic injection. The distal seal applied to the tip of the needle in step c (as an adapter of the syringe) can help retain the liquid within the sealed chamber, and at this time, another adapter of the syringe (e.g., a pressing element for applying pressure) can be used to apply an appropriate pressure to the liquid within the syringe through the piston. During the operation, the operator only needs to focus on the force applied to the piston or the syringe barrel to advance the needle, the advancing speed of the needle, and whether the piston seal suddenly moves distally (towards the tissue), and the operator does not need to simultaneously monitor and / or adjust the pressure applied to the liquid within the syringe (to ensure it is greater than the pressure within tissue B), thereby reducing the number of aspects that the operator must focus on during tissue puncture and improving the safety of tissue puncture (e.g., to avoid over - deep penetration and damage to deeper tissues). By applying the distal seal to the tip of the needle, the actual advancing distance of the needle during puncture is greater than the advancing distance of the needle within tissue A. If tissue A is a relatively thin tissue, increasing the actual advancing distance of the needle during puncture can better control the injection and reduce the operation difficulty.In addition, the distal seal may help reduce the maximum advancement distance of the needle during the puncture (the maximum distance the needle extends beyond the distal seal), which, if appropriately controlled, may help reduce the risk of over - deep penetration. Further, in step c, the distal seal may also increase the rigidity of the needle and reduce the risk of the needle bending, axially moving (such as axial deviation), and / or slipping during the puncture.

[0040] In Figure 17BIn it, step a shows the initial state of the syringe (for example, having two seals, one proximal piston seal and the other a distal floating seal), and step b shows the state of the syringe after drawing in the liquid. At this time, if the needle of the syringe is inserted into the contact member (such as the distal seal) of the opening of the sealed needle, the liquid in the syringe can be kept in the sealed space, as shown in step c. Tissue A can be high-resistance tissue (such as high-density tissue), and tissue B is low-resistance tissue (such as low-density tissue) or potential or obvious voids, chambers or blood vessels. To inject the liquid into tissue B, the distal seal can be made to contact the surface of tissue A by applying pressure to the surface of tissue A in step d. When the needle is advanced by pushing the piston, the tip of the needle first advances within the distal seal (as shown in step e), and then reaches the interface between the distal seal and tissue A (as shown in step f). Then, the tip of the needle enters tissue A (as shown in step g), and subsequently the tip of the needle advances to the interface between tissue A and tissue B (as shown in step h). When the tip of the needle is in the position shown in steps e - g, the fluid cannot be discharged within the distal seal or tissue A because the pressing resistance in the distal seal and tissue A is greater. When the tip of the needle reaches the interface between tissue A and tissue B in step h, if the liquid pressure at the tip of the needle is greater than the pressure within tissue B (such as potential or obvious voids, chambers or blood vessels) at this time, the liquid can be discharged into tissue B. At this time, if the piston continues to advance distally and the pressure is within an appropriate range, the liquid pressure at the tip of the needle can be maintained to be greater than the tissue pressure within tissue B (such as potential or obvious voids, chambers or blood vessels), while the liquid pressure on the floating seal (which engages the needle hub and is connected to the needle) is less than the frictional force, so that the liquid can continue to be discharged into tissue B (in step i), and the tip of the needle does not advance further distally until the pressure reaches equilibrium or the piston seal has reached its limit (such as being blocked by a limiter in the syringe that can be set). The frictional force can be the sum of the static frictional forces between the needle and the distal seal and between the needle and tissue A. By applying the distal seal to the tip of the needle, the actual advancement distance of the needle during puncture is greater than the advancement distance of the needle within tissue A. If tissue A is a relatively thin tissue, increasing the actual advancement distance of the needle during puncture can better control the injection and reduce the operation difficulty. When the liquid is discharged into tissue B (in step i), to prevent the needle from advancing further distally into tissue B, the liquid pressure on the floating seal is less than the sum of the static frictional forces between the needle and the distal seal and between the needle and tissue A. Therefore, when the liquid is discharged into tissue B (in step i), compared with the operation without using the distal seal (where the static frictional force between the needle and the distal seal is 0 because there is no distal seal), by using the distal seal, the puncture operation can tolerate a greater force applied to the piston (this force is transmitted to the floating seal via a substantially incompressible liquid), without the risk of the tip of the needle penetrating too deeply, thus improving the safety of the puncture operation.In addition, the distal seal may help to reduce the maximum distance that the needle advances during penetration (the maximum distance that the needle extends beyond the distal seal), which, if appropriately controlled, may help to reduce the risk of over-penetration. In addition, the distal seal in step c may also increase the rigidity of the needle and reduce the risk of the needle bending, axially moving (e.g., axial offset), and / or slipping during penetration.

[0041] Figure 18A - 18B A schematic illustration of an exemplary method and composition for drainage via SCS is shown. In Figure 18A the exemplary ab externo method shown, a viscoelastic reagent is injected between the sclera and the choroid to form the SCS, and then a permanent or semi-permanent structure (e.g., a stent) is implanted to keep the SCS in an expanded state for a longer time. The implant may form an annular or partial annular structure in a plane parallel to the equator of the eyeball, as Figure 18B shown. Detailed description

[0042] The following is a detailed description of some embodiments of the present disclosure. It should be understood that the specific embodiments described herein are intended to illustrate and explain the embodiments of the present disclosure and should not be considered restrictive.

[0043] It should be noted that when there is no conflict, the embodiments of the present disclosure and the features of the embodiments can be combined in any appropriate manner.

[0044] In some embodiments, positional descriptions such as "front", "rear", "forward", "backward", "distal", and "proximal" are based on the perspective of the operator of the medical penetration device or medical device component. That is, when the operator is using the medical penetration device or medical device component, the direction away from the operator and relatively far from the operator is the forward direction, and the direction pointing to the operator and relatively close to the operator is the backward direction.

[0045] As used herein, the terms "proximal" and "distal" refer to the directions closer to and farther from the operator (e.g., surgeon, physician, nurse, technician, etc.) who inserts the medical device into the patient, respectively, where the tip (distal) of the device is first inserted into the patient. Thus, for example, the end of the needle (e.g., micro-needle) described herein that is first inserted into the patient is the distal end, and the opposite end of the needle (e.g., the end of the medical device manipulated by the operator) is the proximal end of the needle.

[0046] As used herein, unless the context clearly dictates otherwise, the singular forms "a", "an", and "the" include plural referents. For example, "a" or "an" means "at least one" or "one or more". Similarly, the term "component" is intended to refer to a single component or a combination of components, and the term "material" is intended to refer to one or more materials or a combination thereof.

[0047] As used herein, the terms "about" or "approximately" refer to the conventional error range of the corresponding value known to those skilled in the art. The "about" values or parameters mentioned herein include (and describe) embodiments involving the value or parameter itself. For example, "about" can refer to within 1 or greater than 1 standard deviation according to practices in the relevant art. Alternatively, "about" can refer to a range of up to 20%, up to 10%, up to 5%, or up to 1% of a given value.

[0048] As used herein, the terms "prefilled", "preloaded", and "prepackaged" refer to the state of an injection device or system in which a composition (such as a drug or medicament) has been filled into the injection device or system before using these injection devices or systems. In some embodiments, "prefilled", "preloaded", and "prepackaged" injection devices or systems encompass injection devices or systems that are filled with a drug and stored in that 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 encompass injection devices or systems that are filled with all of the drug to be administered and stored in that 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 encompass injection devices or systems that are filled with a portion or certain components of the drug to be administered and stored in that prefilled form for a period of time before administering the drug to a subject, and the remaining portion and components are filled immediately before administration.

[0049] Throughout this disclosure, various aspects are presented in range form. It should be understood that the description in range form is merely for convenience and brevity and should not be construed as a rigid limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to specifically disclose all possible subranges as well as individual numerical values within that range. For example, in the case of providing a range of values, it should be understood that each intermediate value between the upper and lower limits of that range, as well as any other stated or intermediate value within the range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges can be independently included in the smaller ranges and are also encompassed within the disclosure, subject to any specific exclusions within the stated range. Where the stated range includes one or both of the limiting values, those ranges excluding one or both of the included limiting values are also included in the disclosure. This applies regardless of how broad the range is.

[0050] The use of ordinal numbers such as "first", "second", "third", etc. to modify claim elements themselves in a claim does not mean that one claim element is prior to, ahead of, or temporally prior in order to another claim element or the acts of a method of performing, but rather is only used as a label to distinguish one claim element having a certain name from another element having the same name (but using an ordinal number) to distinguish claim elements. Similarly, the use of a), b), etc. or i), ii), etc. themselves does not mean any priority, ahead position, or order of the steps in the claim. Similarly, the use of these terms in the specification itself does not mean any required priority, ahead position, or order.

[0051] As used herein, the terms "puncturing member" and "punctured member" are used interchangeably and refer to an article configured to puncture a tissue layer and deliver a substance to a target tissue layer, such as a needle or a microneedle.

[0052] As used herein, the terms "drug container" and "drug-containing chamber" are used interchangeably and refer to an article (e.g., a syringe) configured to contain a volume of a substance (e.g., a drug or a pharmaceutical).

[0053] As used herein, the term "syringe" can include any type of conventional syringe, which includes a needle having a proximal end and a distal end, a barrel having a distal end and an open proximal end, and a plunger shaft having a distal end and a proximal end, wherein the proximal end of the needle is connected to the distal end of the barrel, wherein a fluid chamber is formed between the distal end of the plunger shaft and the distal end of the barrel, and wherein fluid communication can be established from the fluid chamber to the proximal end of the needle and further to the distal end of the needle. The term "syringe" can encompass all common syringes, regardless of their size or volume. For example, a 1 μL syringe is encompassed within the "syringe" described herein, and a 1 L syringe is also encompassed within the "syringe" described herein. In some embodiments, the syringe may not include any valves. In some embodiments, the syringe may not include any springs. In some embodiments, the syringe may not include any floating seals.

[0054] In some embodiments, the terms "connected" and "engaged" are intended to cover both cases where the two components being connected or engaged are joined together and cannot be separated, and cases where the two components are in contact with each other without being joined together. For example, an elastic element connected to a needle hub may mean that the elastic element is joined to the needle hub and always remains with the needle hub, and may also mean that the elastic element can contact the needle hub when the needle moves to a certain position, but may not contact the needle hub at certain time points.

[0055] 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 were incorporated by reference separately. If the definitions set forth herein are contrary to or otherwise inconsistent with the definitions set forth in the patents, applications, published applications, and other publications incorporated by reference herein, the definitions set forth herein shall control over the definitions incorporated by reference herein.

[0056] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. I. Overview

[0057] Direct delivery of drugs and / or implants to the eye is a major approach for treating various eye diseases. Among drug delivery methods, intravitreal injection is the mainstream method and is an effective way to achieve high intraocular concentrations of antibiotics, antivirals, antifungals, steroids, and anti-VEGF drugs (Peyman G.A. et al. Retina. 2009, 29(7), 875–912). Intravitreal injections have good safety, but they can cause ocular complications, including the formation of cataracts, glaucoma, choroidal hemorrhage, endophthalmitis, vitreous hemorrhage, and retinal detachment, and the injected drugs can be absorbed and cause systemic side effects (Prasad A.G. et al., Compr Ophthalmol Update. 2007, 8(5), 259–269). Some drugs or gene therapy vectors may penetrate the posterior hyaloid membrane and the inner retina, reaching the outer retina or the retinal pigment epithelium layer, thus having low efficiency. Additionally, since the vitreous cavity is a semi-open cavity, drugs injected into the vitreous cavity are likely to flow out of the eye with the aqueous humor circulation, which affects the local concentration and pharmacokinetics of the drugs and may also cause side effects such as increased intraocular pressure and cataracts. Another commonly used method for drug delivery is topical administration of drugs, which usually has a low concentration in the vitreous and is generally not used for treating eye diseases, especially those not on the eye surface (Abdelkader H. et al., Curr Drug Deliv. 2012, 9(4), 421–430). Systemic treatment is also limited because the blood-retinal barrier restricts the ability of drugs to reach the eye, and high doses may cause systemic side effects (Rai Udo J. et al., Drug Discov Today. 2015, 20(4), 491–495). Periocular (subconjunctival, sub-Tenon's, or retrobulbar) injection can bypass the blood-retinal barrier without the need for intraocular penetration. However, the injected drugs still need to penetrate the sclera, and the sclera has low permeability to larger molecules and may not be able to achieve therapeutic drug concentrations at the retinal level (Geroski D.H. et al., Adv Drug Deliv Rev. 2001, 52(1), 37–48).

[0058] In contrast, suprachoroidal injection can achieve higher drug concentrations in the choroid / ciliary body, retinal pigment epithelium, and / or outer retina, with lower drug concentrations in the vitreous. Animal studies have shown that the SCS can accommodate up to 1 ml of fluid, which rapidly diffuses into the posterior segment (Seiler G.S. et al., Invest Ophthalmol Vis Sci. 2011, 52(8), 5730–5736). This volume is much larger than that required to reach therapeutic levels of clinically relevant drugs. It has been confirmed that injecting 10 - 50 μL into the SCS results in good ocular tolerance and a low risk of complications (Gu B. et al., Invest Ophthalmol Vis Sci. 2015, 56(6), 3623–3634). Therefore, the SCS is an attractive drug delivery route as it allows for a larger volume of drug and a longer duration of action with a safer procedure. In addition, drug delivery via the SCS bypasses the inner limiting membrane barrier and the blood - retinal barrier and may be a preferred route for drug delivery targeting the retinal pigment epithelium.

[0059] However, precise drug delivery to the suprachoroidal space (SCS) is challenging. In some cases, targeted injection of therapeutic agents is desirable. However, in such cases, the relatively small anatomical structure of the eye typically presents significant challenges in placing a needle at the target location using known devices and methods, particularly with respect to placing the distal end of the needle at the desired depth within the eye. Many known methods of directly injecting drugs into the eye involve inserting a needle or catheter at a small angle relative to the eye surface, which can pose challenges in controlling the insertion depth. For example, some such methods involve controlling the angular orientation of the needle such that the injected substance exits the needle at a specific location. In addition, some known methods of injecting substances into ocular tissue involve using complex visualization systems or sensors to control the placement of the needle or catheter.

[0060] The dimensions and thicknesses of the various layers contained within the eye can vary from person to person, thus exacerbating these deficiencies in known systems and methods. For example, the thicknesses of the conjunctiva and sclera can vary widely and are difficult to pre - determine accurately using standard techniques. In addition, the thicknesses of these layers can also differ in different parts of the eye and at different times of the day in the same eye and location. Therefore, it can be difficult to determine and / or adjust the length of the needle piercing the eye using known systems and methods to achieve the desired depth, such as the SCS, with the needle tip.

[0061] In some cases, such as in choroidal melanoma, precisely targeted injection of therapeutic agents into the suprachoroidal space can improve efficacy and reduce side effects. However, for the eye, which has a small structure, it is difficult to achieve puncture, dilation, injection, or catheter placement in the suprachoroidal space using existing devices or methods, especially for medical devices such as catheters, particularly when the device needs to be placed at a specific location in the suprachoroidal space.

[0062] Some puncture methods for the suprachoroidal space involve making the exposed length of the puncture needle equal to the thickness of the sclera. After the puncture needle is fully inserted into the sclera, fluid is injected to achieve suprachoroidal injection. The technical drawback of this puncture method is that the reserved exposed length of the puncture needle may not be exactly the same as the thickness of the sclera. In practical applications, the differences in scleral thickness among different populations, different eyeballs, and different parts of the same eyeball will further magnify the above technical drawbacks. A too-short needle may not be able to penetrate the sclera, while a too-long needle may pass through the SCS and damage the retina of the eye. A convenient method is needed to detect the position of the needle tip inside the eye.

[0063] Due to the sensitivity of intraocular injection (such as tissue sensitivity, potential impact on intraocular pressure, etc.), many known systems use manual injection. More specifically, many known devices and methods involve the user manually applying force (e.g., by pushing a piston with their thumb or finger) to inject fluid (e.g., a drug) into the eye. Due to the small needle size and / or the properties of the injected drug, some such devices and methods involve using a force level beyond the user's comfort range, and in some cases, the user may not be able to correctly deliver the drug using the known systems and methods.

[0064] In addition, injecting into different target layers of the eye can cause changes in the magnitude of the force required for needle insertion and / or drug injection. Different tissue layers of the eye can have different densities. For example, the sclera generally has a higher density than the conjunctiva or the SCS. Differences in the density of the target area or tissue layer can create different backpressures against the needle exit (e.g., the tip of the needle from which the fluid flows out). Therefore, compared to injecting a drug into the SCS, injecting into relatively dense eye tissues such as the sclera requires a greater driving force to expel the drug from the needle. In addition, the injection force for expelling the pharmaceutical agent also depends on the density and viscosity of the liquid pharmaceutical agent, the length of the needle, and the diameter of the needle. Injecting certain drugs into the eye through the required needles (e.g., 27-gauge, 30-gauge, or even smaller) may require a force that is difficult to estimate and / or control in order to achieve proper injection without the risk of damaging the eye tissue of a specific subject.

[0065] Therefore, there is an urgent need to improve devices and methods to help determine whether the needle is at the correct depth, and to facilitate the injection of drugs into tissues such as eye tissues, and / or to facilitate the implantation of certain structures into tissues such as eye tissues.

[0066] Further challenges in precisely delivering drugs and / or implants to the SCS include the high requirements for sterility and precise dosing in intraocular injections. For example, it has been demonstrated that the risk of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents is significantly affected by the sterility of the drug composition and the drug loading environment (VanderBeek B.L., JAMA Ophthalmol., 2019, 137(4), 343–344). Compared with injection devices or systems pre-loaded or pre-filled with drugs, injections prepared in outpatient settings have shown a higher incidence of endophthalmitis. By eliminating outpatient drug transfer, common sources of contamination can be eliminated, and side effects related to contamination can be significantly reduced. At the same time, precise control of the dose and volume is also crucial, especially for the small spaces and thin tissues in the eye. Therefore, there is still an urgent need for injection devices or systems that can not only achieve precise injection into the SCS, but also improve sterility, better control the dose, and minimize inconvenience to medical personnel.

[0067] To achieve one or more of the above objectives, in some aspects, the present disclosure provides a pre-filled drug medical puncture device for injecting a drug composition, comprising: A syringe barrel, including a proximal end and a distal end; A floating seal located within the syringe barrel; A needle hub located proximal to the floating seal, wherein the floating seal and the needle hub are elastically engaged with each other; A needle for intraocular puncture, the needle comprising: (i) A proximal end of the needle engaged with the needle hub; (ii) A distal end of the needle; (iii) A distal opening of the needle; (iv) A body opening of the needle located between the proximal end and the distal end of the needle, wherein the body opening is proximal to the distal opening of the needle; and (v) A body channel connecting the distal opening of the needle and the body opening of the needle, wherein the needle hub is configured to advance the needle distally towards and / or through the floating seal; and wherein the drug composition is contained within a chamber formed by the floating seal and the distal end of the syringe barrel.

[0068] In other aspects, the present disclosure provides an adapter assembly that can be combined with a syringe to significantly improve the injection depth accuracy of the syringe, facilitate the injection of drugs into tissues such as eye tissues, and / or facilitate the implantation of certain structures into tissues such as eye tissues. In some aspects, once the adapter described herein is installed on a syringe, it can improve the injection accuracy and safety of the syringe. In some embodiments, once the adapter described herein is installed on other syringes (such as the syringe disclosed in US2020 / 0069883), it can improve the injection accuracy and safety of that syringe. In some aspects, the adapter assembly includes: a contact member extending from a proximal end to a distal end; and a pressing unit including a first elastic element; wherein the contact member is assembled to the distal end of the needle of the syringe such that the distal end of the contact member is located distal to the distal opening of the needle, and the distal end of the contact member can directly contact the surface tissue of the target injection site; and wherein the pressing unit is assembled to the syringe barrel and the plunger shaft such that the pressing unit is elastically engaged with the plunger shaft and / or the syringe barrel through the first elastic element.

[0069] In other aspects, the present disclosure provides a method for improving the injection accuracy and safety of a syringe, which includes: (1) providing a syringe, the syringe including: a syringe barrel extending from a proximal end to a distal end and forming a chamber extending from the proximal end to the distal end; a plunger shaft extending from the proximal end to the distal end and forming a seal between the distal end of the plunger shaft and the syringe barrel; and a needle extending from the proximal end to the distal end, the needle including a distal opening for allowing fluid to flow out of the chamber through the needle hub and through the distal end of the syringe barrel; (2) providing an adapter assembly including: a contact member extending from a proximal end to a distal end, and a pressing unit including a first elastic element; (3) installing the contact member to the distal end of the needle of the syringe; (4) installing the pressing unit to the syringe, wherein the distal end of the contact member is located distal to the distal opening of the needle, and the distal end of the contact member can directly contact the surface tissue of the target injection site; and wherein the pressing unit is elastically engaged with the plunger shaft and / or the syringe barrel through the first elastic element.

[0070] In some embodiments, after injection into the suprachoroidal space (SCS), one or more structures such as a permanent or semi-permanent stent may be implanted into the SCS to maintain it for an extended period of time, e.g., 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) puncturing 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 micro-stent) into the SCS through the injection site or an enlarged insertion site (e.g., formed by enlarging the injection site, e.g., surgically), thereby placing the stent into the eye to maintain the SCS in a dilated state and facilitate the drainage of aqueous humor.

[0071] Certain embodiments of the present disclosure will be described with reference to several views in the accompanying drawings. II. Injection Device or System

[0072] Integrated devices (e.g., prefilled syringes) containing pharmaceutical formulations are disclosed. In some aspects, a prefilled injection device or system is provided herein that includes an injection device for puncturing an auxiliary puncturing component (e.g., a needle or micro-needle) into the eye and / or injecting a drug prefilled in an auxiliary device into a target ocular tissue. In some embodiments, a prefilled injection device or system is described herein that includes an injection device for controlling the depth of penetration of a puncturing component (e.g., a micro-needle) into the eye to deliver a therapeutic agent prefilled in the device to, for example, a posterior region of the eye (e.g., via the suprachoroidal space). In some embodiments, a prefilled injection device or system is described herein that includes an injection device for introducing an implant prefilled in the device into a tissue, such as an apparent or potential tissue void, chamber, or blood vessel.

[0073] In some embodiments, provided herein is a prefilled injection device or system, comprising: a syringe having a proximal end and a distal end; a floating seal located within the syringe; a needle hub located proximal to the floating seal (e.g., the needle hub is closer to the operator while the floating seal is closer to the subject), and the floating seal and the needle hub are elastically engaged with each other. In some embodiments, the prefilled injection device or system further comprises a needle having a proximal end of the needle and a distal end of the needle, and the proximal end of the needle is engaged with the needle hub. In any embodiment herein, the proximal end of the needle 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) an opening at the distal end of the needle; (ii) a body opening of the needle located between the proximal end and the distal end of the needle; and (iii) a body channel connecting the opening at the distal end of the needle and the body opening. In any embodiment herein, the body opening of the needle may be located proximal to the opening at the distal end of the needle. In any embodiment herein, the needle hub may be configured to advance the needle distally towards the floating seal (e.g., when the distal end of the needle is proximal to the floating seal), through the floating seal (e.g., when the distal end of the needle has entered or penetrated the floating seal), and / or through the distal end of the syringe.

[0074] In any embodiment herein, a proximal chamber and a distal chamber may be provided on different sides of the floating seal within the syringe. In some embodiments, the distal chamber contains a prefilled flowable composition (e.g., a drug, a pharmaceutical product, 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 sterilized air, and / or be capable of communicating with the external environment (such as the atmosphere) when the needle is advanced within the syringe and / or through the syringe.

[0075] In some embodiments, the needle included in the embodiments described herein has a bevel, which enables the needle to easily penetrate tissue, such as the sclera and / or suprachoroidal space, with minimal collateral damage. In some embodiments, the needle disclosed herein may define a narrow chamber (e.g., having a gauge size greater than or equal to 30 gauge, 32 gauge, 34 gauge, 36 gauge, etc.) so as to minimize the diameter of the needle track caused by needle insertion while performing suprachoroidal drug delivery. In some embodiments, the aspect ratio of the chamber of the needle described herein to the bevel is the same as or different from that of the standard 27-gauge and 30-gauge needles commonly used for intraocular injection.

[0076] In some embodiments, the prefilled injection device or system disclosed herein includes an injection device, which includes or is configured to be connected to a prefilled drug container containing a drug (such as a gel, etc.). The drug container may be at least partially constituted by the syringe.

[0077] In some embodiments, the needle is coupled to the distal end of a pre-filled drug container (e.g., the needle is located at the distal end of a syringe), for example, as described in US9,180,047, US9,539,139, US9,572,800, US9,636,253, US9,636,332, US9,770,361, US9,937,075, US10,555,833, and US10,517,756, which are hereby incorporated 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 neither exposed at the distal end of the syringe barrel nor directly engaged with the distal end of the syringe barrel.

[0078] In some embodiments, the pre-filled injection device or system disclosed herein includes an injection device that includes an energy storage member (e.g., one or more springs) configured to engage with a needle hub and a floating seal. In some embodiments, the distal portion of the energy storage member is configured to be disposed within the syringe barrel and directly or indirectly engage with the floating seal. In some embodiments, the energy storage member is configured to generate a force on the proximal portion of the floating seal. In some embodiments, when the distal tip of the needle is located in an apparent or potential tissue void, chamber, or blood vessel, the force is sufficient to cause the floating seal to move within the syringe barrel, thereby delivering at least a portion of the substance from the drug container (e.g., the flowable composition chamber) through the needle. Additionally, when the distal tip of the needle is located in adjacent tissue (e.g., tissue above or below) of an apparent or potential tissue void, chamber, or blood vessel, the force is not sufficient to cause the floating seal to move within the syringe barrel. In some embodiments, the apparent or potential tissue void, chamber, or blood vessel has a first density, while the adjacent tissue has a second density, and the second density is higher than the first density. In some embodiments, the apparent or potential tissue void, chamber, or blood vessel generates a first backpressure, while the adjacent tissue generates a second backpressure, and the second backpressure is higher than the first backpressure.

[0079] In some embodiments, the needle is coupled to the floating seal. In other embodiments, the needle employed in the present disclosure has its proximal end connected to a drive member within the syringe barrel, where the drive member is separately provided and located proximal to the floating seal. In some embodiments, the proximal end of the needle disclosed herein is not coupled to the floating seal. In some embodiments, prior to use, the needle may be located distal to the floating seal, or may pass through the floating seal, but the proximal end of the needle remains distal to the floating seal and is not fixedly connected to the floating seal.

[0080] 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 seal and a distal seal, both of which are movable within the syringe barrel, e.g., as described in U.S. Patent No. 11,413,397 and US2020 / 0069883, which are hereby incorporated by reference for all purposes. In some embodiments, a system is provided herein that is prefilled with any one or more of the compositions disclosed herein (e.g., the pharmaceutical formulations disclosed in Section III herein) for delivering the composition into an apparent or potential void, chamber, or blood vessel within a subject, the system comprising: a syringe barrel that extends from a first end to a second end and forms a chamber that extends from the first end to the second end; a piston disposed within the chamber near the first end and forming a seal between the piston and the syringe barrel to prevent fluid (prefilled within the chamber) from flowing out of the chamber between the piston and the syringe barrel; a floating seal disposed within the chamber near the second end and forming a seal between the floating seal and the syringe barrel to prevent fluid from flowing out of the chamber between the floating seal and the syringe barrel; a hollow needle that extends from a proximal end connected to the floating seal to a distal end having an opening such that fluid (e.g., containing one or more of the compositions disclosed herein) can flow out of the chamber, through the floating seal, and through the second end of the syringe barrel via the hollow needle; and wherein the materials and dimensions of the syringe barrel, piston, and floating seal are selected based on a threshold flow rate of the fluid disposed within the chamber: when a force is applied to the fluid, overcoming a counterforce, the floating seal and the hollow needle are moved from the second end of the syringe barrel and the distal end of the hollow needle is extended into the tissue of the subject; and when the distal end of the hollow needle extends through the tissue of the subject and into a void of the subject, under the action of a counteracting force, the fluid enters the void through the opening formed at the distal end of the hollow needle. Any adapter disclosed herein (e.g., as disclosed in Section VII herein) can be used in combination with the system to further improve injection accuracy and / or safety.

[0081] In some of the above embodiments, the force applied to the proximal end of the proximal seal is transmitted through the liquid to the distal seal connected to the needle. Since liquids are generally incompressible, when an operator applies too much force or applies force suddenly to the proximal seal (e.g., by means of a piston connected to the proximal seal), this force is transmitted to the needle. In some embodiments, in those devices disclosed in US2020 / 0069883, since the liquid provides little compressibility to cushion the impact of the force, the needle may be inserted too deeply or forcefully, thereby causing damage to the target tissue (such as the suprachoroidal space) and / or surrounding tissues. Although the positions of the proximal seal and the distal seal may be observable during injection, once a force that may cause the needle to penetrate too deeply is applied, it may be too late to prevent the movement of the needle due to the lack of ability to cushion the impact of the force. 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, wherein the contact member is elastically connected to the distal end of the syringe barrel by an elastic element. The contact member can be in direct contact with the surface tissue of the target injection site, and the elastic connection can help the operator apply the correct force when inserting the needle and cushion the impact of the force, thereby preventing the needle from penetrating too deeply. In some embodiments, the elastic element is in the form of a spring, wherein one side of the spring is connected to the contact member and the other side of the spring is connected to the distal seal. In some embodiments, the elastic element is an elastic sleeve or sheath, wherein the needle is located inside and surrounded by the elastic sleeve or sheath. In some embodiments, the prefilled injection device or system disclosed herein may include any of the devices disclosed in US2020 / 0069883. In some embodiments, the prefilled injection device or system disclosed herein may include any of the devices disclosed in US2020 / 0069883 and may further include any of the adapters described herein.

[0082] 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 chamber) located between a floating seal and the distal end of the syringe barrel (where the distal end does not move relative to the syringe barrel). In some embodiments, the distal end of the syringe barrel includes a distal seal, and the flowable composition chamber is disposed between the floating seal and the distal seal. In some embodiments, since the needle hub is elastically connected to the floating seal (and thus to the flowable composition), this elastic connection can help the operator apply the correct force and buffer the impact of the force. Additionally, the operator can keep the needle hub stationary relative to the syringe barrel and observe the movement of the floating seal to evaluate the depth of needle insertion. Once a fluid communication is established between the flowable composition and an apparent or potential tissue void, chamber, or blood vessel, and the pressure in the flowable composition is greater than the pressure in the apparent or potential tissue void, chamber, or blood vessel, the floating seal can move while the needle and needle hub do not have to move as the flowable composition enters the tissue. Thus, precise needle insertion and stable injection can be achieved, and the likelihood of the needle being inserted too deeply can be effectively reduced or eliminated.

[0083] In some embodiments, the prefilled injection device or system disclosed herein includes an injection device provided and / or packaged as an integrated device including interengaging components. In some embodiments, the prefilled injection device or system disclosed herein includes an injection device that does not require the operator to assemble one or more components prior to use. In some embodiments, the prefilled injection device or system disclosed herein includes a prefilled drug container (e.g., a flowable composition chamber) containing 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.

[0084] The flowable composition includes a liquid that is easy to handle (such as a solution, suspension, etc.) or a semi-solid composition (such as a gel), and when it solidifies, it can be injected, shaped, and / or molded at or near the target tissue site. "Flowable" includes formulations ranging from low-viscosity or aqueous consistency to high-viscosity (such as viscoelastic or pasty substances). In some embodiments, the methods disclosed herein include injecting a viscoelastic substance (such as 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 from a viscous component and an elastic component, such as a mixture of a solvent and a polymeric material. Examples of viscoelastic substances that can be used herein include sodium hyaluronate, Provisc (a 1% viscous clear substance, a specific component of sodium hyaluronate), Viscoat (a dispersive viscoelastic preparation composed of sodium hyaluronate and chondroitin sulfate), Amvisc (a purified component of sodium hyaluronate), Amvisc Plus (a 1.6% sodium hyaluronate product derived from chicken combs), sodium chondroitin sulfate / sodium hyaluronate, or DisCoVisc (4% sodium chondroitin sulfate, 1.65% sodium hyaluronate).

[0085] In various embodiments, the flowability of the formulation enables it to conform to irregularities, cracks, fissures, and / or voids in the tissue site. For example, in various embodiments, the formulation can be used to fill one or more voids, expand tissue voids (such as apparent tissue voids), and / or create tissue voids from potential tissue voids, and optionally expand the resulting voids. In some embodiments, when contacted with an aqueous medium (such as body fluid, water, etc.), the flowable composition can harden to form a drug depot for controlled drug release.

[0086] In some embodiments, the device is pre-filled with a therapeutic agent (e.g., a drug), such as 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, dipivefrin), carbonic anhydrase inhibitors (e.g., acetazolamide, dorzolamide), topoisomerase inhibitors (e.g., topotecan, irinotecan, camptothecin, spongistatin D, etoposide, teniposide, doxorubicin, mitoxantrone, amsacrine), prostaglandins, antimicrobial compounds (including antibacterial and antifungal agents, e.g., chloramphenicol, chlortetracycline, ciprofloxacin, neomycin B, fusidic acid, gentamicin, neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline, tobramycin, quinolones), antiviral compounds (e.g., acyclovir, cidofovir, idoxuridine, interferon), aldose reductase inhibitors, anti-inflammatory and / or anti-allergy compounds (e.g., steroid compounds such as triamcinolone, betamethasone, clobetasone, dexamethasone, fluorometholone, hydrocortisone, prednisolone, and non-steroid compounds such as antazoline, bromfenac, diclofenac, indomethacin, lodoxamide, sapropterin, sodium cromoglycate), artificial tears / dry eye treatment drugs, local anesthetics (e.g., tetracaine, lidocaine, oxybuprocaine, proxymetacaine), cyclosporine, diclofenac, uroguanylin, and growth factors (such as epidermal growth factor), mydriatics and cycloplegics, mitomycin C, collagenase inhibitors, and drugs for treating age-related macular degeneration (such as pegaptanib sodium, ranibizumab, aflibercept, and bevacizumab).

[0087] 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 induces 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 one formulation or in two separate formulations administered sequentially. For example, both a VEGF inhibitor and 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-induced growth factor monoclonal antibody), VGX300, COSMIX, DLX903 / 1008 antibody, ENMD2076, sunitinib (sunitinib malate), INDUS815C, R84 antibody, KD019, NM3, allogeneic mesenchymal progenitor cells used in combination with an anti-VEGF drug or antibody, MGCD265, MG516, VEGF receptor tyrosine kinase inhibitor, MP0260, NT503, anti-DLL4 / VEGF bispecific antibody, PAN90806, Palomid529, BD0801 antibody, XV615, lucitanib (AL3810, E3810), AMG706 (motesanib diphosphate), AAV2-sFLT01, soluble Flt1 receptor, cediranib (Recentin), AV-951 (tivozanib, KRN-951), Stivarga (regorafenib), volasertib (BI6727), CEP11981, KH903, lenvatinib (E7080), tramiprosate (EM1421), ranibizumab (Lucentis), Votrient (pazopanib hydrochloride), PF00337210, PRS050, SP01 (curcumin), carboxyaminotriazole lactobionate, hydroxychloroquine, linifanib (ABT869, RG3635), Iluvien (fluocinolone acetonide), 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, lenvatinib mesylate, 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, GSK2136773, anti-VEGFR allosteric enzyme, Avila, CEP7055, CLT009, ESBA903, HuMax-VEGF antibody, GW654652, HMPL010, GEM220, HYB676, JNJ17029259, TAK593, XtendVEGF antibody, Nova21012, Nova21013, CP564959, intelligent 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 antibody, apatinib (YN968D1), and AL3818. Additionally, the delivery of VEGF inhibitors or VEGF antagonists using the microneedle devices and methods described herein can be used in combination with one or more of the agents listed herein or with other known agents.

[0088] In some embodiments, one or more components of the prefilled injection device or system described herein are configured to be assembled with each other. For example, the system or device can include one or more syringe barrels.

[0089] In some embodiments, a prefilled injection device or system may include two or more units, such as a first syringe unit that includes: a first barrel; a needle seat located within the first barrel; and a needle that includes a proximal needle end and a distal needle end that engages the needle seat. In some embodiments, the prefilled injection device or system may include a second syringe unit configured to engage the distal end of the first syringe unit, which includes: a second barrel; and a floating seal located within the second barrel that is configured to elastically engage the needle seat when the first and second syringe units are engaged. In some embodiments, the prefilled injection device or system may include a third syringe unit configured to engage the distal end of the second syringe unit, which includes a third barrel that contains a flowable composition, and the needle seat may be configured to advance the needle such that the proximal end and / or the distal end of the needle enters the flowable composition. In any of the embodiments described herein, the prefilled injection device or system may include one or more syringe units, optionally including a fourth syringe unit configured to engage the distal end of the third syringe unit.

[0090] In some embodiments, a prefilled injection device or system may include a first syringe unit that includes: a first barrel; a needle seat and a floating seal that are elastically engaged with each other within the first barrel, with the needle seat located proximal to the floating seal; and a needle that includes a proximal needle end and a distal needle end that engages the needle seat, the needle including: (i) a distal needle opening, (ii) a needle body opening located between the proximal needle end and the distal needle end and proximal to the distal needle opening, and (iii) a needle body channel connecting the distal needle opening and the needle body opening. In some embodiments, the prefilled injection device or system may further include a second syringe unit configured to engage the distal end of the first syringe unit, including a second barrel that contains a flowable composition, and the needle seat may be configured to advance the needle such that the proximal end and / or the distal end of the needle enters the flowable composition. In any of the embodiments described herein, the device may include one or more syringe units, optionally including a third syringe unit configured to engage the distal end of the second syringe unit.

[0091] In some embodiments, a pre-filled injection device or system may include a first syringe unit comprising: a first syringe barrel; a needle seat located within the first syringe barrel; and a needle including a needle proximal end and a needle distal end that is engaged with the needle seat, the needle including: (i) a needle distal opening, (ii) 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 opening, and (iii) a needle body channel connecting the needle distal opening and the needle body opening. In some embodiments, the system or device may further include a second syringe unit configured to connect to the distal end of the first syringe unit, the second syringe unit including: a second syringe barrel; a floating seal located within the second syringe barrel, the floating seal being configured to elastically engage with the needle seat when the first and second syringe units are engaged; and a flowable composition, the needle seat being configured to advance the needle such that the needle proximal end and / or the needle distal end enters the flowable composition. In any of the embodiments described herein, the pre-filled injection device or system may include one or more syringe units, optionally including a third syringe unit configured to engage with the distal end of the second syringe unit.

[0092] In some embodiments, the present disclosure provides a pre-filled injection device or system comprising: a syringe barrel, wherein the syringe barrel includes a distal closed end and a proximal open end; an actuation unit (e.g., an elastically movable unit) including a drive member (e.g., a pressing element) and a floating seal, wherein the floating seal is located within the syringe barrel and is elastically engageable with the drive member (e.g., the pressing element); a hollow piercing needle connected to the drive member (e.g., the pressing element), wherein the hollow piercing needle includes a needle distal opening and a needle body opening, and wherein the needle body opening is proximal to the floating seal (the needle distal opening may be proximal to the floating seal, e.g., the entire length of the needle is proximal to the floating seal, or the needle may pass through the floating seal such that the needle distal opening is distal to the floating seal); and a pre-filled flowable composition chamber (e.g., for a liquid or a gel), wherein the flowable composition chamber is formed by the distal closed end of the syringe barrel, the syringe barrel wall (e.g., a portion of the syringe barrel), and the floating seal.

[0093] In some embodiments, the pre-filled injection device or system is configured to advance a hollow piercing needle forward by pressing a drive member (e.g., a pressing element). In some embodiments, the hollow piercing needle sequentially pierces a floating seal and a distal closed end of the syringe barrel, thereby connecting the flowable composition chamber, the needle body opening, and the needle distal opening. In some embodiments, the hollow piercing needle is pre-inserted into the floating seal. For example, the needle distal opening may be located within the floating seal and blocked by the floating seal, and then the needle may pass through the flowable composition chamber and pierce the distal closed end of the syringe barrel. In some embodiments, the hollow piercing needle is pre-inserted into the floating seal. For example, the needle distal opening may be located within the flowable composition chamber, and the needle body opening may be located proximal to the floating seal or within the floating seal (e.g., as shown in Figure 3E ), and then the needle may be advanced to pierce the distal closed end of the syringe barrel. In some embodiments, the hollow piercing needle is pre-pierced through the floating seal and is located at or through the distal closed end of the syringe barrel. For example, the needle distal opening may be located within a distal seal of the distal closed end of the syringe barrel (e.g., the needle distal opening may be blocked by the distal seal) or distal to the distal seal and / or the distal closed end of the syringe barrel, and the needle body opening may be located proximal to the floating seal (e.g., as shown in Figure 3D , 6 b1), within the floating seal (e.g., as shown in Figure 3D , 6 b2, the needle body opening may be blocked by the floating seal), or within the flowable composition chamber (e.g., as shown in Figure 3D , 6 b3), and then the needle may pass through the distal closed end of the syringe barrel and expose the needle distal opening to pierce tissue.

[0094] Optionally, the pre-filled injection device or system may include a state in which the flowable composition chamber, the needle body opening, and the needle distal opening are in fluid communication. For example, in the fluid communication state, the needle body opening may be located proximal to the floating seal, and the needle distal opening may be located distal to the floating seal and within the flowable composition chamber. In the fluid communication state, the needle and / or the floating seal may move. For example, the floating seal may move under the elastic restoring force between the floating seal and the drive member (e.g., a pressing element) such that the floating seal seals or blocks the needle body opening, thereby preventing or terminating the discharge of the flowable composition (e.g., a gel) from the needle body opening and / or the needle distal opening.

[0095] Optionally, in the fluid communication state, the floating seal may seal the needle body opening when moving forward and contacting the distal closed end of the syringe barrel, thereby preventing or terminating the discharge of the flowable composition (e.g., a gel) from the needle body opening and / or the needle distal opening.

[0096] Optionally, a limiter, such as an axial limiter, may be provided at the distal end of the floating seal within the syringe chamber. In some embodiments, the limiter can be used to restrict the forward movement of the floating seal. In some embodiments, the prefilled injection device or system includes a fluid communication state in which the flowable composition chamber is connected to the needle body opening and the needle distal opening. When the medical puncture device is in the fluid communication state, the needle body opening can be located distal to the limiter (e.g., as shown in Figure 2D ), and the floating seal moves forward due to elastic engagement with the drive member (e.g., the pressing element).

[0097] Optionally, the prefilled injection device or system includes a manual control element that is connected to the floating seal and extends outside the syringe barrel.

[0098] Optionally, the prefilled injection device or system includes a pre-puncture state, a surface tissue puncture state, and a post-puncture fluid communication state after the hollow puncture needle punctures the distal closed end of the syringe barrel. In the pre-puncture state, the surface tissue puncture state, and the fluid communication state, the lengths of the hollow puncture needle extending from the distal closed end of the syringe barrel can respectively correspond to a pre-puncture length range, a surface tissue puncture length range, and a fluid communication length range, where: when the length of the hollow puncture needle extending from the distal closed end of the syringe barrel is within the pre-puncture length range, the needle body opening remains above the flowable composition chamber (e.g., the needle body opening can be located proximal to the floating seal and within the floating seal); and / or when the length of the hollow puncture needle extending from the distal closed end of the syringe barrel is within the surface tissue puncture length range, at least a portion of the needle body opening is connected to the flowable composition chamber; and / or when the length of the hollow puncture needle extending from the distal closed end of the syringe barrel is within the fluid communication length range, the needle body opening is located within the flowable composition chamber.

[0099] Optionally, an axially extending annular contact element is formed at the distal closed end of the syringe barrel, where 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.

[0100] Optionally, the elastic movement unit includes an elastic sheath covering the outside of the hollow puncture needle. When the needle body opening is located proximal to the floating seal, the elastic sheath can seal the needle body opening. 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 proximal to the floating seal.

[0101] Optionally, the prefilled injection device or system includes a catheter guiding structure for threading a catheter into the cavity of the hollow puncture needle (e.g., the needle body channel connecting to the needle distal opening and / or the needle body opening).

[0102] Optionally, the catheter guiding structure includes an inclined guiding groove formed on the floating seal and extending at an angle towards the hollow puncture needle.

[0103] Optionally, the inclined guiding groove is arranged to penetrate the floating seal from front to back. In some embodiments, the catheter guiding structure further includes a one-way valve embedded in the inclined guiding groove and capable of being opened and closed, and / or a guiding groove plug inserted into the inclined guiding groove.

[0104] Optionally, the inclined guiding groove is arranged on the upper surface of the floating seal and is a non-penetrating groove.

[0105] Optionally, the needle body opening is formed as an inclined opening that opens obliquely backward.

[0106] Optionally, the catheter guiding structure includes an inclined guiding needle hole formed on the wall of the hollow puncture needle body, which opens obliquely backward. In some embodiments, the prefilled injection device or system includes a fluid communication state in which the flowable composition chamber is connected to the needle body opening and the needle distal opening. In the fluid communication state, the inclined guiding needle hole is located at the proximal end of the floating seal.

[0107] Optionally, the catheter guiding structure further includes a one-way valve embedded in the inclined guiding needle hole and capable of being opened and closed, or a guiding groove plug inserted into the inclined guiding needle hole.

[0108] Optionally, the catheter guiding structure includes a pierceable central guiding groove formed at the center of the proximal surface of the driving member (such as a pressing element). In some embodiments, a needle proximal opening is formed on the hollow puncture needle, and the needle proximal opening is arranged to be axially aligned with the central guiding groove.

[0109] Optionally, the prefilled injection device or system includes a separately manufactured and formed puncture control module and a fluid storage module, wherein: the puncture control module includes a first syringe unit, an elastic moving unit and a hollow puncture needle arranged within the first syringe unit; the fluid storage module includes a second syringe unit, a flowable composition chamber formed within the second syringe barrel and a prefilled pharmaceutical composition or implant, and a module packaging assembly that is 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.

[0110] In a second aspect, the present disclosure provides a medical device assembly. In some embodiments, the medical device assembly includes a catheter and a medical puncture device with a catheter guiding structure.

[0111] Optionally, the medical device assembly further includes a hollow auxiliary guide needle for use in conjunction with the catheter guiding structure. In some embodiments, when the hollow auxiliary guide needle is connected to the catheter guiding structure, the catheter can sequentially pass through the needle body channel of the auxiliary guide needle and the catheter guiding structure and penetrate into the needle body channel of the hollow puncture needle.

[0112] In some embodiments, when using the prefilled injection device or system of the present disclosure, the user can first apply pressure to the driving member (such as a pressing element) to drive the hollow puncture needle to sequentially penetrate through the floating seal and the distal closed end of the syringe barrel. When the distal opening of the needle of the hollow puncture needle reaches an apparent or potential tissue space, chamber system, and blood vessel, the body opening of the needle is already located in the flowable composition chamber, and the floating seal has formed an elastic engagement with the driving member (such as a pressing element). In some embodiments, the fluid pressure in the flowable composition chamber can be set higher than the pressure in the apparent or potential tissue space, chamber, or blood vessel.

[0113] At this time, the prefilled fluid in the flowable composition chamber can flow into the apparent or potential tissue space, chamber, or blood vessel through the body opening and the distal opening of the needle. During the injection process, by simply keeping the position of the driving member (such as a pressing element) unchanged, under the action of the elastic engagement between the floating seal and the driving member (such as a pressing element), the fluid in the flowable composition chamber can flow into the body opening of the needle (and then through the needle body channel and out of the distal opening of the needle), thereby achieving injection, puncture, and / or dilation of the apparent or potential tissue space, chamber, or blood vessel. In addition, the medical device assembly described in the present disclosure can be used to implant a catheter and other medical devices through a medical puncture device, such as through the catheter guiding structure and the cavity of the needle described herein.

[0114] In some embodiments, before the hollow puncture needle penetrates into an apparent or potential tissue space, chamber, or blood vessel, the external pressure on the distal opening of the needle is higher than the fluid pressure in the flowable composition chamber, so the fluid cannot flow out of the distal opening of the needle. Therefore, by observing whether the floating seal moves forward due to the elastic engagement with the driving member (such as a pressing element), it can be determined whether the hollow puncture needle has penetrated into an apparent or potential tissue space, chamber, or blood vessel, thereby reminding the operator of the current puncture depth to ensure accurate puncture. Since the injection is controlled by the change in the fluid pressure in the flowable composition chamber, there is no need for the operator to manually apply thrust or force during the injection process, thereby preventing fluctuations in the flow rate and achieving stable injection. III. Drug Composition of the Prefilled Injection Device or System

[0115] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and any pharmaceutical composition. In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and any implant. In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein, any pharmaceutical composition, and any implant.

[0116] It should be noted that the present disclosure encompasses any combination of any embodiment of the injection devices 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 combinations of any embodiment of the pharmaceutical composition described herein and any embodiment of the implant, provided that they are pharmaceutically compatible. For example, in some embodiments, a pre-filled syringe or system of the present disclosure may include an injection device and a pharmaceutical composition described herein. As another example, in some embodiments, a pre-filled 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 any pharmaceutical composition or does not carry any pharmaceutical composition.

[0117] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition may be contained within any chamber of any of the injection devices described herein. In some embodiments, the pharmaceutical composition contains only one drug. In some embodiments, the pharmaceutical composition contains more than one drug. In some embodiments, the pharmaceutical composition contains only one drug, wherein the drug is contained within one chamber. In some embodiments, the pharmaceutical composition contains only one drug, wherein the drug is contained within multiple chambers. In some embodiments, the pharmaceutical composition contains more than one drug, wherein the drugs are contained within one chamber. In some embodiments, the pharmaceutical composition contains more than one drug, wherein the drugs are contained within separate chambers.

[0118] 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 one corticosteroid. In some embodiments, the pharmaceutical composition comprises a combination of more than one corticosteroid.

[0119] In some embodiments, the pharmaceutical composition comprises a preparation of a corticosteroid, which preparation comprises a corticosteroid or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the preparation comprises: (1) triamcinolone; (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof; (3) a buffering agent; and (4) an osmotic pressure regulator. In some embodiments, the preparation comprises: (1) triamcinolone acetonide; (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof; (3) a buffering agent; and (4) an osmotic pressure regulator. In some embodiments, the preparation comprises: (1) triamcinolone acetate; (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof; (3) a buffering agent; and (4) an osmotic pressure regulator. In some embodiments, the preparation comprises: (1) dexamethasone; (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof; (3) a buffering agent; and (4) an osmotic pressure regulator. In some embodiments, the preparation comprises: (1) fluocinonide; (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof; (3) a buffering agent; and (4) an osmotic pressure regulator. In some embodiments, the preparation comprises: (1) prednisolone; (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof; (3) a buffering agent; and (4) an osmotic pressure regulator. In some embodiments, the preparation comprises: (1) loteprednol etabonate; (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof; (3) a buffering agent; and (4) an osmotic pressure regulator. In some embodiments, the preparation comprises: (1) diflorasone diacetate; (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof; (3) a buffering agent; and (4) an osmotic pressure regulator. In some embodiments, the preparation comprises: (1) flumethasone pivalate; (2) hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof; (3) a buffering agent; and (4) an osmotic pressure regulator.

[0120] In some embodiments, which can 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 the sodium salt of hyaluronic acid. In some embodiments, the molecular weight of hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof is in the range of from about 50,000 Daltons to about 2,000,000 Daltons. For example, the molecular weight of 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 thereof.

[0121] In some embodiments, which can be combined with any of the above or below embodiments, the formulation comprises a buffer. In some embodiments, the buffer comprises acetate buffer, citrate buffer, phosphate buffer, borate buffer or any mixture thereof. In some embodiments, the buffer comprises 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 form of monohydrate and disodium hydrogen phosphate in the form of dodecahydrate. In some embodiments, the amount of buffer is sufficient to maintain the pH of the formulation in the range of from about 5.5 to about 9.0. In some embodiments, the amount of buffer is sufficient to maintain the pH of the formulation in the range of from about 6.0 to about 8.5. In some embodiments, the amount of buffer is sufficient to maintain the pH of the formulation in the range of from about 6.5 to about 8.0. In some embodiments, the amount of buffer is sufficient to maintain the pH of the formulation in the range of from about 7.0 to about 9.5. In some embodiments, the amount of buffer is 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 thereof. In some embodiments, the formulation further comprises a pH regulator. In some embodiments, the formulation further comprises a pH regulator, wherein the pH regulator is sodium hydroxide. In some embodiments, the pH regulator is a sodium hydroxide solution, wherein the sodium hydroxide solution has a sodium hydroxide concentration of about 1.5 - 2.5 mol / L (e.g., 2.0 mol / L).

[0122] In some embodiments, which may be combined with any of the above or below embodiments, the formulation comprises an osmotic pressure regulator. In some embodiments, the osmotic pressure regulator comprises sodium chloride, potassium chloride, magnesium chloride, calcium chloride, or any mixture thereof. In some embodiments, the osmotic pressure regulator comprises sodium chloride, potassium chloride, or any mixture thereof. In some embodiments, the osmotic pressure regulator comprises sodium chloride. In some embodiments, the osmotic pressure regulator is sodium chloride. In some embodiments, the amount of the osmotic pressure regulator is sufficient to maintain the osmotic pressure in the range of about 200 mOsm / kg to about 400 mOsm / kg. In some embodiments, the amount of the osmotic pressure regulator is sufficient to maintain the osmotic pressure in the range of about 250 mOsm / kg to about 300 mOsm / kg. In some embodiments, the amount of the osmotic pressure regulator is sufficient to maintain the osmotic pressure at 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 thereof.

[0123] In some embodiments, which may be combined with any of the above or below embodiments, the formulation comprises water. In some embodiments, the water is water for injection.

[0124] In some embodiments, which may be combined with any of the above or below embodiments, the formulation comprises a corticosteroid, wherein the weight ratio of the corticosteroid to the whole formulation is about 1.0 - 8.0% (w / w). In some embodiments, the formulation comprises triamcinolone acetonide, wherein the weight ratio of triamcinolone acetonide to the whole formulation is about 1.0 - 8.0% (w / w). For example, the weight ratio of triamcinolone acetonide to the whole 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.

[0125] In some embodiments, which can 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 hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof to the whole 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 hyaluronic acid or a pharmaceutically acceptable derivative, salt or solvate thereof to the whole 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 whole formulation is 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.

[0126] In some embodiments that can be combined with any of the above or below embodiments, the formulation comprises a buffering agent, wherein the weight ratio of the buffering agent to the entire formulation is about 0.05 - 0.8% (w / w). In some embodiments, the formulation comprises triamcinolone acetonide and a buffering agent, wherein the weight ratio of the buffering agent to the entire formulation is about 0.05 - 0.8% (w / w). For example, the weight ratio of the buffering agent to the entire 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 buffering agent comprises disodium hydrogen phosphate and sodium dihydrogen phosphate, wherein the weight ratio of sodium dihydrogen phosphate to the entire formulation is about 0.01 - 0.50% (w / w), and wherein the weight ratio of disodium hydrogen phosphate to the entire formulation is about 0.05 - 0.20% (w / w). For example, the weight ratio of sodium dihydrogen phosphate to the entire 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 disodium hydrogen phosphate to the entire formulation is about 0.05, 0.10, 0.15, 0.20% (w / w) or any intermediate value thereof.

[0127] In some embodiments that can be combined with any of the above or below embodiments, the formulation comprises an osmotic pressure regulator, wherein the weight ratio of the osmotic pressure regulator to the entire formulation is about 5.0 - 10.0% (w / w). In some embodiments, the formulation comprises triamcinolone acetonide and an osmotic pressure regulator, wherein the weight ratio of the osmotic pressure regulator to the entire formulation is about 5.0 - 10.0% (w / w). For example, the weight ratio of the osmotic pressure regulator to the entire 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 thereof. Preferably, the weight ratio of the osmotic pressure regulator to the entire formulation is about 6.0 - 9.0% (w / w).

[0128] In some embodiments, the formulation comprises: (1) 3.0 - 5.0% (w / w) triamcinolone acetonide; (2) 0.1 - 5.0% (w / w) sodium hyaluronate; (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; (7) water. In some embodiments, the formulation consists of the following components: (1) 3.0 - 5.0% (w / w) triamcinolone acetonide; (2) 0.1 - 5.0% (w / w) sodium hyaluronate; (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; (7) water.

[0129] In some embodiments that can be combined with any of the above or below embodiments, the formulation is a suspension.

[0130] In some embodiments that can be combined with any of the above or below embodiments, the formulation comprises triamcinolone acetonide, wherein the volume median diameter (VMD) of triamcinolone acetonide in the formulation is about 0.5 - 3.5 μm. For example, the VMD of 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 D 10 of triamcinolone acetonide in the formulation is about 0.4 - 1.0 μm. For example, the D 10 of triamcinolone acetonide in the formulation is about 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0 μm, or any intermediate value thereof. In some embodiments, the D 50 of triamcinolone acetonide in the formulation is about 1.0 - 2.0 μm. For example, the D 50 of triamcinolone acetonide in the formulation 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 90 of triamcinolone acetonide in the formulation is about 2.0 - 3.8 μm. For example, the D 90is 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 thereof.

[0131] In some embodiments, the pharmaceutical composition comprises a triamcinolone acetonide preparation, wherein the preparation is a suspension of triamcinolone acetonide particles, and wherein the D 10 of triamcinolone acetonide in the preparation is about 0.4 - 1.0 μm, the D 50 of triamcinolone acetonide in the preparation is about 1.0 - 2.0 μm, and the D 90 of triamcinolone acetonide in the preparation is about 2.0 - 3.8 μm. In some embodiments, the preparation is a suspension of triamcinolone acetonide particles, wherein the D 10 of triamcinolone acetonide in the preparation is about 0.6 - 0.85 μm, the D 50 of triamcinolone acetonide in the preparation is about 1.5 - 1.8 μm, and the D 90 of triamcinolone acetonide in the preparation is about 3.0 - 3.5 μm. In some embodiments, the preparation is a suspension of triamcinolone acetonide particles, wherein the D 10 of triamcinolone acetonide in the preparation is about 0.7 - 0.8 μm, the D 50 of triamcinolone acetonide in the preparation is about 1.6 - 1.8 μm, and the D 90 of triamcinolone acetonide in the preparation is about 3.1 - 3.5 μm.

[0132] In some embodiments, the pharmaceutical composition comprises a triamcinolone acetonide preparation, wherein the preparation is a suspension of triamcinolone acetonide particles, and wherein the volume - average diameter (VMD) of about 10% of the triamcinolone acetonide particles is less than 0.4 - 1.0 μm, the VMD of about 50% of the triamcinolone acetonide particles is less than 1.0 - 2.0 μm, and the VMD of about 90% of the triamcinolone acetonide particles is less than 2.0 - 3.8 μm. For example, when the D 10 of triamcinolone acetonide in the preparation is about 0.4 μm, the D 50 is about 1.0 μm, and the D 90 is about 2.0 - 3.8 μm, the VMD of 10% of the triamcinolone acetonide particles in the preparation is less than 0.4 μm, the VMD of 50% of the triamcinolone acetonide particles is less than 1.0 μm, and the VMD of 90% of the triamcinolone acetonide particles is less than 2.0 μm. Another example, when the D 10 of triamcinolone acetonide in the preparation is about 1.0 μm, the D 50 is about 2.0 μm, and the D 90When it is about 3.8 μm, the VMD of 10% of the triamcinolone acetonide particles in the formulation is less than 1.0 μm, the VMD of 50% of the triamcinolone acetonide particles is less than 2.0 μm, and the VMD of 90% of the triamcinolone acetonide particles is less than 3.8 μm. In some embodiments, the VMD of about 10% of the triamcinolone acetonide particles in the formulation is less than 0.6 - 0.85 μm, the VMD of about 50% of the triamcinolone acetonide particles is less than 1.5 - 1.8 μm, the VMD of about 90% of the triamcinolone acetonide particles is less than 3.0 - 3.5 μm, and the average VMD of the triamcinolone acetonide particles in the formulation is about 1.5 - 2.5 μm. In some embodiments, the VMD of about 10% of the triamcinolone acetonide particles in the formulation is less than 0.7 - 0.8 μm, the VMD of about 50% of the triamcinolone acetonide particles is less than 1.6 - 1.8 μm, the VMD of about 90% of the triamcinolone acetonide particles is less than 3.1 - 3.5 μm, and the average VMD of the triamcinolone acetonide particles in the formulation is about 1.8 - 2.0 μm.

[0133] In some embodiments, the pharmaceutical composition comprises a triamcinolone acetonide formulation, wherein the formulation is a suspension of triamcinolone acetonide particles, and wherein the VMD of about 10% of the triamcinolone acetonide particles is less than about 0.5 μm to about 0.85 μm, the VMD of about 50% of the triamcinolone acetonide particles is less than about 1.2 μm to about 1.9 μm, and the VMD of about 90% of the triamcinolone acetonide particles is less than about 2.5 μm to about 3.6 μm. In some embodiments, the VMD of about 10% of the triamcinolone acetonide particles is less than about 0.7 μm to about 0.8 μm, the VMD of about 50% of the triamcinolone acetonide particles is less than about 1.5 μm to about 1.8 μm, and the VMD of about 90% of the triamcinolone acetonide particles is less than about 3.0 μm to about 3.5 μm. In some embodiments, the VMD of about 10% of the triamcinolone acetonide particles is less than about 0.75 μm to about 0.78 μm, the VMD of about 50% of the triamcinolone acetonide particles is less than about 1.63 μm to about 1.79 μm, and the VMD of about 90% of the triamcinolone acetonide particles is less than about 3.15 μm to about 3.48 μm. In some embodiments, the average VMD of the triamcinolone acetonide particles in the formulation is about 0.5 - 2.5 μm. In some embodiments, the average VMD of the triamcinolone acetonide particles in the formulation is about 0.7 - 2.1 μm. In some embodiments, the average VMD of the triamcinolone acetonide particles in the formulation is about 0.8 - 2.0 μm. In some embodiments, the average VMD of the triamcinolone acetonide particles in the formulation is about 0.81 - 1.99 μm.

[0134] In some embodiments, which can be combined with any of the above or below embodiments, the pharmaceutical composition comprises a triamcinolone acetonide preparation, wherein the preparation is prepared by a method comprising wet milling. In some embodiments, the preparation is prepared by a method comprising ball milling. For example, the preparation 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 preparation is prepared by a method comprising adding triamcinolone acetonide particles to a mixture comprising hyaluronic acid (e.g., an aqueous solution of hyaluronic acid) and milling the triamcinolone acetonide particles in the mixture comprising hyaluronic acid until the VMD of the triamcinolone acetonide particles reaches 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).

[0135] In some embodiments, the pharmaceutical composition comprises a triamcinolone acetonide preparation, wherein the preparation is substantially free of triamcinolone acetonide particles having a VMD less than 0.2 μm. In some embodiments, the preparation is substantially free of triamcinolone acetonide particles having a VMD of 0.2 - 0.4 μm. In some embodiments, more than 10%, more than 50% or more than 90% of the triamcinolone acetonide particles in the preparation have a VMD greater than 0.2 μm, 0.3 μm, 0.4 μm, greater than 0.5 μm, greater than 0.6 μm, greater than 0.7 μm, greater than 0.8 μm, greater than 0.9 μm, greater than 1.0 μm, greater than 1.5 μm, greater than 2.0 μm, greater than 2.5 μm, greater than 3.0 μm or greater than 3.8 μm. In some embodiments, at least about 10% of the triamcinolone acetonide particles in the preparation have a VMD greater than 3.8 μm. In some embodiments, at least about 50% of the triamcinolone acetonide particles in the preparation have a VMD greater than 2.0 μm. In some embodiments, at least about 90% of the triamcinolone acetonide particles in the preparation have a VMD greater than 1.0 μm. In some embodiments, at least about 10% of the triamcinolone acetonide particles in the preparation have a VMD greater than 2.0 μm, at least about 50% of the triamcinolone acetonide particles have a VMD greater than 1.0 μm, and at least about 90% of the triamcinolone acetonide particles have a VMD greater than 0.4 μm.

[0136] 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 triamcinolone acetonide preparation, wherein the preparation is free of polysorbate 80 and any of its derivatives or analogs.

[0137] In some embodiments, which can be combined with any of the above or below embodiments, the pharmaceutical composition comprises a triamcinolone acetonide formulation, wherein the formulation further comprises one or more viscosity modifiers.

[0138] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system comprising any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises 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.

[0139] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system comprising any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises a complement inhibitor. In some embodiments, the pharmaceutical composition comprises a plasma kallikrein inhibitor.

[0140] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system comprising any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises 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, taurolithocholic acid, ursodeoxycholic acid, or any combination thereof. In some embodiments, the pharmaceutical composition comprises a neuroprotective agent, wherein the neuroprotective agent is taurolithocholic acid.

[0141] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises a hypoxia-inducible factor inhibitor. Exemplary hypoxia-inducible factor inhibitors include, but are not limited to, EZN-2698, aminoflavone, camptothecins (e.g., topotecan, EZN-2208, SN38, irinotecan, temsirolimus, everolimus, sirolimus, LY294002, wortmannin, cardenolides, digoxin, ouabain, proscillaridin, 2ME2, romidepsin (KF228), trichostatin, LW6, acridine yellow, echinosporin, anthracyclines (e.g., doxorubicin and daunorubicin), chetomin, bortezomib, or any combination thereof. In some embodiments, the pharmaceutical composition comprises a hypoxia-inducible factor inhibitor, wherein the inhibitor is acridine yellow.

[0142] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises an adrenergic receptor agonist. Exemplary adrenergic receptor agonists include, but are not limited to, epinephrine, norepinephrine, isoproterenol, dopamine, phenylephrine, methoxamine, midodrine, oxymetazoline, α-methyldopa, clonidine, brimonidine, dobutamine, salbutamol / abuterol, terbutaline, salmeterol, formoterol, pirbuterol, clenbuterol, or any combination thereof. In some embodiments, the pharmaceutical composition comprises an adrenergic receptor agonist, wherein the agonist is brimonidine.

[0143] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes 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, or AAV9 vectors, gene therapy agents using ET, liposomes, or DNA nanoparticles as vectors, or any combination thereof. For example, electroporation or electropermeabilization is a physical method that can be used for gene therapy by exposing cells to electrical pulses to introduce polar molecules (such as DNA) through the cell membrane into eukaryotic cells.

[0144] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more protein or polypeptide drugs. Exemplary protein or polypeptide drugs include, but are not limited to, anti-VEGF drugs (such as bevacizumab, ranibizumab, aflibercept, conbercept, etc.), bispecific antibody drugs (such as faricimab), vasoconstrictors (such as endothelin-1), TNF-α inhibitors (such as adalimumab), or any combination thereof.

[0145] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more therapeutic cells or therapeutic components (such as 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.

[0146] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises a gel or an aqueous polymer solution, such as one or more viscoelastic substances. Examples of gels or aqueous polymer solutions useful herein include, but are not limited to, sodium hyaluronate, Provisc (a 1% viscous clear substance, a specific component of sodium hyaluronate), Viscoat (a dispersive viscoelastic preparation composed of sodium hyaluronate and chondroitin sulfate), Amvisc (a purified component of sodium hyaluronate), Amvisc Plus (a 1.6% sodium hyaluronate product derived from chicken combs), sodium chondroitin sulfate / sodium hyaluronate, or DisCoVisc (4% sodium chondroitin sulfate, 1.65% sodium hyaluronate), sodium carboxymethylcellulose, poloxamer, or any combination thereof.

[0147] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more anti-tumor drugs. Exemplary anti-tumor drugs include, but are not limited to, paclitaxel, immunosuppressive agents (such as ipilimumab), or any combination thereof.

[0148] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more herbal medicines. Exemplary herbal medicines include, but are not limited to, artemisinin, curcumin, pilocarpine, or any combination thereof.

[0149] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises 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.

[0150] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes 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.

[0151] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more non-steroidal 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.

[0152] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more prostaglandin derivatives. Exemplary prostaglandin derivatives include, but are not limited to, latanoprost, travoprost, bimatoprost, or any combination thereof.

[0153] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more anticholinergic drugs. Exemplary anticholinergic drugs include, but are not limited to, atropine, homatropine, tropicamide, or any combination thereof.

[0154] In some aspects, provided herein is a pre-loaded or pre-filled injection device or system that includes any of the injection devices described herein and a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more anesthetics. Exemplary anesthetics include, but are not limited to, tetracaine, oxybuprocaine, proxymetacaine, or any combination thereof. IV. Adapter for Syringe

[0155] In some aspects, provided herein is an adapter set that can be used in combination with a syringe to significantly improve the injection depth accuracy of the syringe, facilitate injecting a drug into a tissue (such as ocular tissue), and / or facilitate implanting certain structures in a tissue (such as ocular tissue). In some aspects, the adapters described herein can improve the injection accuracy and safety of a syringe once installed on the syringe. In some embodiments, the adapters described herein can improve the injection accuracy and safety of a syringe (such as the syringe disclosed in US2020 / 0069883) once installed on the other syringe.

[0156] In some aspects, the adapter set includes: a contact member extending from a proximal end to a distal end; and a pressing unit including a first elastic element; wherein the contact member can be installed at the distal end of the needle of the syringe such that the distal end of the contact member is located at the distal end of the distal opening of the needle, and the distal end of the contact member can be in direct contact with the surface tissue of the target injection site; and wherein the pressing unit can be installed to engage with the syringe barrel and the plunger shaft such that the pressing unit is elastically engaged with the plunger shaft and / or the syringe barrel through the first elastic element.

[0157] In some embodiments, the pressing unit can be assembled onto the syringe, wherein the pressing unit is elastically engaged with the plunger shaft and / or the syringe barrel through the first elastic element. In some embodiments, the first elastic element is in the form of a spring (e.g., Figure 16A and 16B 31 in). In some embodiments, the first elastic element can apply a force to the plunger shaft and push the plunger shaft towards the distal end. In some embodiments, the pressing unit can limit the movement of the syringe barrel, particularly the distal movement. In some embodiments, the pressing unit has a pair of limiters (e.g., Figure 16A 32 in) or locking elements (e.g., Figure 16B 33 in), and after assembling the pressing unit onto the syringe, the limiters or locking elements can prevent the syringe barrel from moving distally.

[0158] In some embodiments, the adapter set described herein includes a contact member, wherein after assembling the contact member onto the syringe, the proximal end of the contact member is in direct contact with the needle hub or the distal end of the syringe barrel. In some embodiments, as Figure 15A shown, after assembling the contact member 25 onto the syringe, the proximal end of the contact member is in direct contact with the distal end of the syringe barrel 1. In some embodiments, after assembling the contact member onto the syringe, the proximal end of the contact member is in indirect contact with the needle hub. In some embodiments, as Figure 15AAs shown, after the contact member is assembled to the syringe, the proximal end of the contact member is in indirect contact with the needle hub or the syringe barrel, and the contact member 25 is made of one or more materials having a low elastic modulus (such as Young's modulus). In some embodiments, the Young's modulus of the contact member is from about 0.001 GPa to about 15 GPa. In some embodiments, the Young's modulus of the contact member is from 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.

[0159] In some embodiments, the adapter set described herein further includes a second elastic element (such as Figure 15C - 15E 26 in), wherein after the contact member and the second elastic element are assembled to the syringe, the second elastic element elastically connects the proximal end of the contact member to the distal end of the needle hub or the syringe barrel of the syringe. In some of the foregoing embodiments, as Figure 15B shown, the contact member 25 has a high elastic modulus (such as Young's modulus) and is elastically engaged with the distal end of the needle hub or the syringe barrel through 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, wherein the first portion is located distal to the second portion. In some embodiments, the first portion and the second portion have different elasticities. In some embodiments, the first portion is more elastic than the second portion. In some embodiments, the first portion is less elastic than the second portion. In some embodiments, as Figure 15D shown, the contact member 25 includes a first portion 25a and a second portion 25b, wherein the first portion 25a is more elastic than the second portion 25b, the first portion 25a is located distal to the second portion 25b, and the proximal end of the second portion 25b is connected to the needle hub or the syringe barrel through the second elastic element 26.

[0160] In some embodiments, the adapter set described herein further includes a connector (such as, Figure 15F 27 in), wherein after the contact member is assembled to the syringe, the connector connects the proximal end of the contact member to the distal end of the needle hub or the syringe barrel, and wherein the elasticity of the connector is less than that of the contact member. In some of the foregoing embodiments, the contact member has a low elastic modulus. In some embodiments, the Young's modulus of the contact member is from about 0.001 GPa to about 10 GPa. In some embodiments, the connector has a high elastic modulus. In some embodiments, the Young's modulus of the connector is greater than 10 GPa.

[0161] 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 (such asFigure 15A 25) in some embodiments, the contact member is in a block shape (e.g., Figure 15B 25) in some embodiments, the contact member is in a block shape, and the distal end of the needle can pierce the block. In some embodiments, the contact member is an elastic block, and the distal end of the contact member has a surface shape suitable for the surface tissue of the target injection site. For example, the distal end of the contact member may have certain patterns (e.g., Figure 15G ). Also, for example, the distal end of the contact member may be beveled (e.g., Figure 15H ). In some embodiments, the second elastic element is in the form of a spring (e.g., Figure 15B and Figure 15D 26). In some embodiments, the second elastic element is in the form of a sleeve or sheath surrounding the needle (e.g., Figure 15C and Figure 15E 26). In some embodiments, the second elastic element is an elastic sheath surrounding the needle. In some embodiments, the connector is in the form of a sleeve or sheath surrounding the needle (e.g., Figure 15F 27). V. Methods of Medical Puncture and Implantation

[0162] In some embodiments, methods of medical puncture are described herein, such as in the eye or other organs or tissues.

[0163] As shown in FIGS. 1 to 11B, in some embodiments, the present disclosure provides a prefilled injection device or system, which includes an injection barrel 1, an actuation unit (e.g., an elastic movement unit for pushing the needle), a hollow puncture needle 6, and a flowable composition chamber 7.

[0164] In some embodiments, the injection barrel 1 includes a distal closed end and a proximal open end. In some embodiments, the injection barrel 1 can be designed to have two open ends axially, and the distal seal can be achieved by installing a distal seal 8 at the distal opening of the injection barrel 1. In some embodiments, the distal seal 8 can be made of a material that can be pierced by the hollow puncture needle 6, such as rubber, etc.

[0165] In some embodiments, the actuating unit (e.g., the resiliently movable unit) includes a driving member (e.g., a pressing element) 2 and a floating seal 3, wherein the floating seal 3 is sealingly engaged with the inner wall of the syringe barrel and is configured to move axially, e.g., move towards the distal or proximal end of the syringe barrel. In some embodiments, the driving member (e.g., the pressing element) 2 or a part thereof is located outside the proximal opening of the syringe barrel such that an operator can manually press the driving member (e.g., the pressing element) or a part thereof. In some embodiments, the floating seal 3 is resiliently engaged with the driving member 2, and when pressure is applied to the driving member 2, the floating seal 3 can move forward or backward relative to the driving member (e.g., the pressing element). In some embodiments, the floating seal 3 is configured to move towards the distal end of the syringe barrel. In some embodiments, the floating seal 3 is configured to move towards the proximal end of the syringe barrel. In some embodiments, with the position of the driving member (e.g., the pressing element) relative to the syringe barrel unchanged, the floating seal 3 is configured to move forward (e.g., in the distal direction) due to the elastic restoring force generated by the resilient engagement with the driving member (e.g., the pressing element).

[0166] In some embodiments, the hollow puncture needle 6 is fixedly connected to the driving member 2. When no pressure is applied to the driving member 2, the hollow puncture needle 6 remains proximal to the floating seal 3 and they do not contact. In some embodiments, the hollow puncture needle 6 itself includes a needle distal opening 6a and a needle body opening 6b. In some embodiments, the needle distal opening 6a and the needle body opening 6b are connected through the needle lumen or the needle body channel of the hollow puncture needle 6.

[0167] In some embodiments, the flowable composition chamber 7 is, for example, used to store drugs and other flowable compositions, such as liquids or gels. In some embodiments, the flowable composition chamber is enclosed by the distal closed end of the syringe barrel, the chamber wall of the syringe barrel, and the floating seal 3; that is, the flowable composition chamber occupies the distal part of the syringe barrel chamber. In some embodiments, since the floating seal 3 can move axially, the flowable composition chamber 7 is configured to have a variable volume, and thus the fluid pressure within the flowable composition chamber 7 may change due to the axial movement of the floating seal 3. In some embodiments, the flowable composition chamber contains a pre-filled drug composition. In some embodiments, the flowable composition chamber contains a pre-filled fluid and / or one or more structures to be implanted into the eye, such as implanted into the suprachoroidal space (SCS).

[0168] In some embodiments, the applications of the prefilled syringe or system disclosed herein include applying pressure to the drive member 2, thereby advancing the hollow piercing needle 6 distally to sequentially penetrate the floating seal 3 (e.g., by piercing the floating seal or an existing hole or slit in the floating seal) and the distal closed end of the syringe barrel (e.g., by piercing the distal closed end or an existing hole or slit in the distal closed end). The existing hole or slit may penetrate the floating seal, e.g., from the proximal surface to the distal surface of the floating seal, thereby forming a through-hole in the floating seal. The existing hole or slit may not penetrate the entire floating seal, and the advancement of the distal end of the needle through the floating seal may include advancement by any suitable combination of the existing hole or slit and piercing a portion of the floating seal. For example, the distal end of the needle may first be advanced through the existing hole or slit in the proximal surface, then pierce the floating seal, and then exit through the distal surface of the floating seal, and vice versa. In some embodiments, the hollow piercing needle 6 pierces into an apparent or potential tissue void, chamber, or blood vessel, such that the distal opening 6a of the needle is located within the apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the body opening 6b of the needle is located within the flowable composition chamber 7, and the floating seal 3 is elastically engaged with the drive member 2. In some embodiments, the fluid pressure within the flowable composition chamber 7 is higher than the pressure within the apparent or potential tissue void, chamber, or blood vessel.

[0169] At this time, the flowable composition within the flowable composition chamber 7 may flow into the apparent or potential tissue void, chamber, or blood vessel through the body opening 6b of the needle and the distal opening 6a of the needle. In some embodiments, during injection, the user may simply maintain pressure on the drive member 2, e.g., without further increasing the pressure. Under the action of the elastic engagement between the floating seal 3 and the drive member 2, the flowable composition (e.g., solution, suspension, or gel) within the flowable composition chamber 7 may enter the body opening 6b of the needle and pass through the needle body channel, thereby achieving injection, penetration, and / or dilation of the apparent or potential tissue void, chamber, or blood vessel.

[0170] In some embodiments, before the hollow puncture needle 6 penetrates an apparent or potential tissue space, chamber, or blood vessel, the external pressure on the distal opening 6a of the needle is higher than the fluid pressure within the flowable composition chamber 7, for example because the distal opening of the needle is located in a tissue that is denser, harder, and / or less deformable than the apparent or potential tissue space, chamber, or blood vessel. Accordingly, the flowable composition within the flowable composition chamber cannot flow out of the distal opening 6a of the needle and into the surrounding tissue. Taking the puncture process of SCS of the eye as an example, when the hollow puncture needle 6 has penetrated the sclera 13 but has not penetrated the SCS 14, the flowable composition will not flow out of the distal opening 6a of the needle regardless of whether the body opening 6b of the needle is in fluid communication with the flowable composition chamber 7. This is because the sclera 13 is relatively dense, and when the distal opening 6a of the needle is located within the sclera 13, the distal opening 6a of the needle is subject to a relatively high external pressure. The external pressure is higher than the fluid pressure within the flowable composition chamber 7, and the dense tissue such as the sclera actually acts as a piston to prevent the flowable composition from flowing out.

[0171] In some embodiments, by observing whether the floating seal 3 moves forward due to elastic engagement when the driving member 2 remains stationary under pressure, the operator can determine whether the hollow puncture needle 6 has penetrated an apparent or potential tissue space, chamber, or blood vessel, thereby informing the operator of the current depth of the needle and / or the position of the distal opening of the needle to ensure accurate placement of the needle. In some embodiments, since the injection process is controlled by the change in fluid pressure within the flowable composition chamber 7, there is no need to manually apply a force transmitted via a relatively rigid medium (such as a solid or a liquid) to push the needle tip and accurately place it into an apparent or potential tissue space, chamber, or blood vessel. Instead, due to the elastic engagement between the driving member 2 and the floating seal 3, a sudden force applied to the driving member 2 can be buffered, thereby allowing the floating seal to move more controllably and stably. In some embodiments, by using the device disclosed herein, fluctuations in the flow rate can be prevented or reduced, and stable injection can be achieved.

[0172] In some embodiments, when the hollow puncture needle 6 pierces the distal closed end of the syringe barrel, the medical puncture device can be in at least three states: a pre-puncture state, a surface tissue puncture state, and a fluid communication state.

[0173] In some embodiments, in the pre-puncture state, the length of the hollow puncture needle 6 extending from the distal closed end of the syringe barrel ranges within a pre-puncture length range. Within this range, the hollow puncture needle 6 has not yet started to puncture a living organism or its tissue.

[0174] In some embodiments, the systems or devices of the present disclosure include a flowable composition chamber pre-filled with a flowable composition. In some embodiments, the needle has passed through the floating seal before using the system or device. In some embodiments, before using the system or device, the needle has passed through the floating seal and the distal end of the syringe barrel, e.g., a distal seal for sealing the distal end of the syringe barrel.

[0175] In some embodiments, the flowable composition has a relatively high viscosity, e.g., higher than a water-like consistency, such as a gel or paste. The elastic sheath or sleeve 4 as shown in the drawings of the present disclosure is optional, particularly when the viscosity of the flowable composition is sufficient to prevent the flowable composition from exiting through the needle body opening and / or the needle distal opening when the openings are within the flowable composition chamber. For example, as Figure 3A shown, the needle can pass through the floating seal such that the needle body opening 6b is proximal to the floating seal and the needle distal opening 6a is within the flowable composition chamber. Due to the viscosity of the composition, the flowable composition can be prevented from exiting through the needle body opening, and the elastic sheath is optional. Alternatively, as Figure 3B shown, the needle body opening 6b can be within the flowable composition chamber and the needle distal opening 6a can be outside the flowable composition chamber. Due to the viscosity of the composition, the flowable composition can be prevented from exiting through the needle distal opening until the needle distal opening reaches the target tissue, e.g., an apparent or potential tissue void, chamber, or blood vessel.

[0176] In some embodiments, e.g., before or during using the system or device, the needle distal opening 6a can be outside the flowable composition chamber and the needle body opening 6b can be proximal to the floating seal (e.g., as Figure 3C shown at 6b1) or within the floating seal (e.g., as Figure 3C shown at 6b2). Due to the viscosity of the composition, the flowable composition can be prevented from exiting through the needle distal opening until the needle distal opening reaches the target tissue, e.g., an apparent or potential tissue void, chamber, or blood vessel.

[0177] In some embodiments, e.g., before or during using the system or device, the needle distal opening 6a can be within the distal seal at the distal closed end of the syringe barrel (e.g., the needle distal opening can be blocked by the distal seal), and the needle body opening 6b can be proximal to the floating seal (e.g., as Figure 3D shown at 6b1), within the floating seal (e.g., as Figure 3D shown at 6b2), or within the flowable composition chamber (e.g., as Figure 3D shown at 6b3). The flowable composition can be prevented from exiting through the needle distal opening and the needle body opening.

[0178] In some embodiments, for example, before or during use of the system or device, the distal opening 6a of the needle may be located within the cavity of the flowable composition, while the body opening 6b of the needle may be located within the floating seal (e.g., as shown in Figure 3E , 6b1) or within the cavity of the flowable composition (e.g., as shown in Figure 3E , 6b2). Discharge of the flowable composition from the body opening of the needle can be prevented. Figure 3E as shown in Figure 3E , 6b1 Figure 3E as shown in Figure 3E , 6b2

[0179] In some embodiments, for example, before or during use of the system or device, the distal opening 6a of the needle may be located within the floating seal, while the body opening 6b of the needle may be located proximal to the floating seal (e.g., as shown in Figure 3F , 6b). Discharge of the flowable composition from the body opening of the needle can be prevented. Figure 3F as shown in Figure 3F , 6b

[0180] In some embodiments, in the state of surface tissue puncture, the length range that the hollow puncture needle 6 extends from the distal closed end of the syringe is the surface tissue puncture length range. Within this range, the distal end of the hollow puncture needle 6 has entered the surface tissue (e.g., penetrated the sclera 13), but has not entered an obvious or potential tissue void, chamber, or blood vessel (e.g., has not penetrated the SCS 14). In some embodiments, due to the relatively dense surface tissue, the external pressure at the distal opening 6a of the needle is higher than the fluid pressure within the cavity 7 of the flowable composition. Therefore, regardless of whether the body opening 6b is connected to the cavity 7 of the flowable composition, the flowable composition will not enter the body opening 6b and / or discharge from the distal opening 6a of the needle.

[0181] In some embodiments, in the state of fluid communication, the length range that the hollow puncture needle 6 extends from the distal closed end of the syringe is the fluid communication length range. Within this range, the distal end of the hollow puncture needle 6 has penetrated an obvious or potential tissue void, chamber, or blood vessel. In some embodiments, the device can be designed such that in the state of fluid communication, the fluid pressure within the cavity 7 of the flowable composition is higher than the pressure within the obvious or potential tissue void, chamber, or blood vessel. In some embodiments, in the state of fluid communication, the body opening 6b is already located within the cavity 7 of the flowable composition, and due to the pressure difference between the inside (e.g., within the obvious or potential tissue void, chamber, or blood vessel) and the outside (e.g., within the cavity 7 of the flowable composition), the flowable composition within the cavity 7 of the flowable composition can flow through the body opening 6b, the body channel, and then through the distal opening 6a of the needle into the obvious or potential tissue void, chamber, or blood vessel.

[0182] In some embodiments, due to the elastic engagement of the floating seal 3 with the drive member 2 (e.g., due to the pressure within the cavity of the flowable composition being higher than the back pressure at the distal opening of the needle within the obvious or potential tissue void, chamber, or blood vessel), the floating seal 3 moves distally until the floating seal seals the body opening 6b (e.g., asFigure 4A - 4B as shown). In some embodiments, the axial dimension of the needle body opening is not greater than the thickness of the floating seal. In some embodiments, the needle body opening can be completely sealed or blocked by the floating seal, and at this time, the flowable composition no longer flows into the tissue void from the distal opening 6a of the needle. In some embodiments, when the floating seal blocks the needle body opening, only a part of the total volume of the flowable composition flows out from the distal opening 6a of the needle (e.g., as Figure 4A shown). In some embodiments, when the floating seal blocks the needle body opening, the total volume of the flowable composition in the chamber has been discharged from the distal opening 6a of the needle (e.g., as Figure 4B shown).

[0183] In some embodiments, the needle body opening can be located within the distal seal or the subject's tissue, and the flowable composition stops flowing out from the distal opening 6a of the needle (e.g., as Figure 4C shown). In some embodiments, the distance between the distal opening 6a of the needle and the needle body opening 6b can remain unchanged. In some embodiments, the distance between the distal opening 6a of the needle and the needle body opening 6b can vary. For example, a needle with a suitable distance between the distal opening 6a of the needle and the needle body opening 6b can be selected according to the known or estimated depth of the tissue to be reached. In some embodiments, a limiter 1a is provided in the syringe chamber and can be used to limit the forward movement of the floating seal 3 to achieve precise injection, e.g., injecting a predetermined volume.

[0184] In some embodiments, once the floating seal 3 contacts the limiter 1a, the further distal movement of the floating seal will be restricted, thereby stabilizing the floating seal 3 for subsequent operations, e.g., as Figure 6 - 11B shown.

[0185] In some embodiments, the systems or devices disclosed herein include two or more floating seals. For example, as Figure 5AAs shown, a first chamber is formed between the floating seal 3b and the distal seal of the syringe barrel, and a second chamber is formed between the floating seal 3a and the floating seal 3b. In some embodiments, the first chamber and the second chamber contain the same flowable composition. In some embodiments, the first chamber and the second chamber contain different flowable compositions. In some embodiments, the first chamber and the second chamber contain the same drug (e.g., active pharmaceutical ingredient) in the same or different flowable carriers or excipients. In some embodiments, the first chamber and the second chamber contain different drugs (e.g., active pharmaceutical ingredients) in the same or different flowable carriers or excipients. In some embodiments, the first chamber contains a drug and the second chamber contains a pharmaceutically acceptable carrier or excipient, such as saline, and vice versa. In some embodiments combinable with any of the foregoing embodiments, the first chamber is pre-filled with a first flowable composition. In some embodiments combinable with any of the foregoing embodiments, the second chamber is pre-filled with a second flowable composition. The first flowable composition and the second flowable composition may be the same or different. For example, the first flowable composition and the second flowable composition may contain the same active pharmaceutical ingredient (but in different carriers or excipients, for example), or may contain different active pharmaceutical ingredients. In some embodiments combinable with any of the foregoing embodiments, both the first chamber and the second chamber are pre-filled with the same flowable substance (e.g., the same drug formulation) or different flowable substances (e.g., different drug formulations).

[0186] In some embodiments, the flowable compositions in the first chamber and the second chamber can be sequentially delivered to apparent or potential tissue voids, chambers, or blood vessels. In some embodiments, the flowable compositions in the first chamber and the second chamber can be mixed in apparent or potential tissue voids, chambers, or blood vessels. In some embodiments, the flowable composition in the first chamber enters an apparent or potential tissue void, chamber, or blood vessel to reach and / or dilate the tissue void, chamber, or blood vessel. Subsequently, the flowable composition containing the drug in the second chamber can enter the apparent or potential tissue void, chamber, or blood vessel. For example, as Figure 5A shown, when the distal opening 6a of the hollow puncture needle 6 is in an apparent or potential tissue void, chamber, or blood vessel and the needle body opening 6b is in the first chamber (between the floating seal 3b and the distal seal of the syringe barrel), the flowable composition in the first chamber is delivered to the tissue. In Figure 5BIn [the situation], when the floating seal 3b moves distally and the needle body opening 6b contacts the second chamber (between the floating seal 3a and the floating seal 3b), the distal needle opening 6a can remain stationary in an apparent or potential tissue void, chamber, or blood vessel. Thus, the flowable composition in the second chamber begins to be delivered into the tissue until a certain volume has been delivered and / or the floating seal 3a (or the floating seals 3a and 3b together) blocks the needle body opening 6b, as Figure 5C shown. In some embodiments, a set (e.g., predetermined) volume of the flowable composition in the first chamber and / or a set (e.g., predetermined) volume of the flowable composition in the second chamber can be delivered into an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the dimension of the needle body opening 6b along the needle axis is greater than the thickness of the floating seal 3b, such that the first flowable composition (between the floating seal 3b and the distal seal of the syringe barrel) and the second flowable composition (between the floating seal 3b and the floating seal 3a) can be delivered sequentially and continuously through the distal needle opening into an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the dimension of the needle body opening 6b along the needle axis is not greater than the sum of the thicknesses of the floating seals 3a and 3b. In some embodiments, the dimension of the needle body opening 6b along the needle axis is greater than the thickness of the floating seal 3b and less than the sum of the thicknesses of the floating seals 3a and 3b. In some embodiments, the systems or devices disclosed herein include one or more additional floating seals (e.g., a third floating seal 3c), which are located proximal to the floating seal 3a, distal to the floating seal 3b, and / or between the floating seals 3a and 3b, thereby forming a third chamber, and the third flowable composition can 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 chamber is pre-filled with a flowable substance.

[0187] In some embodiments, the pre-filled injection devices or systems disclosed herein include two or more needle body openings. In some embodiments, the pre-filled syringes or systems disclosed herein include two or more needle body openings and two or more floating seals. For example, as Figure 5D shown, when the distal needle opening 6a is in an apparent or potential tissue void, chamber, or blood vessel, while the needle body opening 6b1 is in the first chamber (between the floating seal 3b and the distal seal of the syringe barrel) and the needle body opening 6b2 is blocked by the floating seal 3b, the flowable composition in the first chamber is delivered into the tissue. In Figure 5EIn [the context], when the floating seal 3b moves distally to block the needle body opening 6b1 and the needle body opening 6b2 contacts the second chamber (between the floating seal 3a and the floating seal 3b), the distal needle opening 6a remains stationary in an apparent or potential tissue void, chamber, or blood vessel. Thus, the flowable composition in the second chamber begins to be delivered to the tissue until a certain volume has been delivered and / or the floating seal 3a (or the floating seals 3a and 3b together) blocks the needle body opening 6b2 (and / or the needle body opening 6b1), as Figure 5F shown. In some embodiments, a set (e.g., predetermined) volume of the flowable composition in the first chamber and / or a set (e.g., predetermined) volume of the flowable composition in the second chamber can be delivered to an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the first chamber is pre-filled with a set (e.g., predetermined) volume of the flowable composition. In some embodiments, the second chamber is pre-filled with a set (e.g., predetermined) volume of the flowable composition. In some embodiments, the distance along the needle axis between the needle body opening 6b1 and the needle body opening 6b2 is greater than the thickness of the floating seal 3b such that the first flowable composition (between the floating seal 3b and the distal seal of the syringe barrel) and the second flowable composition (between the floating seal 3b and the floating seal 3a) can be delivered sequentially and continuously through the distal needle opening to an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the distance along the needle axis between the needle body opening 6b1 and the needle body opening 6b2 is not greater than the sum of the thicknesses of the floating seals 3a and 3b. In some embodiments, the distance along the needle axis between the needle body opening 6b1 and the needle body opening 6b2 is greater than the thickness of the floating seal 3b and less than the sum of the thicknesses of the floating seals 3a and 3b. In some embodiments, the system or device disclosed herein includes one or more additional needle body openings (e.g., a third needle body opening 6b3) located proximal to the needle body opening 6b2, distal to the needle body opening 6b1, and / or between the needle body openings 6b1 and 6b2, thereby forming a third chamber, and a third flowable composition can be delivered before the first flowable composition, after the second flowable composition, or between the first and second flowable compositions.

[0188] Described below are various embodiments of controlling injection termination using the medical puncture device disclosed herein.

[0189] In some embodiments, when the prefilled syringe or system is in a fluid communication state, the floating seal 3 moves forward due to the resilient 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 terminates. In some embodiments, the axial position of the needle body opening 6b within the flowable composition chamber 7 limits the maximum injection volume of the medical puncture device. In some embodiments, when the needle body opening 6b is blocked or sealed by the floating seal 3, the floating seal 3 has not yet contacted the wall of the distal closed end of the syringe barrel. In some embodiments, the flowable composition chamber 7 is not completely emptied, and there is still flowable composition between the floating seal 3 and the wall of the distal closed end of the syringe barrel.

[0190] In some embodiments, when it is desired to empty the flowable composition chamber 7, the floating seal 3 can be designed to seal the needle body opening 6b when the floating seal contacts the wall of the distal closed end of the syringe barrel. In some embodiments, the needle body opening 6b is located at the distal end of the flowable composition chamber 7. In some embodiments, the floating seal 3 contacts the wall of the distal closed end of the syringe barrel, and the needle body opening 6b is blocked or sealed by the floating seal 3 and / or the wall of the distal closed end of the syringe barrel. In some embodiments, the flowable composition chamber 7 is emptied, and there is no or almost no flowable composition between the floating seal 3 and the wall of the distal closed end of the syringe barrel.

[0191] In some embodiments, as the flowable composition within the flowable composition chamber 7 gradually enters the apparent or potential tissue voids, chambers, or blood vessels, a state may occur where the fluid pressure within the flowable composition chamber 7 balances with the pressure within the apparent or potential tissue voids, chambers, or blood vessels. At this time, due to the balance of forces, the floating seal 3 no longer moves. To continue the injection and / or empty the flowable composition chamber 7, an additional force needs to be applied to the floating seal 3 to move it forward towards the distal closed end of the syringe barrel.

[0192] For example, as Figure 2A - 2EAs shown, one, two or more axially extending sliding grooves (not shown) may be provided in the body wall of the syringe barrel 1. A slider matching the sliding groove may be provided on the driving member 2 (for example, the slider may include a part of the driving member 2 extending outside the syringe barrel 1), so as to increase the upper limit of the moving distance or stroke of the driving member 2, because the movement is no longer limited by the proximal end of the driving member 2. When the floating seal 3 can no longer move due to the balance of forces (for example, the balance between the pressure in the flowable composition chamber 7 and the pressure in the obvious or potential tissue voids, chambers or blood vessels), a greater pressure can be applied to the slider of the driving member 2 to drive the driving member 2 to move distally, which in turn can increase the elastic restoring force between the floating seal 3 and the driving member 2, thereby breaking the balance of forces and causing the floating seal 3 to move forward towards the distal end of the syringe barrel. In this way, more flowable composition is discharged from the flowable composition chamber 7, and in some embodiments, the flowable composition chamber 7 is emptied.

[0193] In some embodiments, other driving structures may be used to further move the floating seal 3 until it contacts the wall of the distal closed end of the syringe barrel. Some exemplary driving structures are described below.

[0194] In some embodiments, the prefilled syringe or system includes an element configured to enable an operator to manually control the movement of the floating seal 3 with one hand 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 holding the syringe barrel. In some embodiments, the manual control element is fixed to the floating seal 3 and partially extends outside the syringe barrel. In some embodiments, when the volume of the flowable composition injected into the obvious or potential tissue voids, chambers or blood vessels does not reach the target volume and the floating seal 3 no longer moves due to the balance of forces, the operator can further drive the floating seal 3 to move forward by moving the part of the manual control element extending outside the syringe barrel until the volume of the discharged flowable composition reaches the target volume. In some embodiments, using the manual control element helps to empty the flowable composition chamber 7. These embodiments are not limited to the case where the flowable composition chamber 7 needs to be emptied.

[0195] In some embodiments, the prefilled syringe or system can achieve precise delivery (e.g., by injection) of a certain volume of the flowable composition, and / or be capable of controlling the volume to be delivered. In some embodiments, the certain volume is a volume preset before delivery. In some embodiments, the certain volume is a volume prefilled before delivery. In some embodiments, the certain volume is one of a plurality of volumes that the operator can select during the delivery process, and the delivered volume can be different from the preset volume. In some embodiments, as Figure 1A - 1E 、 Figure 2A - 2E andFigure 11A - 11B As shown, the axial limiter 1a is disposed within the syringe cavity and at the distal end of the floating seal 3 for restricting the forward movement of the floating seal 3. In some embodiments, when the medical puncturing device is in a fluid communication state, the needle body opening 6b can be located at the distal end of the axial limiter 1a, and the floating seal 3 can move forward due to elastic engagement with the drive member 2.

[0196] In some embodiments, the floating seal 3 moves to a position restricted by the axial limiter 1a. In some embodiments, when the floating seal 3 moves to a position restricted by the axial limiter 1a, the pressure within the flowable composition chamber 7 remains not lower than the pressure within the apparent or potential tissue voids, chambers, or blood vessels. In some embodiments, the floating seal 3 can be pushed forward to the position restricted by the axial limiter 1a by the elastic restoring force between the floating seal 3 and the drive member 2 without relying on an additional drive structure or force to move the floating seal 3 to the position restricted by the axial limiter 1a.

[0197] In some embodiments, before the floating seal 3 moves to the position restricted by the axial limiter 1a through the elastic restoring force between it and the drive member 2, the pressure within the flowable composition chamber 7 has become equal to the pressure within the apparent or potential tissue voids, chambers, or blood vessels (i.e., due to the balance of forces, before the floating seal 3 reaches the axial limiter 1a, it no longer moves). At this time, solely relying on the elastic restoring force between the floating seal 3 and the drive member 2, the floating seal 3 will not be pushed forward to the position restricted by the axial limiter 1a. Therefore, in some embodiments, one or more additional drive structures or mechanisms can be employed to further push the floating seal 3 forward. For example, the additional drive structure or mechanism can include the manual control element described herein (e.g., as Figure 2A - 2E shown). In some embodiments, the axial limiter 1a provides a mechanism for achieving a set volume of fluid injection.

[0198] The following are multiple embodiments of the puncturing and injection timing of the medical puncturing device disclosed herein.

[0199] In some embodiments, when the prefilled syringe or system is in a pre-puncturing state, i.e., when the length by which the hollow puncturing needle 6 extends from the distal closed end of the syringe barrel is within the pre-puncturing length range (or when the hollow puncturing needle 6 has pierced the distal closed end of the syringe barrel but has not yet started to puncture a living body or its tissue), the needle body opening 6b remains above the flowable composition chamber 7 (e.g., at its proximal end). When provided in this way, early leakage from the distal opening 6a of the needle can be prevented, and the reliability of the medical puncturing device can be improved.

[0200] In some embodiments, corresponding structures can be provided on the pre-filled syringe or system to prevent early leakage before the hollow puncture needle 6 punctures the tissue and / or before the distal opening 6a of the needle reaches an apparent or potential tissue void, chamber, or blood vessel. For example, an axially extending annular contact element 1b (which is optional) can be formed at the distal closed end of the syringe barrel. In some embodiments, the axial length of the annular contact element 1b is set to be the same as the difference between the upper and lower limits of the pre-puncture length range of the hollow puncture needle 6 (i.e., the difference in the pre-puncture length of the needle when the hollow puncture needle 6 pierces the distal closed end of the syringe barrel and when it starts to puncture the organism or tissue). In this setting, as long as the distal end of the hollow puncture needle 6 remains within the axial length range of the annular contact element 1b, early leakage will not occur at the distal opening 6a of the needle. During puncture, the annular contact element 1b can first contact the surface of the organism or tissue to stabilize the medical puncture device. Then, pressure can be applied to the driving member 2 to start the puncture operation.

[0201] In some embodiments, when the pre-filled syringe or system is in a state of surface tissue puncture, that is, when the length of the hollow puncture needle 6 extending from the distal closed end of the syringe barrel is within the surface tissue puncture length range (or when the distal end of the hollow puncture needle 6 has pierced the surface tissue but has not entered an apparent or potential tissue void, chamber, or blood vessel), the body opening 6b of the needle is at least partially connected to the flowable composition chamber 7. In some embodiments, before the distal end of the hollow puncture needle 6 pierces an apparent or potential tissue void, chamber, or blood vessel, a fluid communication has been established between the flowable composition chamber 7, the distal opening 6a of the needle, and the body opening 6b of the needle. In some embodiments, the flowable composition in the chamber 7 can enter the body channel of the hollow puncture needle 6 in advance (via the body opening 6b), thereby removing at least a part of the air that may be present in the body channel, and thus reducing the amount of air entering the apparent or potential tissue void, chamber, or blood vessel.

[0202] In some embodiments, when the distal end of the hollow puncture needle 6 starts to pierce the surface tissue, the body opening 6b of the needle starts to be connected to the flowable composition chamber 7. In some embodiments, when the distal end of the hollow puncture needle 6 pierces an apparent or potential tissue void, chamber, or blood vessel, the body channel of the hollow puncture needle 6 has been filled with the flowable composition, thereby eliminating or reducing the possibility of air entering the apparent or potential tissue void, chamber, or blood vessel.

[0203] In some embodiments, when the prefilled syringe or system is in a fluid communication state, that is, when the length of the hollow piercing needle 6 extending from the distal closed end of the syringe barrel is within the fluid communication length range (or when the distal end of the hollow piercing needle 6 has penetrated an apparent or potential tissue void, chamber, or blood vessel), the needle body opening 6b has been located within the flowable composition chamber 7, thereby achieving a maximum flow rate at the needle body opening 6b, thus increasing the injection speed.

[0204] The embodiments described herein can be implemented individually or in any suitable combination.

[0205] In some embodiments, the device disclosed herein can prevent fluid from flowing back and / or leaking reversely through the needle body opening 6b.

[0206] In some embodiments, when the distal needle opening 6a is connected to the flowable composition chamber 7 while the needle body opening 6b is still proximal to the floating seal 3, there is a risk of fluid flowing back and / or leaking reversely through the needle body opening 6b. In some embodiments, when the distal opening 6a is within an apparent or potential tissue void, chamber, or blood vessel while the needle body opening 6b is still proximal to the floating seal 3, there is a risk of fluid flowing back and / or leaking reversely through the needle body opening 6b. In some embodiments, an elastic sheath 4 covering the outside of the hollow piercing needle 6 can be provided within the actuation unit (such as an elastic movement unit), for example, between the needle hub and the floating seal 3. In some embodiments, when the needle body opening 6b is proximal to the floating seal 3 (for example, when the needle body opening 6b has not yet been connected to the flowable composition chamber 7), the elastic sheath 4 can maintain the seal of the needle body opening 6b, thus effectively avoiding the backflow and / or reverse leakage of the flowable composition, preventing contamination of the area near the floating seal 3, reducing fluid loss, and improving the reliability of the product.

[0207] In some embodiments, the resilient sheath 4 does not seal the needle body opening 6b, but rather serves simply as an elastic engagement part between the floating seal 3 and the drive member 2. In some embodiments, by pushing the drive member 2 forward, the resilient sheath 4 between the floating seal 3 and the drive member 2 can be compressed, thereby forming an elastic restoring force between the floating seal 3 and the drive member 2, which in turn can drive the floating seal 3 to move forward. In some embodiments, the elastic engagement part between the floating seal 3 and the drive member 2 can comprise or be a spring 5 that is connected to the floating seal 3 and the drive member 2 at its two axial ends 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, the floating seal, and the drive member (such as a pressing element) can be manufactured separately and then assembled together in any suitable order. Alternatively, any two or more of the spring 5, the floating seal 3, and the drive member (such as a pressing element) can be integral, for example, manufactured as a single unit. The spring 5 and the resilient sheath 4 can be used separately or in combination.

[0208] In some embodiments, the elastic engagement between the floating seal 3 and the drive member 2 can be achieved by other methods than providing one or more elastic engagement parts. For example, the floating seal 3 and the drive member 2 can be provided as an integral integrated actuation unit (such as an elastic movement unit).

[0209] In some embodiments, provided herein are devices and methods for implanting into apparent or potential tissue voids, chamber systems, and blood vessels using the medical puncture devices disclosed herein. For ease of understanding, a stent is used as an example to illustrate the implanted medical device. In some embodiments, the methods disclosed herein include guiding a stent 11 into the needle body channel of a hollow puncture needle 6 using a stent guiding structure. In some embodiments, the stent guiding structure is provided in the pre-filled syringe or system disclosed herein.

[0210] In some embodiments, as Figure 6 - 8 shown, the stent guiding structure includes an inclined guiding groove 3a that is provided in or engages with the floating seal 3 and extends at an angle towards the hollow puncture needle 6. In some embodiments, when the flowable composition chamber 7, the needle body opening 6b, and the needle distal opening 6a are connected, the flowable composition can enter and expand an apparent or potential tissue void, chamber, or blood vessel. In some embodiments, the stent 11 can be implanted into the expanded apparent or potential tissue void, chamber, or blood vessel through the inclined guiding groove 3a, the needle body opening 6b, the needle body channel of the hollow puncture needle 6, and the needle distal opening 6a.

[0211] It should be noted that the inclined guiding groove 3a can be provided as a groove penetrating in the proximal / distal direction of the floating seal 3, or as a non-penetrating groove formed on the proximal surface of the floating seal 3.

[0212] In some embodiments, the inclined guiding groove 3a is a through groove. In some embodiments, the catheter guiding structure further includes a valve 9 disposed within or engaging with the inclined guiding groove 3a, and the valve can be a one-way valve configured to open and close. In some embodiments, the valve includes a plurality of valve flaps configured to open or close the valve. In some embodiments, in the absence of an external force, the one-way valve 9 is closed to prevent the flowable composition within the flowable composition chamber 7 from leaking through the valve. In some embodiments, in the presence of an opening force, the plurality of valve flaps of the valve can be opened, such that the catheter 11 can penetrate through the opened valve into the needle body opening 6b. In some embodiments, the catheter guiding structure further includes a guiding groove plug configured to be removably inserted into the inclined guiding groove 3a, and when it is necessary to implant the catheter 11, the guiding groove plug can be pulled out.

[0213] In some embodiments, the inclined guiding groove 3a is a non-penetrating groove. In some embodiments, the inclined guiding groove is directly punctured by the catheter 11 to be implanted. In some embodiments, the inclined guiding groove is punctured by a puncturing component other than the catheter, and then the catheter 11 can enter the needle body opening 6b through the punctured opening.

[0214] In some embodiments, in order to match the guiding direction of the inclined guiding groove 3a, the needle body opening 6b can be provided in the form of an inclined opening that is obliquely opened backward, such that the needle body opening 6b can be aligned with the inclined guiding groove 3a, thereby precisely guiding the catheter 11 through the inclined guiding groove and into the needle body opening.

[0215] In some embodiments, such as Figure 9 and Figure 10 shown, the catheter guiding structure includes an inclined guiding needle hole 6c that is formed or provided on the body wall of the hollow puncturing needle 6 and is obliquely opened backward. In some embodiments, for example, when the medical puncturing device is in a fluid communication state, the inclined guiding needle hole 6c is held at the proximal end of the floating seal 3. In some embodiments, the catheter 11 can penetrate through the inclined guiding needle hole 6c into the needle body channel of the hollow puncturing needle 6. In some embodiments, the catheter 11 can be implanted into an apparent or potential tissue space, chamber, or blood vessel (or an apparent or potential tissue space, chamber, or blood vessel dilated with a flowable composition) through the needle distal opening 6a.

[0216] In some embodiments, the catheter guiding structure may further include a valve 9 disposed within or engaged with the angled guide needle aperture 6c. The valve may be a one-way valve configured to open and close. In some embodiments, the valve includes a plurality of valve flaps configured to open or close the valve. In some embodiments, in the absence of an external force, the one-way valve 9 is closed, preventing the flowable composition within the flowable composition chamber 7 from leaking through the valve. In some embodiments, in the presence of an opening force, the plurality of valve flaps of the valve can be opened, allowing the catheter 11 to penetrate through the opened valve and the angled guide needle aperture 6c into the needle body channel (which may or may not be connected to the needle body channel connecting the needle body opening 6b and the needle distal opening 6a). In some embodiments, the catheter guiding structure may further include a needle aperture plug 10 configured to be removably inserted into the angled guide needle aperture 6c, and the needle aperture plug 10 can be removed to initiate the implantation operation of the catheter 11. In some embodiments, the guide needle aperture 6c is connected to the needle distal opening 6a. The needle body channel connecting the needle distal opening 6a and the needle body opening 6b may be the same as or separate from the needle body channel connecting the needle distal opening 6a and the guide needle aperture 6c. In some embodiments, the guide needle aperture 6c is connected to a needle distal opening other than the needle distal opening 6a connected to the needle body opening 6b. The needle body channel connecting the needle body opening 6b to the needle distal end may be completely separate from the needle body channel connecting the guide needle aperture 6c to the needle distal end. The needle body channel 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 channel connecting the guide needle aperture 6c to the needle distal end.

[0217] In some embodiments, such as, for example, as Figure 11A - 11B shown, the catheter guiding structure includes a central guiding groove 2c formed or provided on the proximal surface of the drive member 2. In some embodiments, the central guiding groove 2c includes a hole, or a hole may be provided at the center of the proximal surface of the drive member 2. In some embodiments, the central guiding groove 2c can be punctured to provide a hole. In some embodiments, a needle proximal opening is provided on the hollow puncture needle 6 and is axially aligned with the central guiding groove 2c. In some embodiments, when it is necessary to implant the catheter 11, the central guiding groove 2c can be punctured, and the catheter 11 can penetrate through the opening of the punctured central guiding groove 2c and the needle proximal opening of the hollow puncture needle 6 into the needle body channel (which may or may not be connected to the needle body channel connecting the needle body opening 6b and the needle distal opening 6a). In some embodiments, the catheter 11 can be implanted into an apparent or potential tissue space, chamber, or blood vessel (or an apparent or potential tissue space, chamber, or blood vessel that has been expanded by a flowable composition) through the needle distal opening (such as the needle distal opening 6a or a different needle distal opening).

[0218] In some embodiments, a kit is disclosed herein that includes components configured to be assembled to form a prefilled syringe or system disclosed herein.

[0219] In some embodiments, a kit for assembling a prefilled syringe 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 manufactured and / or provided independently. In some embodiments, the puncture control module includes a first syringe unit, and an actuating unit (e.g., an elastically movable unit) and a hollow puncture needle 6 disposed within the barrel of the first syringe unit. Based on the embodiments disclosed herein, it can be seen that the puncture control module may further include other parts or components, 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 chamber 7 formed within the barrel of the second syringe unit, and a module packaging member removably disposed 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 a barrel 1. Based on the embodiments disclosed herein, it can be seen that the fluid storage module may further include other parts, such as a distal seal 8.

[0220] In some embodiments, the puncture control module and the fluid storage module can be separately manufactured, assembled, and / or packaged and then assembled with each other (and optionally with other modules, components, and / or parts) into the medical puncture device disclosed herein. In some embodiments, the module packaging member is used to seal the proximal end of the flowable composition chamber 7. In some embodiments, the module packaging assembly can be removed when assembling the puncture control module and the fluid storage module.

[0221] In some embodiments, a prefilled medical device assembly and a system including it are provided herein. As Figure 7 and Figure 11A - 11B shown, in some embodiments, the medical device assembly includes a stent 11 and a medical puncture device including a stent guiding structure disclosed herein. In some embodiments, the stent 11 can be implanted into an apparent or potential tissue void, chamber, or blood vessel through a prefilled syringe or system. The medical device assembly described herein can have all the technical effects provided by the prefilled syringe or system.

[0222] In some embodiments, the medical device assembly includes a hollow auxiliary guiding needle 12, which is used in combination with a stent guiding structure. In some embodiments, the diameter of the needle body channel of the auxiliary guiding needle 12 is large enough to accommodate the stent 11 and allow the stent to penetrate. In some embodiments, during the operation of implanting the stent 11, the auxiliary guiding needle 12 is connected to the stent guiding structure, so that the stent 11 can sequentially pass through the needle body channel of the auxiliary guiding needle 12, the stent guiding structure, the needle body channel of the hollow puncture needle 6, and then enter the apparent or potential tissue space, chamber or blood vessel through the needle distal opening 6a. In some embodiments, before implanting the stent, the apparent or potential tissue space, chamber or blood vessel is expanded with a flowable composition using the prefilled syringe or system disclosed herein. In some embodiments, the stent is implanted while expanding the apparent or potential tissue space, chamber or blood vessel with the prefilled flowable composition using the prefilled syringe or system herein. In some embodiments, the stent is implanted before expanding the apparent or potential tissue space, chamber or blood vessel with the flowable composition using the prefilled syringe or system disclosed herein.

[0223] In some embodiments, as Figure 7 shown, the stent guiding structure includes a through inclined guiding groove 3a and a one-way valve 9, and the one-way valve 9 is embedded in the inclined guiding groove 3a and can be opened and closed. In some embodiments, the needle body opening 6b is provided in the form of a backwardly inclined opening. In some embodiments, when implanting the stent 11, the auxiliary guiding needle 12 is used to open the one-way valve 9 so that the auxiliary guiding needle can be positioned within the inclined guiding groove 3a. In some embodiments, the distal end of the auxiliary guiding needle 12 is advanced into the needle body opening 6b, and the stent 11 can sequentially pass through the needle body channel of the auxiliary guiding needle 12, the needle body channel of the hollow puncture needle 6, and the needle distal opening 6a, and then be implanted into the apparent or potential tissue space, chamber or blood vessel.

[0224] In some embodiments, as Figure 11A - 11B shown, the stent guiding structure includes a central guiding groove 2c. In some embodiments, a needle proximal opening is formed on the hollow puncture needle 6, which is axially aligned with the central guiding groove 2c. In some embodiments, when implanting the stent 11, the auxiliary guiding needle 12 can penetrate the central guiding groove 2c so that the auxiliary guiding needle 12 is axially aligned with the proximal opening of the hollow puncture needle 6. In some embodiments, the stent 11 passes through the needle body channel of the auxiliary guiding needle 12 and the proximal opening of the hollow puncture needle 6 in sequence, penetrates into the needle body channel of the hollow puncture needle 6, and then is implanted into the apparent or potential tissue space, chamber or blood vessel through the needle distal opening (such as the needle distal opening 6a).

[0225] In some embodiments, a prefilled system is disclosed herein, comprising: a syringe barrel including a proximal end and a distal end; a floating seal located within the syringe barrel; a needle hub proximal to the floating seal, a piston rod between the floating seal and the needle hub, the needle hub and the piston rod being elastically engaged with each other; and a needle located within the piston rod, the needle including a proximal end of the needle engaged with the needle hub and a distal end of the needle, wherein the needle includes: (i) a distal opening of the needle, (ii) a body opening of the needle located between the proximal end of the needle and the distal end of the needle, wherein the body opening is proximal to the distal opening of the needle, and (iii) a body passage connecting the distal opening of the needle and the body opening of the needle, wherein the needle hub is configured to advance the needle distally towards the floating seal through the piston rod, and / or through the floating seal.

[0226] In some embodiments, the floating seal may be fixedly attached to the distal end of the piston rod and form a sliding and sealing engagement with the inner surface of the syringe barrel. In any of the embodiments herein, the needle hub may be fixedly engaged to a drive member (e.g., a push element), and a spring may be engaged with the drive member and the piston rod, thereby providing an elastic engagement between the needle hub and the piston rod.

[0227] In some embodiments, when the distal opening of the needle is in tissue or an apparent or potential tissue space, chamber, or vessel such that a higher pressure is provided at the distal opening of the needle than at the body opening of the needle, the needle may be advanced distally through the piston rod and through the floating seal without the floating seal moving distally. In some embodiments, tissue resistance or tissue pressure does not permit injection of a flowable composition through the distal opening of the needle, and even when the needle is advanced distally under the force of a pressing shaft, the floating seal (and the piston rod in embodiments having a piston rod) does not move distally under the force of the spring. For example, when tissue pressure does not permit injection, the distal opening of the needle may be in tissue while the body opening of the needle is located distal to the floating seal and in contact with the flowable composition. The floating seal may maintain its position axially while the needle is further advanced until the distal opening of the needle reaches an apparent or potential tissue space, chamber, or vessel.

[0228] In some embodiments, when the distal opening of the needle is in tissue or an apparent or potential tissue space, chamber, or blood vessel, such that a lower pressure is provided at the distal opening of the needle than at the body opening of the needle, the floating seal may move distally. In some embodiments, tissue resistance or tissue pressure permits injection of the flowable composition through the distal opening of the needle, and the floating seal (and the piston rod in embodiments having a piston rod) moves distally under the force of a spring, without the needle having to be advanced further distally. For example, when tissue pressure permits injection, the distal opening of the needle may be in an apparent or potential tissue space, chamber, or blood vessel, while the body opening of the needle is located distally of the floating seal and in contact with the flowable composition. The floating seal may move distally, and the flowable composition is discharged from the distal opening of the needle, without the needle being advanced further distally.

[0229] In some embodiments, provided herein is a method of performing a medical puncture using a prefilled syringe or system as described herein. In some embodiments, a preassembled prefilled syringe or system is provided, as Figure 17A shown. In some embodiments, the housing of the preassembled device can be rotated to separate the syringe from the device body. In some embodiments, the proximal portion of the syringe can be threadedly engaged with the distal portion of the housing. For example, the proximal portion of the syringe can be provided with a threaded groove on its inner surface, the threaded groove configured to engage a threaded ridge on the outer surface of the distal portion of the housing, as Figure 17B shown.

[0230] In some embodiments, after the syringe is separated, the proximal end of the piston rod is exposed. A handle can be connected to the piston rod, for example, by proximal threaded engagement with the piston rod, as shown in FIG. 17C. In some embodiments, an adapter including a built-in adapter needle can be connected to the syringe. In some embodiments, the adapter includes a distal opening and a proximal opening. In some embodiments, the distal end of the syringe (e.g., having a distal seal connected thereto) is inserted into the proximal opening of the adapter, such that the adapter needle contacts the distal seal connected to the syringe. In some embodiments, the proximal end of the adapter needle passes through the distal seal connected to the syringe, such that the proximal opening of the adapter needle is located within the chamber of the syringe. In some embodiments, a container or a portion thereof containing a pre-filled flowable composition (e.g., a pharmaceutical composition) is inserted into the distal opening of the adapter, such that the adapter needle contacts the container. In some embodiments, the distal end of the adapter needle is inserted into the container, such that the distal opening of the adapter needle is located within the container and is capable of establishing fluid communication between the flowable composition and the inner lumen of the syringe. In some embodiments, pulling the handle moves the piston rod proximally, drawing the flowable composition into the inner lumen of the syringe through the adapter needle, and undesired gas can be expelled by pushing the handle to move the piston rod distally. By pulling and / or pushing the handle, seals at the distal end of the piston rod and within the syringe can be positioned appropriately to set a suitable volume of the flowable composition within the syringe, e.g., 0.1 mL or 0.05 mL, as shown in FIG. 17D, and then the handle and the adapter can be disconnected from the piston rod and the syringe, respectively. The syringe having the flowable composition therein can be connected to the device body, for example, by a syringe needle (e.g., as Figure 17B6) Insert the piston rod (e.g., 15 as shown in FIG. 17D), insert the piston rod into the guide tube within the outer housing, and re-screw the proximal end of the syringe back onto the distal end of the outer housing, as shown in FIG. 17E. In some embodiments, the control knob can be rotated to advance the plunger axially in the distal direction, thereby advancing the syringe needle connected to the plunger shaft distally towards and / or through a seal within the syringe. The syringe needle can be further advanced through the seal tip, as shown in FIG. 17F, and inserted into the sclera of the eye. In some embodiments, since the sclera is a dense tissue, the pressure at the distal opening of the syringe needle is greater than the pressure at the body opening of the syringe needle, and the body opening can be in fluid communication with the flowable composition within the syringe; in such a case, the syringe needle can be further advanced within the sclera without changing the position of the floating seal within the syringe. In some embodiments, the operator monitors the position of the floating seal within the syringe while pushing the plunger shaft to advance the syringe needle. Once the distal opening of the syringe needle is outside the sclera and enters the choroid / ciliary body, the pressure at the distal opening of the syringe needle decreases, and the pressure at the body opening of the syringe needle can drive the flowable composition through the body channel and out of the distal opening of the syringe needle, thereby creating and expanding a suprachoroidal space containing the flowable composition. Since a portion of the flowable composition within the syringe is discharged, the seal (along with the piston rod) moves to a more distal position within the syringe. Thus, by observing the movement of the seal, the operator can determine whether the distal opening of the syringe needle has left the first tissue and reached the second tissue with a lower density, e.g., from the sclera into the choroid / ciliary body. In some embodiments, once the seal has moved past a preset volume marker or indicator line (e.g., 0.1 mL or 0.05 mL), the distal advancement of the syringe needle stops.

[0231] In some examples, such as Figure 17A - shown in FIG. 17F, a portion of the fluid chamber in a prefilled syringe or system is not prefilled with a flowable substance or composition, but rather the flowable substance or composition is drawn into the syringe from a container and then delivered to a tissue or an apparent or potential tissue space, chamber, or vessel.

[0232] In some examples, the prefilled syringe or system disclosed herein is prefilled with a flowable substance or composition. In some embodiments, the syringe (e.g., syringe 1 shown in FIG. 16) may be provided in the form of one or more parts. In some embodiments, the container (e.g., the syringe unit) may include a cylindrical wall and a floating seal (which may move within the container and may be penetrated by the needle) that are sealingly engaged with a fixed seal (which is fixed to the container at the distal end of the container and may be penetrated by the needle), and the space enclosed by the cylindrical wall, the fixed seal, and the floating seal may be prefilled with a flowable substance or composition. In some embodiments, the prefilled syringe or system may include a first syringe unit, and the container may be a second syringe unit configured to engage the distal end of the first syringe unit. The container (e.g., the syringe unit) may be inserted or connected to the body of the device (e.g., the first syringe unit) before or after the flowable substance or composition is filled into the container (e.g., the syringe unit). In some embodiments, the floating seal within the container (e.g., the syringe unit) may contact the distal end of the piston rod, thereby establishing an engagement between the piston rod and the floating seal and transmitting the force of the spring to the floating seal. The fixed seal at the distal end of the container (e.g., the syringe unit) may contact the contact element at the distal end of the device, and the contact element may be the distal seal of the syringe. In some embodiments, the fixed seal of the container (e.g., the syringe unit) also serves as the distal seal and / or contact element of the syringe. In some embodiments, the container (e.g., the syringe unit) may be configured to be at least partially inserted into the barrel. In some embodiments, the fixed seal sealingly engages the container (e.g., the syringe unit), and the container in turn engages the inner wall of the barrel. In some embodiments, the fixed seal sealingly engages both the container (e.g., the syringe unit) and the inner wall of the barrel simultaneously. The engagement of the container (e.g., the syringe unit) with the barrel and the engagement of the fixed seal with the container wall may include any suitable engagement means, such as by insertion, threaded engagement, non-threaded engagement, engagement fixed by a clip, engagement fixed by pressing, or any combination thereof. VI. Methods and Devices for Ocular Drainage

[0233] Glaucoma is a leading cause of irreversible blindness. Current treatments use medications or surgery to lower intraocular pressure (IOP). Drug-free methods have been used (see, e.g., Chae et al., Adv. Sci. 2021, 8, 2001908), but drug-free, non-surgical methods can only lower IOP for about 4 months.

[0234] In some embodiments, methods, compositions, and devices for reducing intraocular pressure are disclosed herein, for example for treating glaucoma in a subject in need thereof. In some embodiments, the methods and the use of the compositions and devices may include dilating the suprachoroidal space (SCS) of the eye with one or more viscoelastic agents. In some embodiments, the SCS is dilated by forming an in situ reservoir in the SCS (which may contain one or more drugs or may be drug-free). In some embodiments, the SCS is dilated by forming a hydrogel in situ, such as by using microneedles to inject into the SCS. In some embodiments, the SCS is dilated by one or more viscoelastic agents configured to form a permanent or semi-permanent structure in the SCS, thereby achieving long-term dilation of the SCS. In some embodiments, the SCS is dilated by one or more viscoelastic agents, followed by implanting a permanent or semi-permanent structure in the SCS, thereby achieving long-term dilation of the SCS. In some embodiments, the SCS is dilated by a composition comprising a hyaluronic acid (HA) hydrogel. In some embodiments, the duration of SCS dilation (e.g., compared to its natural state as a potential tissue space) is at least or about four months, at least or about six months, at least or about eight months, at least or about one year, at least or about two years, at least or about three years, at least or about four years, at least or about eight years, at least or about twelve years, or longer.

[0235] Aqueous humor mainly exits the eye through the conventional outflow pathway including the trabecular meshwork and Schlemm's canal. However, a portion of the aqueous humor exits through an alternative or "non-conventional" pathway including the ciliary muscle, suprachoroidal space, and suprachoroidal cavity. In some embodiments, dilation of the SCS increases the amount of aqueous humor exiting the eye through the non-conventional pathway, thereby reducing intraocular pressure (IOP). In some embodiments, the reduction in IOP is associated with dilation of the SCS. In some embodiments, there is no difference in pressure-dependent aqueous humor outflow in the conventional pathway between eyes with dilated SCS and untreated eyes. In some embodiments, the methods, compositions, and devices provided herein are capable of continuously reducing IOP without the need for drugs or surgery to treat ocular hypertension and / or glaucoma.

[0236] Any system and device disclosed herein can be used to implant a permanent or semi-permanent structure, such as a stent, into the eye to reduce intraocular pressure, for example for treating glaucoma, including: (a) puncturing a needle into the eye at the injection site for injection 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 into the eye to maintain the SCS in a dilated state and facilitate the drainage of aqueous humor.

[0237] In some embodiments, the methods disclosed herein include: (a) piercing a needle into the eye to form a delivery channel within the eye, wherein the delivery channel terminates in the region between the sclera and the 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 micro-stent) within the expanded SCS, wherein the stent is releasably coupled to the needle; and (d) releasing the needle from the stent, thereby placing the stent within the eye to maintain the SCS and facilitate the drainage of fluid (e.g., from the anterior chamber) through the SCS. Prior to releasing the stent from the needle, the stent can 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).

[0238] In some embodiments, the methods disclosed herein include: (a) piercing a needle at an injection site into the eye for injection 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 micro-stent) within the SCS through the injection site or the dilated insertion site (e.g., formed by dilating (e.g., surgically) the injection site), thereby placing the stent within the eye to maintain the dilation of the SCS and facilitate the drainage of aqueous humor. The stent can be inserted through the injection site or the dilated insertion site to further dilate the SCS formed by the injection of the viscoelastic composition. The presence of the viscoelastic composition during the insertion of the stent can facilitate the separation between the sclera and the choroid, provide lubrication for the movement of the stent tip between the sclera and the choroid (e.g., in the plane parallel to the equator of the eyeball), and minimize tissue damage during implantation.

[0239] Figure 18A An ab externo method is exemplarily shown, wherein a viscoelastic agent is injected between the sclera and the choroid to form an SCS, and subsequently a permanent or semi-permanent structure (e.g., a stent) is implanted to keep the SCS in a dilated state for a longer period of time. As Figure 18B shown, the implant can form an annular or partial annular structure in the plane parallel to the equator of the eyeball. Compared with the ab interno aqueous humor drainage method, the ab externo method does not rely on piercing a stent or a drainage tube into the intraocular muscle tissue, causes less tissue damage, has a lower possibility of causing scar formation, and does not rely on inserting a stent or a drainage tube into the anterior chamber (e.g., by piercing the anterior chamber angle).

[0240] In some embodiments, the scaffolds disclosed herein may comprise any suitable material. Materials for fabricating the scaffolds include, but are not limited to, medical stainless steel, titanium or titanium alloy, nitinol, TPU (thermoplastic polyurethane), e-PTFE (expanded polytetrafluoroethylene), silicone, hydrogel, PES (polyethersulfone), SIBS (styrene-isobutylene-styrene block copolymer), or any combination thereof. In some embodiments, the material of the scaffold has high biocompatibility, matches the mechanical properties of ocular tissues, and does not damage ocular tissues or cause side effects. In some embodiments, the scaffolds disclosed herein may have a coating, but it is not necessary. In some embodiments, the scaffolds disclosed herein may be coated with a drug, but it is not necessary. In some embodiments, the scaffolds disclosed herein may contain one or more pharmaceutical compositions.

[0241] In some embodiments, the scaffolds disclosed herein may be in any suitable shape. In some embodiments, the scaffold is a circular tube. In some embodiments, the scaffold comprises a single chamber. In some embodiments, the scaffold comprises multiple chambers, such as chambers parallel to each other, each chamber extending from one end of the scaffold to the other end. In some embodiments, one or more of the individual or multiple chambers in the scaffold may contain one or more pharmaceutical compositions. In some embodiments, the shape of the cross-section of the scaffold may be circular, oval, square, or any other suitable shape. In some embodiments, any one or more surfaces of the scaffold may be planar or curved.

[0242] In some embodiments, the scaffolds disclosed herein include a marker ring and / or a retention ring around the scaffold. In some embodiments, an annular structure around the scaffold, such as a retention ring, may be configured to prevent scaffold displacement. The shape of the retention ring may include, but is not limited to, annular, barbed, finned, or any combination thereof. The structure and dimensions of the scaffold, including the structure and dimensions of the marker ring and the retention ring, may be designed to match the ocular tissue structure, thereby effectively draining aqueous humor and reducing intraocular pressure without causing tissue damage and scar formation.

[0243] In some embodiments, the length of the stent disclosed herein is from about 1.5 mm to about 12 mm, such as a length of about 3 mm, about 4 mm, about 5 mm, or about 6 mm. In some embodiments, the diameter of the stent disclosed herein is from about 0.1 mm to 1 mm, such as 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 inner diameter of the stent disclosed herein is from about 0.025 mm to 0.25 mm, such as 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, the marker ring is located about 0.25 mm to 2.5 mm from one end of the stent to facilitate precise positioning of the stent, such as for positioning in the SCS.

[0244] In some embodiments, the stent disclosed herein may include a solid structure, a porous structure, a multi-layer composite structure, a membrane stent structure, or any combination thereof. A solid structure (such as a uniform solid structure) is simple and effective and can establish a framework to maintain the SCS expanded by the viscoelastic reagent. In some embodiments, to avoid or reduce the risk of fibrosis and scar formation, a microporous material can be used to promote the biointegration of the surrounding tissue into the material, which can reduce fibrosis and scar formation after implantation. In some embodiments, the pore size can be less than 20 microns to prevent tissue or cell overgrowth into the pores while allowing water to pass freely through the pores. In some embodiments, the core or inner layer of the multi-layer composite structure can be designed to provide radial support. The outer layer of the multi-layer composite structure can be a porous or fabric layer with a pore size less than 20 microns to prevent tissue or cell overgrowth into the pores. In some embodiments, the stent is a hollow support structure that can provide sufficient support force and flexibility.

[0245] In some embodiments, the present disclosure provides a method of delivering the stent disclosed herein using the device disclosed herein. In some embodiments, the stent is pre-loaded into the needle of a delivery system (such as a suprachoroidal syringe) and implanted into the suprachoroidal space using the outside-in method described herein. After the tip of the delivery system pierces the sclera and reaches the choroid / ciliary body layer, the viscoelastic reagent is automatically injected to open the suprachoroidal space, and then the stent in the needle is pushed out to the target position, such as by wire pushing. The delivery system can be withdrawn to complete the implantation of the stent. The method disclosed herein can be used for minimally invasive glaucoma surgery (MIGS). In some embodiments, the stent can be inserted into the needle (or can be pre-inserted into the needle before inserting the needle and injecting the viscoelastic material) and deployed at the distal end of the needle.

[0246] In some embodiments, provided herein is a method of delivering a stent disclosed herein using a device disclosed herein. In some embodiments, a flowable substance or composition (e.g., a viscoelastic substance) is first injected into the suprachoroidal space to form the suprachoroidal space. Thereafter, the syringe needle can be removed from the injection site, leaving the suprachoroidal space filled with the viscoelastic substance. In some embodiments, the injection site and path formed by the needle are further enlarged to create a larger incision from the injection site, and / or a larger path from the injection site to the suprachoroidal space, and a linear component, such as a cannula, can be inserted, to which the stent is releasably coupled. In some embodiments, the stent can be the linear component, which is inserted from the injection site through the larger incision. In some embodiments, the injection site is further enlarged to create a larger incision from the injection site, and / or a larger path from the injection site to the suprachoroidal space, and the stent can be inserted into the suprachoroidal space. In some embodiments, there is no need to further enlarge the injection site and path, and a linear component, such as a cannula, can be inserted, to which the stent is releasably coupled. In some embodiments, there is no need to further enlarge the injection site and path, and the stent can be inserted.

[0247] In some embodiments, a flowable composition such as a viscoelastic composition provides lubrication for the stent or a linear component releasably coupled to the stent, such that the stent or the linear component can slide on the boundary between the sclera and the choroid / ciliary body, thereby reducing the resistance during stent insertion and / or reducing the risk of choroidal perforation, or the risk of the stent and / or the linear component piercing the vitreous body, the ciliary body, or other tissues. In some embodiments, the viscoelastic composition forms a protective layer around the stent or a linear component releasably coupled to the stent, and the protective layer can provide lubrication and guide the direction of stent insertion.

[0248] In some embodiments, provided herein is a minimally invasive method of implanting a stent into the eye using a needle, without surgically incising the entire layer of the sclera, or surgically separating the sclera and the choroid / ciliary body, or suturing the incised sclera or conjunctiva after the surgery. Thus, the methods disclosed herein can reduce tissue invasion, lower the surgical technical requirements, and shorten the surgical time.

[0249] It should be understood that any suitable injection device or system, including but not limited to those described herein in conjunction with the figures, can be used for the ocular drainage methods disclosed herein. For example, Figure 12AThe injection device or system shown. The injection device or system can be pre-filled with one or more drugs or other substances, such as viscoelastic reagents. In some embodiments, the injection device or system includes a syringe barrel having a proximal end and a distal end; a floating seal located within the syringe barrel; a puncturing member, such as a needle, located at the distal end of the syringe barrel, wherein the puncturing member is not connected to the floating seal; and a drive member configured to elastically engage the floating seal through an energy storage member (such as a spring, etc. and / or other suitable elastic members). In some embodiments, the puncturing member includes a distal opening configured to form fluid communication with a chamber within the syringe barrel containing a flowable composition. In some embodiments, the injection device or system further includes a limiter located within the syringe barrel, between the floating seal and the distal end of the syringe barrel. As Figure 12A shown in Step 1, the injection device or system is in an initial state, wherein the distal opening of the puncturing member has not entered the tissue of the subject, and the distance between the drive member and the floating seal is x1. In Figure 12A Step 2, the distal opening of the puncturing member has entered relatively dense tissue (e.g., sclera, anterior chamber angle, or ciliary body), wherein the distance between the drive member and the floating seal remains unchanged (x1). In Figure 12A Step 3, the distal opening of the puncturing member remains in relatively dense tissue, and when the energy storage member is compressed, for example, by reducing the distance between the drive member and the floating seal from x1 to x2. In this way, the energy storage member exerts a force on the floating seal and maintains this force. Through the flowable composition and the distal opening of the puncturing member, pressure is exerted on the relatively dense tissue. Due to the density of the tissue, the relatively dense tissue exerts a backpressure on the distal opening of the puncturing member, thereby preventing the flowable composition from being discharged into the tissue. In Figure 12A Step 4, the puncturing member is advanced distally into less dense tissue, such as an apparent or potential tissue void, chamber, or blood vessel (e.g., SCS or subconjunctival space). In some embodiments, due to the reduced tissue density, the backpressure on the distal opening of the puncturing member is less than the pressure of the flowable composition, thereby allowing the flowable composition to be released into the less dense tissue, such as an apparent or potential tissue void, chamber, or blood vessel. As the flowable composition is discharged from the distal opening of the puncturing member, the energy in the energy storage member is released, thereby increasing the distance between the drive member and the floating seal from x2 to x3, as Figure 12A shown in Step 5. The distal movement of the floating seal within the syringe barrel can be stopped by the limiter, for example, in order to control the volume of the flowable composition delivered to the less dense tissue.

[0250] Another example is as Figure 12B shown in Step 1, wherein the medical puncturing device is in an initial state, wherein the distal opening of the puncturing member has not entered the tissue of the subject, in Figure 12BIn step 2, the energy storage component can be compressed while the distal opening of the piercing component remains outside the tissue and the floating seal has not advanced distally to expel the flowable composition from the distal opening. In Figure 12B In step 3, the distal opening of the piercing component has entered relatively dense tissue (e.g., sclera, anterior chamber angle, or ciliary body). The energy storage component applies a force to the floating seal and maintains this force. Through the flowable composition and the distal opening of the piercing component, pressure is applied to the denser tissue. Due to the density of the tissue, the denser tissue applies a backpressure to the distal opening of the piercing component, thereby preventing the flowable composition from draining into the tissue. In Figure 12B In step 4, the distal opening of the piercing component begins to enter less dense tissue, such as an apparent or potential tissue space, chamber, or blood vessel (e.g., SCS or subconjunctival space), while the energy storage component remains compressed. In Figure 12B In step 5, due to the reduced tissue density, the backpressure on the distal opening of the piercing component is less 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 piercing component, the energy in the energy storage component is released. In some embodiments, the distal movement of the floating seal within the syringe can be stopped by a stopper to stop the flow of the flowable composition. In this way, the volume of the flowable composition delivered to the less dense tissue can be controlled. As Figure 12B shown in step 6, the force applied to the driving member can be released.

[0251] Another example is shown in Figure 12C . In some embodiments, the injection device or system includes a syringe having a proximal end and a distal end; a floating seal located within the syringe; a piercing component, such as a needle, located at the distal end of the syringe, wherein the piercing component is not connected to the floating seal; and an energy storage component configured to elastically engage the floating seal and the proximal end of the syringe. In some embodiments, the injection device or system further includes a limiter located within the syringe between the floating seal and the distal end of the syringe. In some embodiments, the medical piercing device includes a contact component. In Figure 12C In step 1, the medical piercing device is in an initial state, wherein the distal opening of the piercing component is within the contact component, and the contact component prevents the flowable composition from being expelled from the distal opening. The energy storage component applies a force to the floating seal, and through the flowable composition and the distal opening of the piercing component, pressure is applied to the contact component. Due to the density of the contact component, the backpressure on the distal opening of the piercing component prevents the flowable composition from leaking from the syringe. In Figure 12C In step 2, the distal opening of the piercing component has entered relatively dense tissue (e.g., sclera, anterior chamber angle, or ciliary body), and the backpressure of the relatively dense tissue on the distal opening prevents the flowable composition from leaking into the tissue. In Figure 12CIn step 3, the distal opening of the piercing member begins to enter a tissue of lower density, such as an apparent or potential tissue space, chamber, or blood vessel (e.g., SCS or subconjunctival space). In Figure 12C In step 4, due to the reduced tissue density, the back pressure on the distal opening of the piercing member is less than the pressure of the flowable composition, thereby allowing the flowable composition to be released into the tissue of lower density. As the flowable composition is discharged from the distal opening of the piercing member, the energy stored in the energy storage member is released. In some embodiments, the distal movement of the floating seal within the syringe barrel can be stopped by a stopper to stop the flow of the flowable composition. In this way, the volume of the flowable composition delivered to the tissue of lower density can be controlled. VII. Methods for Improving Injection Accuracy and Safety

[0252] Any adapter described herein can be assembled with a syringe to improve the injection accuracy and safety of the syringe. In some aspects, provided herein is a method for improving the injection accuracy and safety of a syringe, comprising: (1) providing a syringe comprising: a syringe barrel extending from a proximal end to a distal end and forming a chamber extending from the proximal end to the distal end; a plunger shaft extending from the proximal end to the distal end and forming a seal between the distal end of the plunger shaft and the syringe barrel; and a needle extending from the proximal end to the distal end, comprising an end opening for allowing fluid to flow out of the chamber through the distal end of the syringe barrel via a needle hub; (2) providing an adapter set comprising: a contact member extending from a proximal end to a distal end, and a pressing unit comprising a first elastic element; (3) mounting the contact member to the distal end of the syringe needle; (4) mounting the pressing unit to the syringe, wherein the distal end of the contact member is located distal to the distal opening of the needle, and the distal end of the contact member can directly contact the surface tissue of the target injection site; and wherein the pressing unit elastically engages the plunger shaft and / or the syringe barrel through the first elastic element.

[0253] In some embodiments, the contact member is mounted to the distal end of the syringe needle, wherein the distal end of the contact member is located distal to the distal opening of the needle, and the distal opening of the needle is completely located within the contact member. In some embodiments, as Figure 15A shown, the contact member 25 is a long elastic sheath that can contact the needle hub of the syringe when the contact member is mounted, thus establishing an elastic engagement between the syringe barrel 1 and the surface tissue of the target injection site.

[0254] In some embodiments, the adapter group further includes a second elastic element, wherein when installed, the proximal end of the second elastic element contacts the needle seat. While installing the second elastic element, a contact member is also installed at the distal end of the syringe needle, wherein the distal opening of the needle is completely located within the contact member. In some embodiments, as Figure 15B shown, the contact member 25 is a non-elastic block, and the second elastic element 26 (such as a spring) can establish an elastic connection between the proximal end of the contact member and the needle seat. In some embodiments, as Figure 15C shown, the contact member 25 is a non-elastic block, and the second elastic element 26 (such as an elastic sheath) can establish an elastic connection between the proximal end of the contact member and the needle seat. In some embodiments, as Figure 15D shown, the contact member 25 includes an elastic portion 25a and a non-elastic portion 25b, wherein the elastic portion 25a is located at the distal end of the non-elastic portion 25b, and the second elastic element 26 (such as a spring) can establish an elastic connection between the proximal end of the contact member (such as the proximal end of the non-elastic portion of the contact member) and the needle seat. In some embodiments, as Figure 15E shown, the contact member includes an elastic portion 25a and a non-elastic portion 25b, wherein the elastic portion is located at the distal end of the non-elastic portion, and the second elastic element 26 (such as an elastic sheath) can establish an elastic connection between the proximal end of the contact member (such as the proximal end of the non-elastic portion of the contact member) and the needle seat.

[0255] In some embodiments, the adapter group further includes a connector, wherein the connector is non-elastic, and wherein when installed, the proximal end of the connector contacts the needle seat. While installing the connector, a contact member is also installed at the distal end of the syringe needle, wherein the distal end of the needle is completely within the contact member. In some embodiments, as Figure 15F shown, the contact member 25 is an elastic sheath, thus establishing an elastic connection between the distal end of the connector 27 and the distal surface tissue of the target injection site.

[0256] In some embodiments, the flowable composition is first drawn into the chamber of the syringe, then the contact member is installed, optionally the second elastic element is installed, optionally the connector is installed, and then the pressing unit is installed. In some embodiments, the pressing unit is first installed, then the flowable composition is drawn into the chamber of the syringe, then the contact member is installed, optionally the second elastic element is installed, optionally the connector is installed.

[0257] In some embodiments, as Figure 16A shown, the pressing unit 30 includes a proximal end and a distal end, wherein the first elastic element 31 is connected to the proximal end of the pressing unit. As Figure 16AAs shown in the left figure, before being assembled with the syringe, the pressing unit is in an initial state, in which the first elastic element 31 (such as a spring) is in a static state, neither stretched nor compressed. The pressing unit 30 further includes a pair of stoppers 32 at its distal end, which can non-elastically engage with the barrel of the syringe and prevent the distal end of the barrel from moving. As Figure 16A As shown in the right figure, the pressing unit 30 can be assembled to the proximal end of the barrel 1 and the plunger shaft 2, where the plunger shaft 2 is engaged with the pressing unit through the first elastic element 31 (such as a spring), and the barrel 1 is non-elastically engaged with the pressing unit 30 through a pair of stoppers 32. Therefore, the plunger shaft and the barrel are elastically engaged. In this state, the first elastic element 31 is compressed. The compressed first elastic element 31 exerts a force on the plunger shaft 2, but the contact member at the distal end of the needle prevents the flowable composition from being discharged from the distal opening.

[0258] In some embodiments, as Figure 16B shown, the pressing unit 30 includes a proximal end and a distal end connected by the first elastic element 31. As Figure 16B As shown in the left figure, before being assembled with the syringe, the pressing unit 30 is in an initial state, in which the first elastic element 31 (such as a spring) is in a static state, neither stretched nor compressed. The pressing unit 30 further includes a locking element 33 at its distal end, which can prevent the barrel from moving distally. As Figure 16B As shown in the right figure, the pressing unit 30 can be assembled to the proximal end of the barrel 1 and the plunger shaft 2, where the plunger shaft 2 is elastically engaged with the barrel 1 through the first elastic element 31 (such as a spring), and the first elastic element 31 is stretched. Since the first elastic element 31 is in a stretched state, the proximal end of the pressing unit exerts a force on the plunger shaft 2, but the contact member at the distal end of the needle prevents the flowable composition from being discharged from the distal opening.

[0259] As Figure 17A shown in steps a - c, the adapter is mounted on the syringe and the flowable composition is drawn into the chamber. In Figure 17A steps d and e, the syringe with the adapter is in an initial state, in which the distal opening of the needle is within the contact member, which prevents the flowable composition from being discharged from the distal opening. The first elastic element (not shown in Figure 17A ) in the pressing unit exerts a force on the plunger shaft, and further exerts a pressure on the contact member through the flowable composition and the distal opening of the needle. Due to the density of the contact member 25, the back pressure on the distal opening of the needle prevents the flowable composition from leaking from the barrel. In Figure 17AIn steps f and g, the distal opening of the needle has entered the denser tissue A (e.g., sclera, anterior chamber angle, or ciliary body), and the backpressure from the denser tissue against the distal opening prevents the flowable composition from leaking into the tissue. Meanwhile, the contact member, optional second elastic element, and optional connector can increase the resistance to distal advancement of the needle, thereby reducing the risk of the needle penetrating too deeply. In Figure 17A step h, the distal opening of the needle begins to enter the less dense tissue B, such as an apparent or potential tissue space, chamber, or blood vessel (e.g., SCS or subconjunctival space). In Figure 17A step i, due to the reduced tissue density, the backpressure on the distal opening of the piercing member is less than the pressure of the flowable composition, allowing the flowable composition to be released into the less dense tissue. As the flowable composition is discharged from the distal opening of the piercing member, the energy stored in the first elastic element is released. In some embodiments, the distal movement of the push shaft within the syringe barrel can be stopped by a stopper to halt the flow of the flowable composition. In this way, the volume of the flowable composition delivered to the less dense tissue can be controlled.

[0260] In some aspects, the adapter set described herein can also be used to improve the injection accuracy and safety of other syringes, such as the syringe disclosed in US2020 / 0069883, which is incorporated herein by reference for all purposes. The contact member, optional second elastic element, and optional connector can be mounted to the needle of the syringe in the same manner as described above. The pressing unit can also be mounted to the push shaft of the syringe in the same manner as described above.

[0261] As Figure 17B shown in steps a - c, the adapter is mounted to the syringe disclosed in US2020 / 0069883, and the flowable composition is drawn into the chamber. As Figure 17B shown in steps d and e, the syringe with the adapter is in the initial state, where the distal opening of the needle is within the contact member, which prevents the flowable composition from being discharged from the distal opening. The first elastic element exerts a force on the push shaft, which in turn exerts a pressure on the contact member through the flowable composition and the distal opening of the needle. Due to the density of the contact member 25, the backpressure on the distal opening of the needle prevents the flowable composition from leaking from the syringe barrel. In Figure 17B steps f and g, the distal opening of the needle has entered the denser tissue A (e.g., sclera, anterior chamber angle, or ciliary body), and the backpressure from the denser tissue against the distal opening prevents the flowable composition from leaking into the tissue. Meanwhile, the contact member, optional second elastic element, and optional connector can increase the resistance to distal advancement of the needle, thereby reducing the risk of the needle penetrating too deeply. In Figure 17BIn step h, the distal opening of the needle begins to enter the less dense tissue B, such as an apparent or potential tissue space, chamber, or blood vessel (e.g., the SCS or the subconjunctival space). In Figure 17B In step i, due to the decrease in tissue density, the back pressure on the distal opening of the needle is less than the pressure of the flowable composition, thereby allowing the flowable composition to be released into the less dense tissue. The energy stored in the first elastic element is released, pushing the push shaft distally, while the contact member prevents the distal movement of the floating seal 3. Accordingly, the flowable composition is discharged from the distal opening of the piercing member. In some embodiments, the distal movement of the push shaft within the syringe barrel can be stopped by a stopper to stop the flow of the flowable composition. In this way, the volume of the flowable composition delivered to the less dense tissue can be controlled.

[0262] Exemplary embodiments and optional implementations of the present disclosure have been described in detail above in conjunction with the accompanying drawings. However, the present disclosure is not limited to the details described in the above embodiments. Simple variations can be made to the embodiments of the present disclosure, and all such variations are within the scope of the present invention.

[0263] It should be noted that each technical feature described in the above embodiments can be combined in any reasonable manner when there is no conflict. To avoid unnecessary repetition, possible combinations are not separately described in the embodiments.

[0264] In addition, different implementations of the embodiments of the present disclosure can be freely combined. As long as these combinations do not violate the idea of the present disclosure, they should also be regarded as part of the present disclosure.

Claims

1. A prefilled syringe for injecting a pharmaceutical composition into the eye, comprising: Syringe, comprising a proximal end and a distal end; A floating seal located within the syringe; A needle hub located proximal to the floating seal, wherein the floating seal and the needle hub are elastically engaged with each other; A pharmaceutical composition, wherein the pharmaceutical composition is contained in a chamber formed by the floating seal and the distal end of the syringe; A needle for intraocular puncture, the needle comprising: (i) A proximal end of the needle engaged with the needle hub; (ii) A distal end of the needle; (iii) An opening at the distal end of the needle; (iv) A body opening of the needle located between the proximal end and the distal end of the needle, wherein the body opening is proximal to the opening at the distal end of the needle; (v) A body channel connecting the opening at the distal end of the needle and the body opening; wherein the needle hub is configured to push the needle distally towards and / or through the floating seal.

2. The prefilled syringe according to claim 1, wherein the pharmaceutical composition comprises a triamcinolone preparation.

3. The prefilled syringe according to claim 2, wherein the triamcinolone preparation comprises: (i) Triamcinolone or a pharmaceutically acceptable salt thereof; (ii) Hyaluronic acid or a pharmaceutically acceptable derivative, analogue, salt or solvate thereof; (iii) One or more buffering agents; and (iv) One or more osmotic pressure regulators.

4. The prefilled 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 or alkaline earth metal salt, more preferably a sodium salt, and particularly preferably a pharmaceutically acceptable salt of hyaluronic acid having a molecular weight between about 50,000 and about 2,000,000 daltons.

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

6. The prefilled syringe according to any one of claims 3 to 5, wherein the osmotic pressure regulator comprises sodium chloride, potassium chloride, or a mixture thereof.

7. The prefilled syringe according to any one of claims 3 to 6, wherein the triamcinolone preparation further comprises water, preferably water for injection.

8. The prefilled syringe according to any one of claims 3 to 7, wherein: (i) Triamcinolone has a weight ratio in the whole preparation of 1.0% (w / w) to 8.0% (w / w); (ii) Hyaluronic acid or a pharmaceutically acceptable salt thereof has a weight ratio in the whole preparation of 0.1% (w / w) to 5.0% (w / w); (iii) The one or more buffering agents have a weight ratio in the whole preparation of 0.05% (w / w) to 0.8% (w / w); (iv) The one or more osmotic pressure regulators have a weight ratio in the whole preparation of 5.0% (w / w) to 10.0% (w / w).

9. The prefilled syringe according to any one of claims 3 to 8, wherein the formulation consists of the following components: (i) Triamcinolone having a weight ratio in the whole preparation of 3.0% (w / w) to 5.0% (w / w); (ii) Sodium hyaluronate having a weight ratio in the whole preparation of 0.1% (w / w) to 5.0% (w / w); (iii) Sodium chloride having a weight ratio in the whole preparation of 0.6% (w / w) to 0.8% (w / w); (iv) Sodium dihydrogen phosphate having a weight ratio in the whole preparation of 0.2% (w / w) to 0.4% (w / w); (v) Disodium hydrogen phosphate having a weight ratio in the whole preparation of 0.05% (w / w) to 0.15% (w / w); (vi) Sodium hydroxide in an amount sufficient to adjust the pH value of the preparation to about 6.5 to about 7.5; And (vii) Water.

10. The prefilled syringe according to any one of claims 3 to 9, wherein the pH value of the formulation is from about 6.0 to about 8.0, preferably, wherein the formulation further comprises a pH regulator, and wherein the pH regulator is sodium hydroxide.

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

12. The prefilled syringe according to any one of claims 3 to 11, wherein the formulation is prepared by the following method, the method comprising: (a) Add hyaluronic acid or a pharmaceutically acceptable salt thereof, a buffering agent, an osmotic pressure regulator and optionally a pH regulator to water and mix; (b) Disperse triamcinolone in the mixture of step (a); Preferably, in step (b), dispersion is promoted by stirring; and Preferably, the method further comprises (c) wet milling the mixture of step (b).

13. The prefilled syringe according to claim 1, wherein the pharmaceutical composition comprises one or more corticosteroids.

14. The prefilled syringe according to claim 13, wherein the one or more corticosteroids are selected from dexamethasone, triamcinolone acetonide, triamcinolone, triamcinolone acetate, fluocinolone acetonide, prednisolone, loteprednol etabonate, diflorasone diacetate, fluocortolone and any combination thereof.

15. The prefilled syringe according to claim 1, wherein the pharmaceutical composition comprises one or more tyrosine kinase inhibitors.

16. The prefilled syringe according to 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. The prefilled syringe according to claim 1, wherein the pharmaceutical composition comprises one or more complement inhibitors.

18. The prefilled syringe according to claim 17, wherein the one or more complement inhibitors include plasma kallikrein inhibitors.

19. The prefilled syringe according to claim 1, wherein the pharmaceutical composition comprises one or more neuroprotective agents.

20. The prefilled syringe according to 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, taurolithocholic acid, ursodeoxycholic acid, and any combination thereof.

21. The prefilled syringe according to claim 1, wherein the pharmaceutical composition comprises one or more hypoxia inducible factor inhibitors.

22. The prefilled syringe according to claim 15, wherein the one or more hypoxia inducible factor inhibitors are selected from EZN-2698, aminoflavone, camptothecins (e.g., topotecan, EZN-2208, SN38, irinotecan, temsirolimus, everolimus, sirolimus, LY294002, wortmannin, cardiotonic steroids, digoxin, ouabain, proscillaridin, 2ME2, romidepsin (KF228), trichostatin A, LW6, acridine yellow, echinosporin, anthracyclines (e.g., doxorubicin and daunorubicin), chetomin, bortezomib, and any combination thereof.

23. The prefilled syringe according to 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. The prefilled syringe according to claim 23, wherein the one or more adrenergic receptor agonists are selected from adrenaline, noradrenaline, isoprenaline, dopamine, phenylephrine, methoxamine, midodrine, oxymetazoline, α-methyldopa, clonidine, brimonidine, dobutamine, salbutamol / arbuterol, terbutaline, salmeterol, formoterol, pirbuterol, clenbuterol, and any combination thereof.

25. The prefilled syringe according to claim 23, wherein the one or more gene therapy drugs are selected from drugs carried by AAV2, AAV5, AAV8, and AAV9 vectors, gene therapy drugs carried by electroporation (ET), liposomes, and DNA nanoparticles, and any combination thereof.

26. The prefilled syringe according to claim 23, wherein the one or more protein and polypeptide drugs are selected from anti-VEGF drugs (such as bevacizumab, ranibizumab, aflibercept, conbercept, etc.), bispecific antibody drugs (such as faricimab), vasoconstrictors (such as endothelin-1), TNF-α inhibitors (such as adalimumab), and any combination thereof.

27. The prefilled syringe according to claim 23, wherein one or more for treating cells or cell components are selected from stem cells, regulatory T cells, exosomes, and any combination thereof.

28. The prefilled syringe according to claim 1, wherein the pharmaceutical composition comprises one or more gels or aqueous polymer solutions.

29. The prefilled syringe according to claim 28, wherein the one or more gels or aqueous polymer solutions comprise one or more viscoelastic substances.

30. The prefilled syringe according to 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, a specific component of sodium hyaluronate), Viscoat (a dispersive viscoelastic preparation composed of sodium hyaluronate and chondroitin sulfate), Amvisc (a purified component of sodium hyaluronate), Amvisc Plus (a 1.6% sodium hyaluronate product derived from chicken combs), sodium chondroitin sulfate / sodium hyaluronate, or DisCoVisc (4% sodium chondroitin sulfate, 1.65% sodium hyaluronate), sodium carboxymethylcellulose, poloxamer, and any combination thereof.

31. The prefilled syringe according to claim 1, wherein the pharmaceutical composition comprises one or more anti-tumor drugs, herbs, H1 receptor antagonists, mast cell stabilizers, or any combination thereof.

32. The prefilled syringe according to claim 1, wherein the pharmaceutical composition comprises one or more non-steroidal anti-inflammatory drugs, prostaglandin derivatives, anticholinergic drugs, anesthetics, or any combination thereof.

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

34. The method according to claim 33, wherein the flowable composition comprises a viscoelastic substance.

35. The method according to claim 33 or 34, wherein the injection site is dilated before placing the stent 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 on 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 according to any one of claims 33 to 37, wherein the stent is coated with or loaded with one or more drugs.

39. The method according to claim 38, wherein the one or more drugs are selected from corticosteroids, tyrosine kinase inhibitors, complement inhibitors, neuroprotective agents, hypoxia-inducible factor 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. The method according to any one of claims 33 to 39, which comprises using a device comprising: Syringe, comprising a proximal end and a distal end; A floating seal located within the syringe; A needle hub located at the proximal end of a floating seal, wherein the floating seal and the needle hub are elastically engaged with each other; and a needle, wherein the needle comprises: (i) a proximal end of the needle engaged with the needle hub; (ii) a distal end of the needle; (iii) an opening at the distal end of the needle; (iv) a body opening of the needle located between the proximal end and the distal end of the needle, wherein the body opening is proximal to the opening at the distal end of the needle; (v) a body channel connecting the opening at the distal end of the needle and the body opening, wherein the needle hub is configured to push the needle distally towards and / or through the floating seal.

41. A method for improving the injection accuracy and safety of a syringe, which comprises: (1) Provide a syringe, which comprises: 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 plunger shaft extending from the proximal end to the distal end and forming a seal between the distal end of the plunger shaft and the barrel; and a needle extending from the proximal end to the distal end, which comprises an end opening for allowing fluid to flow out of the chamber and through the distal end of the barrel via the needle hub; (2) Provide an adapter set, which comprises: a contact member extending from a proximal end to a distal end, and a pressing unit comprising a first elastic element; (3) Mount the contact member to the distal end of the syringe needle; (4) Mount the pressing unit to the syringe, wherein the distal end of the contact member is distal to the opening at the distal end of the needle, and the distal end of the contact member can directly contact the surface tissue of the target injection site; and wherein the pressing unit elastically engages the plunger shaft and the barrel through the first elastic element.

42. The method according to claim 41, wherein the proximal end of the contact member is in direct contact with the needle hub, and the Young's modulus of the contact member is from about 0.001 GPa to about 10 GPa.

43. The method according to claim 41, wherein the adapter set further comprises a second elastic element, and the method further comprises step (3a) performed between step (3) and step (4): mounting the second elastic element between the contact member and the needle hub, wherein the second elastic element elastically connects the proximal end of the contact member and the needle hub.

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

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

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

47. The method according to claim 41, wherein the adapter set further comprises a connector, and the method further comprises step (3a') performed between step (3) and step (4): mounting the connector between the contact member and the needle hub, wherein the elasticity of the connector is less than that of the contact member.

48. The 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, comprising: A contact member extending from a proximal end to a distal end; and a pressing unit comprising a first elastic element; wherein the syringe comprises 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 plunger shaft extending from the proximal end to the distal end and forming a seal between the distal end of the plunger shaft and the barrel; and a needle extending from the proximal end to the distal end, which comprises an end opening for allowing fluid to flow out of the chamber through the distal end of the barrel via the needle hub; wherein the contact member can be mounted to the distal end of the syringe needle such that the distal end of the contact member is distal to the opening at the distal end of the needle, and the distal end of the contact member can directly contact the surface tissue of the target injection site; and wherein the pressing unit can be mounted to the barrel and / or the plunger shaft of the syringe such that the pressing unit elastically engages the plunger shaft and / or the barrel of the syringe through the first elastic element.

50. The adapter set according to claim 49, wherein the contact member is mountable to the distal end of the needle of the syringe such that the proximal end of the contact member can be in direct contact with the needle hub, and the Young's modulus of the contact member is from about 0.001 GPa to about 10 GPa.

51. The adapter set according to claim 49, further comprising a second elastic element, wherein the second elastic element is mountable between the contact member and the needle hub, and wherein the second elastic element elastically connects the proximal end of the contact member and the needle hub.

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

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

54. The adapter set according to any one of claims 51 to 53, wherein the contact member includes a first portion and a second portion, wherein the first portion is located at the distal end of the second portion, and the first portion is more elastic than the second portion.

55. The adapter set according to claim 49, further comprising a connector, wherein the connector is mountable between the contact member and the needle seat, and the elasticity of the connector is less than that of the contact member.

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

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