JP5931847B2 - Devices and methods for intraocular drug delivery - Google Patents

Description

(Cross-reference of related applications)
This application claims priority to US Provisional Patent Application No. 61 / 341,582 (filed March 31, 2010) and US Provisional Patent Application No. 61 / 384,636 (filed September 20, 2010 ). And each of these applications is hereby incorporated by reference in its entirety.

(Field of Invention)
Described herein are devices configured to deliver a pharmaceutical formulation safely and accurately into the eye. In particular, the device allows for easy manipulation of the device, and can be beneficial for placement of the device on the surface of the eye and for injecting pharmaceutical formulations atraumatically within the eye. Features can be integrated. Systems and methods for delivering a pharmaceutical formulation into the eye using the device are also described.

  The eye is a complex organ composed of many parts that allow the visual process. The quality of vision depends on the state of each individual part and the ability of these parts to work together. For example, vision may be affected by symptoms that affect the lens (eg, cataract), retina (eg, CMV retinitis), or macula (eg, macular degeneration). Topical and systemic formulations have been developed to treat these and other ocular conditions, but each has drawbacks. For example, local therapies applied on the surface of the eye typically have a short convection time due to tears flowing away from the eye. In addition, drug delivery into the eye is limited by the natural barrier presented by the cornea and sclera, and additional structure if the intended target is in the posterior chamber. For systemic treatment, high doses of drugs are often required to obtain therapeutic levels in the eye, but this increases the risk of adverse side effects.

  Alternatively, intravitreal injection has been performed to deliver the pharmaceutical formulation locally into the eye. The use of intravitreal injection has become more common due to the increased availability of anti-vascular endothelial growth factor drugs for the treatment of acute macular degeneration (AMD). Drugs approved by the FDA for intravitreal injection to treat AMD include ranibizumab (Lucentis®: Genetech, South San Francisco, Calif.), And pegaptanib sodium (Macugen®: Eyetech Pharmaceuticals, New Zealand). York, NY). In addition, intravitreal bevacizumab (Avastin®: Genentech, South San Francisco, Calif.) Has been widely used in unapproved applications to treat choroidal neovascularization. There is also increased interest in developing new agents for delivery directly into the vitreous for the treatment of macular edema, retinal vein occlusion, and vitreous hemorrhage.

  Currently, commercially available intravitreal injection devices have many features that are useful for exposing the injection site, stabilizing the device against the sclera, and / or controlling the angle and depth of the injection. Missing. Many of the devices described in the patent literature, for example, in US Pat. The increased procedure time associated with these devices may in turn increase the risk of complications. In addition, having to operate many components alone may increase the risk of complications due to user errors. Serious complications of intraocular injection include endophthalmitis caused by the introduction of pathogens such as bacteria from the surface of the eye into the intraocular environment, or trauma to the ocular surface tissue such as cornea or conjunctival detachment. It is called an intraocular infection.

International Publication No. 2008/084064 US Patent Application Publication No. 2007/050016

  Therefore, a new device for performing intravitreal injection would be desirable. An ergonomic device that simplifies the ordering technique and reduces the risk of complications would be useful. Devices that accurately and non-traumatically inject drugs, eg, liquid, semi-solid, or suspension-based drugs, into the eye will also be useful.

The present invention provides, for example:
(Item 1)
An integrated device for intraocular drug delivery comprising:
The integrated device is:
A housing sized and shaped for operation with one hand, the housing having a proximal end and a distal end;
An eyepiece at the distal end of the housing;
A measurement component; and
A conduit at least partially within the housing, the conduit having a proximal end, a distal end, and a lumen therethrough;
An actuation mechanism contained within the housing, the actuation mechanism being operatively connected to a reservoir for holding the conduit and an active agent;
A trigger coupled to the housing, the trigger configured to activate the actuation mechanism;
A dynamic resistance component coupled to the housing;
Including integrated devices.
(Item 2)
The integrated device of claim 1, wherein the dynamic resistance component includes a slidable element coupled to the housing.
(Item 3)
The integrated device of claim 2, wherein the slidable element includes a dynamic sleeve having a proximal end, a distal end, and an inner surface.
(Item 4)
4. The integrated device of item 3, wherein the proximal end and the distal end of the dynamic sleeve are tapered.
(Item 5)
5. The integrated device of item 4, wherein the taper sleeve and the housing generate a force between 0N and about 2N.
(Item 6)
5. The integrated device of item 4, wherein the taper sleeve and the housing generate a force between about 0.1 N and about 1 N.
(Item 7)
4. The integrated device of item 3, wherein the inner surface of the dynamic sleeve includes one or more high traction friction surfaces.
(Item 8)
8. The integrated device of item 7, wherein the housing includes one or more high traction friction surfaces.
(Item 9)
9. The integrated device of item 8, wherein the dynamic sleeve and the one or more high traction friction surfaces of the housing generate a force between 0N and about 2N.
(Item 10)
9. The integrated device of item 8, wherein the dynamic sleeve and the one or more high traction friction surfaces of the housing generate a force between about 0.1 N and about 1.0 N.
(Item 11)
4. The integrated device of item 3, wherein the dynamic sleeve further comprises a fine sleeve mobility control component.
(Item 12)
The integrated device of item 1, wherein the eyepiece includes a ring, a flange, or a combination thereof.
(Item 13)
Item 13. The integrated device of item 12, wherein the eyepiece surface comprises a ring.
(Item 14)
14. The integrated device of item 13, wherein the ring has a diameter between about 0.3 mm and about 8 mm.
(Item 15)
Item 4. The integrated device according to Item 1, wherein the eyepiece surface is flat, convex, or concave.
(Item 16)
The integrated device of item 1, wherein the eyepiece surface includes one or more traction friction elements.
(Item 17)
The integrated device of claim 1, wherein the eyepiece surface includes an adhesive component.
(Item 18)
Item 18. The integrated device of item 17, wherein the adhesive component comprises a suction mechanism.
(Item 19)
The eyepiece surface is a material selected from the group consisting of nylon fiber, cotton fiber, hydrogel, spongy material, expanded styrene, other foams, silicone, plastic, polypropylene, polyethylene, polytetrafluoroethylene, and combinations thereof. The integrated device according to item 1, comprising:
(Item 20)
The integrated device of item 1, wherein the actuation mechanism comprises a manual actuation mechanism.
(Item 21)
21. The integrated device of item 20, wherein the manual actuation mechanism includes a control lever for slidable advancement of a plunger.
(Item 22)
The integrated device of item 1, wherein the actuation mechanism comprises an automatic actuation mechanism.
(Item 23)
24. The integrated device of item 22, wherein the automatic actuation mechanism comprises a spring loaded actuation mechanism.
(Item 24)
24. The integrated device of item 23, wherein the spring loaded actuation mechanism is configured to deliver the active agent into the intraocular space at a rate ranging from about 1 μl / second to about 1 ml / second.
(Item 25)
25. The integrated device of item 24, wherein the spring loaded actuation mechanism delivers the active agent into the intraocular space at a rate in the range of about 10 [mu] l / sec to about 100 [mu] l / sec.
(Item 26)
24. The integrated device of item 23, wherein the spring loaded actuation mechanism generates a force of about 0.1 N to about 1.0 N.
(Item 27)
24. The integrated device of item 23, wherein the spring load actuating mechanism includes a first spring and a second spring.
(Item 28)
28. The integrated device of item 27, wherein the second spring is configured to deploy a plunger and to control the delivery rate of the active agent.
(Item 29)
28. The item 27, wherein the first spring is configured to move the conduit from a first undeployed state to a second deployed state and to control the speed and force of deployment of the conduit. Integrated device.
(Item 30)
Item 2. The integrated device of item 1, wherein the actuation mechanism is a partially automated actuation mechanism.
(Item 31)
The integrated device of item 30, wherein the partially automated actuation mechanism includes a control lever for slidable advancement of a plunger.
(Item 32)
32. The integrated device of item 30, wherein the partially automated actuation mechanism comprises a spring loaded actuation mechanism.
(Item 33)
The integrated device of item 32, wherein the spring loaded actuation mechanism is configured to deliver the active agent into the intraocular space at a rate in the range of about 1 μl / second to about 1 ml / second.
(Item 34)
33. The integrated device of item 32, wherein the spring loaded actuation mechanism delivers the active agent into the intraocular space at a rate ranging from about 10 μl / second to about 100 μl / second.
(Item 35)
33. The integrated device of item 32, wherein the spring loaded actuation mechanism generates a force of about 0.1 N to about 1.0 N.
(Item 36)
33. The integrated device of item 32, wherein the spring load actuation mechanism includes a first spring and a second spring.
(Item 37)
38. The integrated device of item 36, wherein the second spring is configured to deploy a plunger and to control the delivery rate of the active agent.
(Item 38)
Item 36. The item 36, wherein the first spring is configured to move the conduit from a first undeployed state to a second deployed state and to control the speed and force of deployment of the conduit. Integrated device.
(Item 39)
Item 2. The integrated device of item 1, wherein the actuation mechanism is a pneumatic actuation mechanism.
(Item 40)
The active agents include steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, anti-infective drugs, anti-allergen drugs, choline antagonists and agonists, adrenergic antagonists and agonists, anti-glaucoma drugs, neuroprotective drugs, cataract prevention Or therapeutic agents, antiproliferative agents, antitumor agents, complement inhibitors, vitamins, growth factors, agents that inhibit growth factors, gene therapy vectors, chemotherapeutic agents, protein kinase inhibitors, small interfering RNA, they The integrated device of item 1, wherein the integrated device is selected from the group consisting of analogs, derivatives and modifications of
(Item 41)
The active agent is selected from the group consisting of ranibizumab, bevacizumab, pegaptanib, dexamethasone, dexamethasone sodium phosphate, triamcinolone, triamcinolone acetonide, fluocinolone, taxol-like drug, aflircept, anecoltab acetate, and the Limus family compound, The integrated device according to 1.
(Item 42)
The Limus family compounds include sirolimus, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, zotarolimus, CCI-779, AP23841, and ABT-578, their analogs, derivatives, complexes, salts, and modifications, and their The integrated device of item 36, selected from the group consisting of combinations.
(Item 43)
The integrated device according to item 1, wherein the storage part is made of a cyclic olefin-based resin.
(Item 44)
41. The integrated device of item 40, wherein the reservoir is devoid of one of silicone oil or derivatives thereof.
(Item 45)
The integrated device of item 1, wherein the measurement component is attached to the eyepiece.
(Item 46)
The integrated device of claim 1, wherein the measurement component includes one or more radially extending members.
(Item 47)
47. The integrated device of item 46, wherein the one or more radially extending members include a raised distal tip.
(Item 48)
49. The integrated device of item 46, wherein the one or more radially extending members are flexible.
(Item 49)
49. The integrated device of item 48, wherein the measurement component comprises a position indicator component.
(Item 50)
The integrated device of item 1, wherein the reservoir is pre-loaded with the active agent.
(Item 51)
4. The integrated device of item 3, wherein one of the proximal and distal ends of the dynamic sleeve is tapered.
(Item 52)
A method for intraocular drug delivery comprising:
The method
In order to determine the location of the injection site, the measurement component is used to place the eyepiece surface of the integrated device on the surface of the eye, the integrated device comprising a housing, a dispensing member, a motion Further comprising a mechanical resistance component, a reservoir for holding the active agent, and an actuation mechanism;
Using the dynamic resistance component to apply pressure against the surface of the eye at a target injection site;
Delivering an active agent from the reservoir into the eye by activating the actuation mechanism;
And wherein the placing, applying, and delivering steps are completed with one hand.
(Item 53)
53. The method of item 52, wherein the injection site is between about 1 mm forward of the edge and about 6 mm behind the edge.
(Item 54)
53. The method of item 52, wherein the injection site is between about 3 mm forward and about 4 mm behind the edge.
(Item 55)
53. The method of item 52, wherein the active agent is preloaded into the reservoir.
(Item 56)
53. The method of item 52, wherein the active agent is loaded into the reservoir using a drug loading mechanism.
(Item 57)
The active agents include steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, anti-infective drugs, anti-allergen drugs, choline antagonists and agonists, adrenergic antagonists and agonists, anti-glaucoma drugs, neuroprotective drugs, cataract prevention Or therapeutic agents, antiproliferative agents, antitumor agents, complement inhibitors, vitamins, growth factors, agents that inhibit growth factors, gene therapy vectors, chemotherapeutic agents, protein kinase inhibitors, small interfering RNA, they 53. The method of item 52, wherein the method is selected from the group consisting of analogs, derivatives, and modifications, and combinations thereof.
(Item 58)
The active agent is selected from the group consisting of ranibizumab, bevacizumab, pegaptanib, dexamethasone, dexamethasone sodium phosphate, triamcinolone, triamcinolone acetonide, fluocinolone, taxol-like drug, aflircept, anecoltab acetate, and the Limus family compound, 52. The method according to 52.
(Item 59)
The Limus family compounds include sirolimus, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, zotarolimus, CCI-779, AP23841, and ABT-578, their analogs, derivatives, complexes, salts, and modifications, and their 59. The method of item 58, selected from the group consisting of combinations.
(Item 60)
The active agent consists of macular edema, cystoid macular edema, diabetic macular edema, postoperative macular edema, retinal edema, age-related macular degeneration, BRVO, CRVO, uveitis, and central serous chorioretinopathy 53. The method of item 52, used to treat an ocular condition selected from the group.
(Item 61)
53. The method of item 52, wherein the actuation mechanism delivers the active agent into the intraocular space at a rate ranging from about 1 μl / second to about 1 ml / second.
(Item 62)
53. The method of item 52, wherein the actuation mechanism delivers the active agent into the intraocular space at a rate ranging from about 5 μl / second to about 200 μl / second.
(Item 63)
53. The method of item 52, wherein the actuation mechanism delivers the active agent into the intraocular space at a rate ranging from about 10 [mu] l / sec to about 100 [mu] l / sec.
(Item 64)
53. The method of item 52, wherein the actuation mechanism generates a force of about 0.1 N to about 1.0 N.
(Item 65)
53. The method of item 52, wherein the dynamic resistance component includes a slidable element coupled to the housing of the integrated device.
(Item 66)
68. The method of item 65, wherein the slidable element comprises a dynamic sleeve having a tapered proximal end and a tapered distal end.
(Item 67)
66. The method of item 65, wherein the step of applying pressure against the surface of the eye retracts the slidable element to expose the dispensing member.
(Item 68)
68. The method of item 67, further comprising the step of manually actuating a plunger to deliver the active agent.
(Item 69)
53. The method of item 52, wherein the step of applying pressure against the eye surface comprises a slidable advancement of the dynamic resistance component.
(Item 70)
70. The method of item 69, wherein the slidable advancement of the dynamic sleeve generates a force in the range of 0N to about 2N between itself and the housing.
(Item 71)
70. The method of item 69, wherein the slidable advancement of the dynamic sleeve generates a force in the range of about 0.1 N to about 1 N between itself and the housing.
(Item 72)
70. The method of item 69, wherein the slidable advance is manually adjustable.
(Item 73)
70. A method according to item 69, wherein the slidable advancement is automatically adjustable.
(Item 74)
53. The method of item 52, wherein the dynamic resistance component comprises an eye wall tension control mechanism.
(Item 75)
An integrated device for intraocular drug delivery comprising:
The integrated device is:
A housing sized and shaped to operate with one hand, the housing having a proximal end and a distal end;
An eyepiece at the distal end of the housing;
A measurement component; and
A conduit at least partially within the housing, the conduit having a proximal end, a distal end, and a lumen therethrough;
An actuation mechanism contained within the housing, the actuation mechanism being operatively connected to a reservoir for holding the conduit and an active agent;
A trigger coupled to the housing, the trigger configured to activate the actuation mechanism;
An eye wall tension control mechanism coupled to the housing;
Including integrated devices.
(Item 76)
76. The integrated device of item 75, wherein the eye wall tension control mechanism includes a slidable cap having a locking mechanism.
(Item 77)
77. The integrated device of item 76, wherein the locking mechanism is manually operated.
(Item 78)
77. The integrated device of item 76, wherein the locking mechanism is an automatically operated mechanism.
(Item 79)
79. The integrated device of item 76, wherein the locking mechanism includes a locking pin.
(Item 80)
79. The integrated device of item 76, wherein the slidable cap includes one or more high traction friction surfaces.
(Item 81)
81. The integrated device of item 80, wherein the one or more high traction friction surfaces comprise ridges on an inner surface of the slidable cap.
(Item 82)
76. The integrated device of item 75, wherein the eye wall tension control mechanism includes a pressure sensor.
(Item 83)
76. The integrated device of item 75, wherein the eye wall tension control mechanism includes a pressure accumulator.
(Item 84)
A method for intraocular drug delivery comprising:
The method
To determine the location of the injection site, the measurement component is used to place the eyepiece surface of the integrated device on the surface of the eye, the integrated device comprising a housing, a dispensing member, Further comprising an eye wall tension control component, a reservoir for holding the active agent, and an actuation mechanism;
Applying pressure to the surface of the eye at the target injection site using the eye wall tension control component;
Delivering an active agent from the reservoir into the eye by activating the actuation mechanism;
And wherein the placing, applying, and delivering steps are completed with one hand.
(Item 85)
85. The method of item 84, wherein the step of applying pressure against the eye surface comprises a slidable advancement of the eye wall tension control component.
(Item 86)
86. The method of item 85, wherein the slidable advancement of the eye wall tension control mechanism generates a force in the range of 0N to about 2N between itself and the housing.
(Item 87)
86. The method of item 85, wherein the slidable advancement of the eye wall tension control mechanism generates a force in the range of about 0.1 N to about 1 N between itself and the housing.
(Item 88)
An injection device for intraocular drug delivery comprising:
The infusion device is
A housing sized and shaped to operate with one hand, the housing having a proximal end and a distal end;
An eyepiece at the distal end of the housing;
A conduit at least partially within the housing, the conduit having a proximal end, a distal end, and a lumen therethrough;
An actuation mechanism contained within the housing, the actuation mechanism being operatively connected to a reservoir for holding the conduit and an active agent;
A trigger coupled to the housing, the trigger configured to activate the actuation mechanism;
With dynamic resistance components
Including an infusion device.
(Item 89)
90. The infusion device of item 88, wherein the dynamic resistance component comprises a dynamic sleeve having a proximal end, a distal end, and an inner surface.
(Item 90)
90. The infusion device of item 89, wherein the proximal end and the distal end of the dynamic sleeve are tapered.
(Item 91)
90. The infusion device of item 89, wherein one of the proximal end and the distal end of the dynamic sleeve is tapered.
(Item 92)
90. The infusion device of item 89, wherein the inner surface of the dynamic sleeve includes a ridge.
(Item 93)
90. The infusion device of item 88, wherein the dynamic sleeve further comprises a fine sleeve mobility control component.
(Item 94)
90. The infusion device of item 88, wherein the device further comprises a measurement component.
Described herein are devices, methods, and systems for delivering pharmaceutical formulations into the eye. Devices can be integrated. By “integrating”, it is intended that various features that may be beneficial, for example, in delivering the pharmaceutical formulation into the eye in a safe, sterile and accurate manner, are incorporated into a single device. For example, assisting in proper placement on the desired ocular surface site, helping to position the device so that the intraocular space is accessed at the proper angle, and when installed during the entire drug infusion, Helps keep the tip of the device stable without moving or sliding on it, regulates or controls intraocular pressure, and / or minimizes trauma due to, for example, drug injection or contact or penetration forces on the eye wall itself Features that may be useful for integration may be incorporated into a single device. More specifically, the integrated device minimizes trauma by direct contact with the target tissue or indirectly through force transmission through another tissue or tissue such as the eye wall or vitreous gel. And intraocular structures including, but not limited to, the cornea, conjunctiva, episclera, sclera, and retina, choroid, ciliary body, and lens, and trauma to blood vessels and nerves associated with these structures It may be used when minimizing. Features that may be beneficial in reducing the risk of intraocular infectious inflammation, such as endophthalmitis, and features that may reduce pain may also be included. It should be understood that the pharmaceutical formulation may be delivered to any suitable target location within the eye, such as the anterior or posterior chamber. Furthermore, the pharmaceutical formulation may comprise any suitable active agent and may take any suitable form. For example, the pharmaceutical formulation may be a solid, semi-solid, liquid or the like. The pharmaceutical formulation may also be adapted for any suitable type of release. For example, they may be adapted to release active agents in an immediate release, controlled release, delayed release, sustained release, or bolus release manner.

  In general, the devices described herein include a housing that is sized and shaped for operation with one hand. The housing typically has a proximal end and a distal end, and an eyepiece at the distal end of the housing. The conduit in its pre-deployment state is usually present in the housing. The conduit is at least partially within the housing in its deployed state. In some cases, the conduit is slidably attached to the housing. The conduit generally has a proximal end, a distal end, and a lumen therethrough. The actuation mechanism may be contained within a housing that is operably connected to a reservoir for holding the conduit and the active agent. The trigger may also be coupled to the housing and configured to activate the actuation mechanism. In one variation, the trigger is positioned at the tip of the device on the eyepiece so that the trigger can be easily activated by the fingertip while the device is placed over the desired ocular surface site by the finger of the same hand. Located on the side of the device housing close to (distance between trigger and device tip is in the range between 5 mm to 50 mm, between 10 mm to 25 mm, or between 15 mm to 20 mm) . In another variation, a trigger is activated by the second or third finger tip of the same hand placing the device on the eye surface when the device tip is placed on the eye surface perpendicular to the edge. As is possible, the trigger is located on the side of the device housing at 90 degrees to the measurement component. In one variation, the measurement component is attached to the eyepiece surface. In some variations, a drug loading mechanism is also included.

  The actuation mechanism may be manual, automated, or partially automated. In one variation, the actuation mechanism is a spring loaded actuation mechanism. Here, the mechanism may include either a single spring or two springs. In another variation, the actuation mechanism is a pneumatic actuation mechanism.

  Application of pressure to the surface of the eye may be achieved and further refined by including a dynamic resistance component in the injection device. The dynamic resistance component may include a slidable element coupled to the housing. In some variations, the slidable element comprises a dynamic sleeve configured to adjust the amount of pressure applied to the surface of the eye. In other variations, the dynamic resistance component is configured as an eye wall tension control mechanism.

  In use, the device further comprises a reservoir for holding the active agent and an actuation mechanism, the eyepiece surface of the integrated device is placed on the surface of the eye, and the target injection is performed using the eyepiece surface. The drug is delivered into the intraocular space by applying pressure against the surface of the eye at the site and then activating the actuation mechanism to deliver the active drug from the reservoir into the eye. The installing, applying, and delivering steps are completed with one hand. In some cases, a local anesthetic is applied to the surface of the eye prior to placing the device on the eye. A disinfectant may also be applied to the eye surface prior to placing the device on the eye.

  Application of pressure to the surface of the eye using the ocular surface may also generate intraocular pressure that ranges between 15 mmHg and 120 mmHg, between 20 mmHg and 90 mmHg, or between 25 mmHg and 60 mmHg. As described further below, the generation of intraocular pressure prior to the deployment of the dispensing member (conduit) may reduce the flexibility of the sclera, which in turn reduces the penetration of the conduit through the sclera. Facilitating and reducing discomfort associated with conduit penetration through the eye wall during the injection procedure and / or preventing repulsion of the device.

  The drug delivery device, its components, and / or various active agents may be provided in the system or kit as separately packaged components. The system or kit may include one or more devices, as well as one or more active agents. The device may be preloaded or configured for manual drug loading. When multiple active agents are included, the same or different active agents may be used. The same or different doses of active agent may also be used. The system or kit generally includes instructions for use. They may also contain anesthetics and / or disinfectants.

1A-1B display a front view of an exemplary eyepiece. 2A-2C show side views of additional exemplary eyepiece surfaces that include measurement components. 3A1-3A3 and 3B1-3B3 show other exemplary eyepiece side views. 4A and 4B1-4B2 display a perspective view and a front view of an exemplary flanged eyepiece. 5A1-5A2 and 5B1-5B2 display side and perspective views of exemplary flat and convex eyepieces. 6A1-6A2 and 6B1-6B2 show side and front views of an exemplary soft or semi-solid eyepiece. 7A1-7A2, 7B1-7B2, 7C1-7C2, and 7D-7E show additional exemplary eyepieces, including an eyepiece having a high traction friction surface. FIG. 8 illustrates how an exemplary measurement component operates to retract the eyelid and measure a distance from the edge. 9A-9C show an exemplary arrangement of measurement components around the eyepiece surface. Figures 10A-10C display other exemplary measurement components and how they operate to measure a distance from the edge. FIGS. 11A-11D illustrate additional exemplary measurement components. FIG. 12 illustrates an exemplary device that includes a marking tip member. FIG. 13 illustrates how a mark placed on the surface of the eye by an exemplary marking tip can be used to place the device at the target injection site. 14A-14C show perspective views of exemplary sharp conduits. 15A1-15A2 show side views of exemplary bevel angles. 16A-16D display cross-sectional views of exemplary conduit geometries. FIG. 17 displays a cross-sectional view of an additional exemplary conduit geometry. 18A-18C show a side view and a cross-sectional view (taken along line AA) of an exemplary flat conduit. FIG. 19 illustrates an exemplary mechanism for controlling exposure of a conduit. FIG. 20 provides another exemplary conduit exposure control mechanism. FIG. 21 shows an exemplary device having a front cover and a back cover. FIG. 22 illustrates how the device may be filled with a pharmaceutical formulation using an exemplary drug loading member. 23A-23C display another example of a drug loading member. Figures 24A-24D illustrate exemplary fenestrated drug loading members. Figures 25A-25B illustrate an exemplary fenestrated drug loading member in interface contact with a drug source. 26A-26C display a vertical cross-sectional view of an exemplary two spring actuation mechanism. FIG. 27 displays a vertical cross-sectional view of another exemplary two-spring actuation mechanism. FIG. 28 displays a perspective view of the device, including a further example of a two-spring actuation mechanism in its pre-activation state. FIG. 29 is a cross-sectional view of the device shown in FIG. 28 and a two-spring actuation mechanism. 30 is a cross-sectional view of the device shown in FIG. 28 after the two spring actuation mechanism has been activated. FIGS. 31A-31C illustrate how the trigger of FIG. 28 actuates the first spring of the two-spring actuating mechanism to deploy the conduit. 32A-32C are enlarged views illustrating how the release of the locking pin of FIG. 28 operates to activate the second spring of the two-spring actuation mechanism. 33A-33B display the device of FIG. 28 with an exemplary loading port. FIG. 34 is a perspective view of an exemplary device with a pneumatic actuation mechanism. 35A-35B provide a cross-sectional view of the device shown in FIG. FIG. 35A shows the pneumatic operating mechanism in a pre-start state. FIG. 35B shows the pneumatic actuation mechanism after deployment of the conduit. FIG. 36 is a cross-sectional view of an exemplary device that includes a single spring actuation mechanism. FIG. 37 is a cross-sectional view of the device shown in FIG. 36 showing a single spring actuation mechanism after deployment of the conduit. FIG. 38 is a vertical cross-sectional view of an exemplary drug loading position. 39A-39I display various views of exemplary device tips. FIG. 40 shows an exemplary device with a sliding cap. 41A-41B provide a cross-sectional view of another exemplary device having a two-spring actuation mechanism. FIG. 42 displays an enlarged cross-sectional view of an exemplary dynamic sleeve. 43A-43D illustrate an exemplary method of dispensing member advancement and drug injection. 43A-43D illustrate an exemplary method of dispensing member advancement and drug injection. 43A-43D illustrate an exemplary method of dispensing member advancement and drug injection. 43A-43D illustrate an exemplary method of dispensing member advancement and drug injection. 44A-44D display exemplary position indicator components. 45A-45J illustrate various aspects of an exemplary fine sleeve mobility control component. FIG. 46 is a graphical representation of the amount of resistance generated by a dynamic sleeve, according to one variation.

  Described herein are handheld devices, methods, and systems for delivering pharmaceutical formulations into the eye, for example, by injection. The device may incorporate (incorporate) various features into a single device that may be beneficial, for example, in delivering a pharmaceutical formulation into the eye in a safe, sterile, and accurate manner. For example, assisting in proper placement on the eye, helping to place the intraocular space to be accessed at the right angle, adjusting or controlling intraocular pressure, and / or, for example, injection or strength Features that may help to minimize trauma to the sclera and intraocular structures due to the penetration force of the membrane itself may be incorporated into a single device. The device may be configured to be disposable, in whole or in part.

(I. Device)
In general, the integrated devices described herein include a housing that is sized and shaped for operation with one hand. The housing typically has a proximal end and a distal end, and an eyepiece at the distal end of the housing. The conduit in its pre-deployment state may be present in the housing. The conduit is at least partially within the housing in its deployed state. In some variations, the conduit is slidably attached to the housing. In addition, the conduit generally has a proximal end, a distal end, and a lumen therethrough. The actuation mechanism may be contained within a housing that is operably connected to a reservoir for holding the conduit and the active agent.

  The device or portions thereof may be formed from any suitable biocompatible material or combination of biocompatible materials. For example, one or more biocompatible polymers may be used, for example, to make device housings, eyepieces, measurement components, and the like. Exemplary biocompatible and non-biocompatible materials include, but are not limited to, methyl methacrylate (MMA), polymethyl methacrylate (PMMA), polyethyl methacrylate (PEM), and other acrylic-based polymers , Fluorine such as polyolefins such as polypropylene and polyethylene, vinyl acetate, polyvinyl chloride, polyurethane, polyvinylpyrrolidone, 2-pyrrolidone, polyacrylonitrile butadiene, polycarbonate, polyamide, polytetrafluoroethylene (for example, TEFLON (registered trademark) polymer) Polymer, polystyrene, styrene acrylonitrile, cellulose acetate, acrylonitrile butadiene styrene, polymethylpentene, polysulfone, polyester, polyimide, natural rubber, polyisobutylene rubber Polymethyl styrene, silicones, and copolymers thereof and mixtures thereof.

In some variations, the device or a portion of the device, such as a drug reservoir, plunger, housing, eyepiece, or measurement component, is made of a material that includes a cyclic olefinic resin. Exemplary cyclic olefin resins include, but are not limited to, Zeonex® cycloolefin polymer (ZEON Corporation, Tokyo, Japan) or Crystal Zenith® olefin polymer (Daikyo Seiko, Ltd., Tokyo, Japan). , And commercial products such as APEL ^™ cycloolefin copolymer (COC) (Mitsui Chemicals, Inc., Tokyo, Japan), cyclic olefin ethylene copolymers, polyethylene terephthalate resins, polystyrene resins, polybutylene terephthalate resins, and Including combinations thereof. In one variation, it has high transparency, high heat resistance, and minimal chemical interaction with pharmaceuticals such as proteins, protein fragments, polypeptides, or chimeric molecules including antibodies, receptors, or binding proteins It may be beneficial to use cyclic olefin-based resins and cyclic olefin ethylene copolymers with little or no.

  Cyclic olefin polymers or hydrogenated products thereof include ring-opening homopolymers of cyclic olefin monomers, ring-opening copolymers of cyclic olefin monomers and other monomers, addition homopolymers of cyclic olefin monomers, cyclic olefin monomers and other monomers. It can be an addition copolymer, as well as a hydrogenation product of such a homopolymer or copolymer. The above cyclic olefin monomers may include monocyclic olefin monomers as well as polycyclic olefin monomers including bicyclic compounds and higher order cyclic compounds. Examples of monocyclic olefin monomers suitable for the production of homopolymers or copolymers of cyclic olefin monomers include monocyclic olefin monomers such as cyclopentene, cyclopentadiene, cyclohexene, methylcyclohexene, and cyclooctene, methyl and / or Or a lower alkyl derivative thereof and an acrylate derivative thereof containing 1 to 3 lower alkyl groups such as an ethyl group as a substituent.

Examples of polycyclic olefin monomers are dicyclopentadiene, 2,3-dihydrocyclopentadiene, bicyclo [2,2,1] -hept-2-ene, and derivatives thereof, tricyclo [4,3,0,1. ^2,5 ] -3-decene and derivatives thereof, tricyclo [4,4,0,1 ^2,5 ] -3-undecene and derivatives thereof, tetracyclo [4,4,0,1 ^2,5 , 0 ^7,10 ] -3-dodecene and derivatives thereof, pentacyclo ^{[6,5,1,1 3,6,} 0 ^{2,7, 0 9, 13} 4-pentadecene and its derivatives, pentacyclo [7,4,0,1 ^{2,5 , 0,} 0 ^{8, 13, 1} 9,12] -3-pentadecene and derivatives thereof, and hexacyclo ^{[6,6,1,1 3,6,} 1 ^10,13, 0 ^{2,7, 0 9,14]} -4-hepta Decene and its derivatives. Examples of bicyclo [2,2,1] -hept-2-ene derivatives are 5-methyl-bicyclo [2,2,1] -hept-2-ene, 5-methoxy-bicyclo [2,2,1 ] -Hept-2-ene, 5-ethylidene-bicyclo [2,2,1] -hept-2-ene, 5-phenyl-bicyclo [2,2,1] -hept-2-ene, and 6-methoxy Including carbonyl-bicyclo [2,2,1-]-hept-2-ene. Examples of tricyclo [4,3,0,1 ^2,5 ] -3-decene derivatives are 2-methyl-tricyclo [4,3,0,1 ^2,5 ] -3-decene, and 5-methyl- Including tricyclo [4,3,0,1 ^2,5 ] -3-decene. Examples of tetracyclo [4,4,0,1 ^2,5 ] -3-undecene derivatives include 10-methyl-tetracyclo [4,4,0,1 ^2,5 ] -3-undecene and tricyclo [4 Examples of, 3,0,1 ^2,5 ] -3-decene derivatives include 5-methyl-tricyclo [4,3,0,1 ^2,5 ] -3-decene.

Tetracyclo ^{[4,4,0,1 2,5, 0} 7,10] Example of 3-dodecene derivatives include 8-ethylidene - tetracyclo - ^{[4,4,0,1 2,5, 0 7,10} ] -3-dodecene, methyl 8 - tetracyclo - ^{[4,4,0,1 2,5, 0} 7,10] -3-dodecene, 9-methyl-8-methoxy - carbonyl - tetracyclo [4,4, 0,1 ^{2,5, 0} 7,10] -3-dodecene, 5,10-dimethyl - tetracyclo ^{[4,4,0,1 2,5,} including ⁰ 7,10] -3-dodecene. Hexacyclo ^{[6,6,1,1 3,6,} 1 ^{10,13, 0 2,7, 0} 9,14] Example -4-heptadecene derivatives, 12-methyl - hexacyclo [6,6,1, 1 ^{3,6, 1 10,13,} 0 ^{2,7, 0} 9,14] -4-heptadecene, and 1,6-dimethyl - hexacyclo ^{[6,6,1,1 3,6, 1 10,13,} 0 ^2,7, including ⁰ 9,14] -4-heptadecene. One example of a cyclic olefin polymer is an addition homopolymer of at least one cyclic olefin monomer, or an addition copolymer of at least one cyclic olefin monomer and at least one other olefin monomer (eg, ethylene, propylene, 4-methyl Pentene-1, cyclopentene, cyclooctene, butadiene, isoprene, styrene, or the like). This homopolymer or copolymer is soluble in a hydrocarbon solvent, for example, using one or more of the above as a known catalyst consisting of a vanadium compound or equivalent and an organoaluminum or equivalent. Can be obtained by polymerizing these monomers (published patent publication No. 6-157672, published patent publication No. 5-43663).

  Another example of a cyclic olefin polymer is a ring-opening homopolymer of the above monomer or a ring-opening copolymer of the above monomer. A catalyst comprising (1) a halide or nitrate of a platinum group metal such as ruthenium, rhodium, palladium, osmium or platinum, and a reducing agent; or (2) a compound of a transition metal such as titanium, molybdenum or tungsten. And using a known catalyst, such as a catalyst comprising an organometallic compound of a metal in one of Groups I to IV of the periodic table, such as an organoaluminum or organotin compound, as a catalyst It can be obtained by polymerizing or by copolymerizing the above-mentioned monomers (JP-A-6-157672, JP-A-5-43663).

  The homopolymer or copolymer may contain unsaturated bonds. The homopolymer or copolymer may be hydrogenated using known hydrogenation catalysts. Examples of hydrogenation catalysts are: (1) Ziegler type homogeneous catalysts, each consisting of an organic acid salt of titanium, cobalt, nickel or equivalent and an organometallic compound consisting of lithium, aluminum or equivalent, (2 Respectively) a support catalyst, consisting of a support such as carbon or alumina, and a platinum group such as palladium or ruthenium supported on the support, and (3) a catalyst each consisting of a complex of one of the above platinum group metals (Japanese Patent Laid-Open No. 6-157672).

  In some variations, the device, or a portion of the device, such as a drug reservoir, is made of a material that includes rubber. Examples of suitable rubber materials include butyl rubber such as butyl rubber, chlorinated butyl rubber, brominated butyl rubber, and divinylbenzene copolymerized butyl rubber, polyisoprene rubber (high-low cis-1,4 bond), polybutadiene rubber (high-low Cis-1,4 bonds), and conjugated diene rubbers such as styrene butadiene copolymer rubber, and ethylene propylene diene terpolymer rubber (EPDM). Crosslinkable rubber materials may also be used and may be made by kneading the above rubber materials with additives such as crosslinkers, fillers and / or reinforcing agents, colorants, or anti-aging agents. Good.

  In some variations, the biocompatible material is a biodegradable polymer. Non-limiting examples of suitable biodegradable polymers include celluloses and esters, polyacrylates (derived from L-tyrosine or free acids), poly (β-hydroxy esters), polyamides, poly (amino acids), polyalkanoates , Polyalkylene alkylate, polyalkylene oxylate, polyalkylene succinate, polyanhydride, polyanhydride ester, polyaspartic acid, polylactic acid, polybutylene diglycolate, poly (caprolactone), poly (caprolactone) / poly ( Ethylene glycol) copolymer, polycarbonate, polycarbonate derived from L-tyrosine, polycyanoacrylate, polydihydropyran, poly (dioxanone), poly-p-dioxanone, poly (ε-caprolactone-dimethyltrimethylene carbonate), poly ( Ester amide), polyester, aliphatic polyester, poly (ether ester), polyethylene glycol / poly (ortho ester) copolymer, poly (glutaric acid), poly (glycolic acid), poly (glycolide), poly (glycolide) / Poly (ethylene glycol) copolymer, poly (lactide), poly (lactide-co-caprolactone), poly (DL-lactide-co-glycolide), poly (lactide-co-glycolide) / poly (ethylene glycol) copolymer Copolymer, poly (lactide) poly (ethylene glycol) copolymer, polyphosphazene, polyphosphoester, polyphosphoester urethane, poly (propylene fumarate-co-ethylene glycol), poly (trimethylene carbonate), polytyrosine Carbonate, polyurethane, Chromatography polymer (glycolide-lactide or a copolymer of dimethyl trimethylene carbonate), and combinations thereof, mixtures, or copolymers of.

  Additives may be added to the polymers and polymer blends to adjust their properties as desired. For example, a polymer that is used in at least a portion of a device such that a biocompatible plasticizer increases its flexibility and / or mechanical strength, or provides a color contrast to the ocular surface. It may be added to the formulation. In other cases, biocompatible fillers such as particulate fillers, fibers, and / or meshes may be added to impart mechanical strength and / or stiffness to a portion of the device.

  The devices described herein can be manufactured, at least in part, by injection or compression molding the above materials.

  In some cases, it may be beneficial to include a viewing and / or magnification element that is removably mounted or integrated on the device. For example, an illumination source such as a magnifying glass and / or LED light may be removably attached to the device to facilitate visualization of the tip of the device and the injection site. Improved visualization can be achieved, for example, by approximately 3. It may help to more accurately and safely install the device at a target location 5 mm to 4 mm behind. The magnifier may be made of any suitable material, for example, any suitable non-resorbable (biodegradable) material previously described, It is lightweight so as not to affect the balance of the injection device. The magnifier and / or illumination source, eg, the LED, may be disposable.

(Casing)
The device housing generally contains a drug reservoir and an actuation mechanism. In its first undeployed state (pre-deployment state), the conduit may be in the housing. The housing may have any suitable shape as long as the housing can be gripped and operated by one hand. For example, the housing may be tubular or cylindrical, rectangular, square, circular, or oval in shape. In some variations, the housing is tubular or cylindrical, similar to a syringe barrel. In this case, the housing has a length between about 1 cm and about 15 cm, between about 2.5 cm and about 10 cm, or between about 4 cm and about 7.5 cm. For example, the housing is about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 12 cm, about 13 cm, about 14 cm, or about It may have a length of 15 cm. The surface of the housing may also be textured, roughened, or otherwise modified in certain areas, eg, by protrusions, ridges, etc., to assist the user in gripping and / or manipulating the housing. Also good.

  The housing may be made of any suitable material. For example, as described above, the components of the device may be made of any suitable biocompatible material or combination of biocompatible materials. Materials that may be beneficial in making the housing include, but are not limited to, cyclic olefin resins, cyclic olefin ethylene copolymers, polyethylene terephthalate resins, polystyrene resins, and polyethylene terephthalate resins. In one variation, it has high transparency, high heat resistance, and minimal chemical interaction with pharmaceuticals such as proteins, protein fragments, polypeptides, or chimeric molecules including antibodies, receptors, or binding proteins It may be beneficial to use cyclic olefin-based resins and cyclic olefin ethylene copolymers with little or no. Additional materials that may be beneficial in making the housing are not limited and include thermoplastics such as fluoropolymers, polyetheretherketone, polyethylene, polyethylene terephthalate, polyurethane, nylon, and the like. Including material, as well as silicone. In some variations, the housing may be made of a transparent material to assist in the deployment of the conduit and / or confirmation of drug delivery. Materials with suitable transparency are typically acrylic copolymers, acrylonitrile butadiene styrene (ABS), polycarbonate, polystyrene, polyvinyl chloride (PVC), polyethylene terephthalate glycol (PETG), styrene acrylonitrile (SAN), etc. The polymer. Acrylic copolymers that may be useful include polymethyl methacrylate (PMMA) copolymer and styrene methyl methacrylate (SMMA) copolymer (eg, Zylar 631® acrylic copolymer), It is not limited to them.

(Eyepiece)
The devices described herein generally include an atraumatic ocular surface at the distal end of the housing. In some variations, the eyepiece is fixedly attached to the proximal end of the housing. In other variations, the eyepiece surface is removably attached to the proximal end of the housing. The ocular surface is typically sterile. In some cases, the eyepiece surface is disposable. In use, the eyepiece surface of the device is placed on the surface of the eye.

  The ocular surface may be of any suitable configuration, such as size, shape, geometry, etc., as long as it allows atraumatic placement of the device on the surface of the eye. In some variations, the eyepiece surface may be annular (eg, FIGS. 1A-1B). When the eyepiece is in the shape of a ring, it may have a diameter of about 0.3 mm to about 8 mm, about 1 mm to about 6 mm, or about 2 mm to about 4 mm. In other variations, the eyepiece surface is oval or circular in shape.

  More specifically, as shown in the front views of FIGS. 1A-1B, the tip of the device includes a ring-shaped eyepiece surface in which the distance between the inner diameter and the outer shape of the ring forms a peripheral edge. In this case, the ring-shaped eyepiece has a narrower eyepiece with a wider eyepiece (10) (periphery) and a smaller internal opening (12) (FIG. 1A), or a larger internal opening (16) (FIG. 1B). You may comprise as a surface (14) (periphery). The dispensing member (conduit) may be an injection needle hidden inside and protected by the device tip. A membrane may also be provided that extends across the internal opening and may be flush with the ocular surface or may be retracted into the lumen of the device tip where the injection needle is present.

  As shown in FIGS. 39A-39B, when the device tip is placed in contact with any surface, such as the skin or eye wall, the tip of the dispensing member is the surface the distance marked by the arrow in FIG. 39B. The tip of the dispensing member can be retracted relative to the end of the device housing tip with the eyepiece surface in a stationary state. This distance may ensure that the tip of the dispensing member does not come into direct contact with any surface prior to the injection procedure, which is due to the source of the dispensing member such as skin secretions, eye secretions, or tears. Prevent accidental bacterial contamination and minimize the risk of introducing intraocular infectious agents during intraocular injection procedures that can cause endophthalmitis.

  In some variations, the tip of the dispensing member is the most of the device by a distance ranging from about 0.01 mm to about 10 mm, from about 0.1 mm to about 5 mm, or from about 0.5 mm to about 2 mm. It has been retracted and separated from the near end.

  In another variation, the eyepiece surface of the device tip that is in direct contact with the eye surface is annular and is approximately 360 degrees between the inner wall of the device housing and the dispensing member, as marked by the arrow in FIG. 39C. There is a gap. Here, if the annular eye interface is contaminated by an infectious agent and is placed on the surface of the eye, the dispensing member is placed on the surface of the eye that is separated from the tip of the device contaminated by the void area. Contact and penetrate it, which prevents accidental bacterial contamination of the dispensing member and minimizes the risk of introducing intraocular infections that can cause endophthalmitis. In contrast, as shown in FIG. 39D, the absence of such voids around the dispensing member may allow accidental infectious contamination of the device tip at the injection site.

  In some variations, between the inner wall of the device housing and the dispensing member in the range of about 0.1 mm to about 5 mm, about 0.3 mm to 3 mm, or about 0.5 mm to about 2 mm. There is a gap.

  In another variation, as shown in FIG. 39E, there is a solid membrane or partition (105) that separates the tip of the dispensing member (107) from the external environment, the membrane or partition being impermeable and / or non-permeable. It may be air permeable. The membrane or partition may ensure that there is no movement of air into or out of the device, creating an air seal and maintaining a certain air pressure inside the device.

  In addition, the membrane or divider may ensure that the tip of the dispensing member does not come into direct contact with any accidental bacterial contaminants such as tears and eye secretions prior to the injection procedure, which Prevents accidental bacterial contamination of the components and minimizes the risk of introducing intraocular infections during intraocular injection procedures that can cause endophthalmitis.

  Membranes or partitions that separate the tip of the dispensing member from the end of the device housing are methyl methacrylate (MMA), polymethyl methacrylate (PMMA), polyethyl methacrylate (PEM), and other acrylic-based polymers , Fluorine such as polyolefins such as polypropylene and polyethylene, vinyl acetate, polyvinyl chloride, polyurethane, polyvinylpyrrolidone, 2-pyrrolidone, polyacrylonitrile butadiene, polycarbonate, polyamide, polytetrafluoroethylene (for example, TEFLON (registered trademark) polymer) Polymer, or fluorinated ethylene propylene (FEP), polystyrene, styrene acrylonitrile, cellulose acetate, acrylonitrile butadiene styrene, polymethylpentene, polysulfone, polyester, Selected from the group consisting of biocompatible and non-biodegradable materials including, but not limited to, imide, natural rubber, polyisobutylene rubber, polymethylstyrene, silicone, and derivatives and copolymers and mixtures thereof. , May include materials.

  In some variations, when the membrane or partition (30) is placed in contact with any surface, such as the skin or eye surface, the membrane or partition as shown in FIG. 39E. , May be retracted inside the device tip so that it is separated from the surface by a distance marked with an arrow. The distance may ensure that the tip (31) of the dispensing member is not in direct contact with any surface prior to the injection procedure, which depends on sources such as skin secretions, eye secretions, or tears. Prevents accidental bacterial contamination of the dispensing member and minimizes the risk of introducing intraocular infection during intraocular injection procedures that can cause endophthalmitis.

  The membrane or divider is relative to the edge of the device housing at the eye interface by a distance ranging from about 0.01 mm to about 10 mm, from about 0.1 mm to about 5 mm, or from about 0.5 mm to about 2 mm. Can be retracted and separated therefrom.

  In a further variation, the measurement component (32) (further described below) is such that when the device tip (34) contacts the eye surface (35) (FIG. 39I), the measurement component (32) It may be retracted relative to the end of the device housing (33) on the eyepiece surface (FIGS. 39F-39H) so as not to contact the eye surface (35). This configuration can minimize the risk of trauma to delicate tissues covering the surface of the eye, such as the cornea and non-keratinized epithelium of the conjunctiva. Avoiding direct contact between the measurement member and the ocular surface may be beneficial in minimizing the risk of trauma to the ocular surface such as cornea or conjunctival detachment, which may reduce corneal ulcers. Prevent further serious complications such as including bacterial infusions. In alternative variations, the tip of the measurement member (32) may be angled away from or toward the eye (FIGS. 39G and 39H, respectively). The measurement component is retracted relative to the edge of the device housing by a distance in the range of about 0.01 mm to about 5 mm, about 0.1 mm to about 3 mm, or about 0.5 mm to about 2 mm. May be.

  In some variations, as shown in FIGS. 2A-2C, the device tip is also positioned at a distance from and perpendicular to the annulus ocular surface and the corneal sclera edge. And a measuring member that helps to determine. In one variation, the measurement component (20) is located on one side of the device tip (22). In another variation, more than one measurement component is located on more than one side of the device tip. Here, the tip of the measurement component is flat (FIG. 2C) and does not substantially protrude above the eyepiece surface. In another variation, the tip of the measurement component is raised above the eyepiece (FIGS. 2A-2B), which prevents the eyelid from sliding over and over the measurement component Thus preventing the eyelid from contacting the device tip or the sterile eyepiece surface of the dispensing member. This in turn may reduce the risk of accidental contamination and intraocular infection during the injection procedure.

  In other variations, the eyepiece surface comprises a flange (eg, FIGS. 3A1-3A3, FIGS. 3B1-3B3, FIGS. 4A, and 4B1-4B2). The flange provides an extended contact surface between the device tip and the eye surface, thus increasing the stability of the device when placed on the eye surface and per unit area of the device-eye interface The pressure of can be reduced. Secondly, reducing the pressure per unit area of the device-eye interface may reduce the possibility of conjunctival damage due to the device tip when pressed against the eye wall. Since the conjunctiva is covered by a delicate non-keratinized epithelium containing multiple sensory nerve endings and pain receptors, it is desirable to avoid such conjunctival damage.

  In some variations, the flange is in contact with the surface of the eye, allowing the eyelid to slide over and over the flange, but the eyelid is in contact with the sterile eyepiece of the device tip It may have a thin edge to prevent. The eyepiece surface may also be an annular flange (eg, FIGS. 4A and 4B1-4B2). Such an annular flange may also prevent the eyelid from coming into contact with the sterile eyepiece surface of the device tip.

  More specifically, as shown in FIG. 3, the flange may have a thin edge (FIG. 3A1) that allows the eyelid to slide on the flange and contact the shaft at the tip of the device. Good. As an alternative variation, the flange may be thick to prevent the eyelid from sliding on it, to contact the device shaft, and thus to prevent inadvertent contamination of the injection site. (FIG. 3B1). When the flange on the eyepiece at the tip of the device is thick, its edges, such as those on the surface of the eye, are covered with a delicate non-keratinized epithelium rich in nerve endings and pain receptors, etc. It may be rounded to prevent accidental damage to the surface tissue. In an alternative variation of the device tip, the eye contact interface facilitates the penetration of the needle through the eye wall, as well as partly aligning the eye during the injection procedure by providing an ocular traction friction interface. Flatten to reduce the chance of accidental damage to the surface tissue of the eye, such as the conjunctiva, while applying a force on the eye wall to provide immobilization and providing a means to increase intraocular pressure. 3A1 and 3B1), convex (FIGS. 3A2 and 3B2), or concave (FIGS. 3A3 and 3B3). 4A and 4B1-4B2 illustrate perspective and front views of the flanged eyepiece.

  In further variations, the eyepiece surface may be configured to be flat, convex, concave, or inclined (eg, FIGS. 5 and 7). In FIGS. 5A1-5A2, the device tip has a flat eyepiece. In an alternative variation, the device tip may be a protrusion or a protrusion that may improve contact between the internal opening of the device tip and the eye surface when the device tip is pressed against the eye wall, resulting in a dimple in the eye wall. It has a convex eyepiece (FIG. 5B1-5B2). In yet another variation, the ocular surface at the tip of the device is concave or concave, reducing the risk of accidental damage to the surface tissue of the eye, such as the conjunctiva. Such a configuration of the eyepiece at the tip of the device facilitates the penetration of the needle through the eye wall as well as in part during the injection procedure by providing a traction friction interface between the device and the eye surface. For immobilization, the possibility of accidental damage to the surface tissue of the eye, such as the conjunctiva, may be reduced while providing a means to apply force on the eye wall and increase intraocular pressure.

  More specifically, as shown in FIG. 7, the eyepiece surface may be flat and perpendicular to the major axis of the device (FIGS. 7A1-7A2), or flat and relative to the major axis of the device. Tilted (7B1-7B2) (eg, oriented at an angle other than 90 degrees, such as about 45 degrees to about 89 degrees with respect to the long axis of the device), or convex and perpendicular to the long axis of the device Yes (FIG. 7C1), or convex and inclined with respect to the long axis of the device (FIG. 7C2), or rounded (FIG. 7D), or oval (FIG. 7E). In one variation, the eye interface is rounded or oval (eg, similar to the tip of a Q-tip). The thickness of the ocular surface may be from about 0.01 mm to about 10 mm, from about 0.05 mm to about 5 mm, or from about 0.1 mm to about 2 mm.

  The ocular surface may include one or more features that help it stabilize on the surface of the eye. For example, in one variation, the ocular surface comprises a plurality of traction friction elements, such as steps, ridges, etc., that increase the surface traction friction of the ocular surface on the surface of the eye without polishing. Such an eyepiece also provides a medium or high traction interface to stabilize the device on the surface of the eye and prevent it from moving during intraocular drug delivery. Good. In another variation, the eyepiece surface includes an adhesive interface such as a suction mechanism. Changing the type of material used to make the eyepiece may also help prevent its sliding on the surface of the eye.

  The material used to make the ocular surface may also help to prevent abrasion, scratching, or irritation of the eye surface. Exemplary non-abrasive materials that may be employed include, but are not limited to, nylon fibers, cotton fibers, hydrogels, spongy materials, expanded styrene materials, other foamed materials, silicones, plastics, PMMA, polypropylene, Including polyethylene, fluorinated ethylene propylene (FEP), and polytetrafluoroethylene (PTFE). These materials may be smooth, hard, semi-rigid, or soft to prevent conjunctival wear such as subconjunctival hemorrhage during transscleral needle deployment, or other accidental trauma to the surface tissue of the eye It may be particularly beneficial (FIG. 6). Materials typically used in contact lens manufacture may also be employed.

  In some variations, the edge of the ocular surface also prevents accidental damage to the surface tissue of the eye, such as the conjunctiva covered with delicate non-keratinized epithelium rich in nerve endings and pain receptors To be rounded. In this case, as shown in FIG. 6, the eyepiece surface may have a circumference corresponding to the circumference of the tip of the device (FIGS. 6A1-6A2). In other variations, the circumference of the eyepiece surface may protrude beyond the circumference of the shaft at the tip of the device to form a flange (FIGS. 6B1-6B2). The flange may increase the eyepiece surface of the device tip while maintaining the narrow profile of the shaft at the tip and allowing its easy insertion into the eyelid intercostal fissure.

  The ocular surface may also be flexible or deformable to provide an inner surface that matches the ocular surface when placed against the ocular surface during an intraocular drug delivery procedure. The surface of the eye that is in direct contact with the inner surface of the disclosed device is about 2 mm to 7 mm posterior to the edge, and the circumferential region surrounding the edge, or between about 2 mm forward and about 2 mm posterior of the edge, and Including, but not limited to, the surface of the eye covering the flat area defined as the corneal scleral rim area at the periphery of the rim. An interface that matches the curvature of the surface of the eye may allow for the formation of an optimal contact interface between the device and the eye, and may ensure sterility and ocular immobilization of the intraocular drug delivery process, Second, the safety of the injection procedure can be enhanced. Examples of ocular surface materials of the device are generally on the surface of the eye (which is deformable or flexible), particularly in the flat area about 2-5 mm behind the corneal sclera edge for intravitreal drug application. Can match the curvature of the outer surface of the eye, as well as the area of the corneal sclera margin for anterior chamber drug application. As mentioned above, materials that do not polish the non-keratinized conjunctiva and corneal epithelium on the surface of the eye may be used. Specifically, the materials and their composition (eg, foam, blaze, knitted fabric, woven fabric, fiber bundles, etc.) form a medium or high traction friction surface that allows for fixation of the eyeball during the injection procedure. Can be included (eg, hydrogel or cotton).

  In some variations, the ocular surface material is fluidized by reducing its traction coefficient of friction, such as in cotton fibers that may reduce the risk of conjunctival wear during eye contact with the ocular surface. Changes its properties when in contact with. In other variations, the material comprising the eyepiece does not change its physical and chemical properties when exposed to a fluid covering the surface of the eye, such as tears.

  The ocular surface described herein may be beneficial in preventing conjunctival and / or superior scleral hemorrhage during intraocular needle injection. For example, a device with an annular eye interface may be pressed against the eye wall, which in turn applies pressure to the conjunctival and superior scleral blood vessels, thereby reducing blood flow therethrough. Considering the reduced blood flow through these vessels, the risk of subconjunctival hemorrhage during intraocular injection procedures can be reduced. After completion of intraocular drug application, the needle is withdrawn, but the annular tip may remain pressed against the eye wall, thus applying continuous pressure on the conjunctiva and superior scleral vessels, Reduce the risk of bleeding and / or minimize the degree of bleeding.

  In some variations, the device comprises an eyepiece that functions as a drug reservoir. Here, the drug may be incorporated into or coated on the ocular surface material. The drug may then diffuse from the eyepiece surface onto the surface of the eye, stick, etc. Exemplary materials for containing the drug are hydrogels and their derivatives.

  The ocular surface may also dispense a dispensing member (such as an infusion needle) that may allow the injector to apply pressure onto the eye by pressing the tip (eg, the distal end of the cap) against the eye wall. Conduit) (eg, a cap that completely covers the needle). This in turn may increase the intraocular pressure before the needle contacts the eye wall, thus making the eye wall more strained compared to the eye wall being penetrated by the needle on a conventional syringe. Therefore, the needle can be easily penetrated. Needle penetration is typically more difficult with conventional syringes because the lower intraocular pressure produced makes the eye wall more deformable and movable. In addition, the tip of the device covering a dispensing member (conduit) such as an injection needle may also protect the dispensing member from being contaminated by its accidental contact with the eyelid.

(Intraocular pressure control mechanism (ocular wall tension control mechanism))
Control of intraocular pressure (IOP) during drug delivery procedures such as intraocular injection or intravitreal injection may be beneficial. Application of limited intraocular pressure prior to deployment of the dispensing member (conduit) may reduce scleral flexibility, which in turn reduces discomfort on the surface of the eye during the injection procedure, and / or Or the repulsion of a device can be prevented. The term “repulsion” typically refers to the flexibility and elasticity of the sclera that causes the sclera to dent to a point and push the conduit and device backwards before the conduit penetrates the sclera. It means that it cannot penetrate the eye wall smoothly. Thus, the devices described herein may include one or more IOP control mechanisms, also referred to herein as eye wall tension control mechanisms. This is because eye wall tension is proportionally related to intraocular pressure and is determined in part by intraocular pressure. Other factors that can affect wall tension are the thickness and stiffness of the sclera, which can vary with patient age, gender, and individual differences.

  The IOP mechanism controls the placement and placement of the device tip at the target location on the surface of the eye and / or the placement of the dispensing member (conduit) in the eye or in the vitreous during intraocular or intravitreal injection of the drug Can do. For example, the IOP mechanism may control the IOP before or during placement of the dispensing member used for transscleral or transcorneal penetration in the eye or in the vitreous. Once penetration of the eye surface by the dispensing member occurs, IOP typically decreases. This decrease in IOP may occur immediately after penetration of the eye surface by the dispensing member.

  In some variations, the IOP control mechanism generates a 15-120 mmHg IOP during device placement and placement at the target location on the surface of the eye and / or placement of the dispensing member in the eye. Allow (allow). In other variations, the IOP control mechanism may cause the device to generate an IOP of 20-90 mmHg during placement and placement of the device tip at a target location on the surface of the eye and / or during placement of the dispensing member in the eye. Is allowed (allowed). In a further variation, the IOP control mechanism may cause the device to generate an IOP of 25-60 mmHg during placement and placement of the device tip at a target location on the surface of the eye and / or during intraocular placement of the dispensing member. Allow (allow).

  The IOP control mechanism also allows (allows) the device to maintain an IOP of 10-120 mmHg, or 15-90 mmHg, or 20-60 mmHg during any duration of the intraocular injection procedure. In some variations, when the intraocular pressure exceeds a certain predetermined value, eg, 120 mmHg, or 60 mmHg, or 40 mmHg, the drug infusion rate is slowed down by the device or is completely discontinued. Here, the IOP control mechanism may be configured to detect an IOP level during, for example, 90 mmHg, or 60 mmHg, or 40 mmHg intraocular drug infusion.

  The IOP control mechanism may include a spring or may comprise a mechanical or electrical control mechanism. In general, the IOP control mechanism is configured to balance the friction force of the injection plunger and the fluid injection resistance pressure (the force required to push the fluid through the needle into the pressurized eye fluid). The IOP control mechanism may be coupled to the device housing and actuation mechanism in a manner that allows automatic adjustment of the dispensing member deployment and plunger advance forces. That is, the IOP control mechanism may be configured to achieve a predetermined level of force and a predetermined intraocular pressure level of the dispensing member. Again, the use of the IOP control mechanism is less than the rest before deployment of the dispensing member so that the scleral elasticity and the possibility of device repulsion are reduced and to facilitate penetration of the sclera by the dispensing member. Higher IOPs may be generated.

  In one variation, the IOP control mechanism is a pressure relief valve that bypasses the injection flow once the maximum pressure is reached. In another variation, the IOP mechanism is a pressure accumulator that attenuates the IOP within a specified range. Some variations of the IOP control mechanism may include a pressure sensor. In yet another variation, the IOP control mechanism covers the dispensing member prior to its deployment, but may, for example, expose, deploy, or advance the dispensing member upon reaching a predetermined IOP level. A slidable cap that can slide or retract along the surface of the device housing. The sliding of the cap may be manually adjustable using, for example, a dial, or may be automatically adjustable, stepped, or incremental in nature. For example, as shown in FIG. 40, the integrated infusion device (500) includes, among other elements, a cap (502), a stop (504), a trigger (506), a spring (508), a plunger ( 510), a seal (512), a drug reservoir (514), a needle (516), and a syringe (518). In use, as the cap (502) is placed against the eye surface and the pressure is applied against the eye surface, the syringe (518) and needle (516) are advanced as the cap (502). Is slidably retracted proximally (in the direction of the arrow) to the stop (504). A trigger (506), e.g., a lever, may then be depressed to release the spring (508), which will inject the drug from the drug reservoir (514) through the needle (516) ( 510) and seal (512) are advanced. Once the drug is injected, the cap (502) slides back over the needle (516).

  The locking mechanism may also be used to prevent sliding of the cap, cover, or eyepiece surface or to prevent deployment of the dispensing member until a predetermined IOP is reached. The locking mechanism may also be used to prevent sliding of the cap, cover, or eyepiece when the predetermined IOP is not reached. For example, the locking mechanisms included on the devices described herein, including slidable covers, caps, etc., can be performed manually when the IOP reaches a predetermined level, such as between 20 mmHg and 80 mmHg, or It may be automatically released. Such locking mechanisms are not limited and include high traction friction surfaces, locking pins, interlocking raised ridges, or the tip of the device, e.g., the device cap or cover sliding, Thus, any other type of locking mechanism that prevents the needle from being exposed may be included.

  In a further variation, the IOP control mechanism includes a high traction friction surface or raised ridge on a cap, cover, or eyepiece surface located over the dispensing member. Such features may be located on the inner surface of the cap, cover, or eyepiece surface, and when slid proximally, a high traction friction surface or raised ridge may result in a device housing or other suitable Engage with corresponding structures on the surface of the device component (eg, wrinkles, indentations, protrusions, other raised ridges) to provide cap, cover, or ocular resistance to the eye wall ( Thus, it may be configured to increase eye wall tension and IOP). In this case, the IOP control mechanism comprises a dynamic resistance component, as will be further described below. As noted above, the cap, cover, or eyepiece surface may be configured such that sliding is manually or automatically adjustable, stepped, or essentially incremental. Where raised ridges are utilized, any suitable number may be used and they may be any suitable size, shape, and geometry. For example, the raised ridges may be placed circumferentially within the cap, cover, or eyepiece. In some cases, the raised ridges are constructed with different sloped surfaces. For example, the distal surface may be configured to be steeper than the proximal surface. In this design, incremental sliding and incremental increase in IOP can be generated when the cap, cover, or eyepiece is slid proximally, but the cap, cover, or on the dispensing member Sliding back of the eyepiece surface may also be accomplished by a reduced slope of the proximal raised surface.

(Dynamic resistance component)
Application of pressure to the surface of the eye may be achieved and further refined by including a dynamic resistance component in the injection device. The dynamic resistance component may include a slidable element coupled to the housing. In some variations, the slidable element comprises a dynamic sleeve configured to adjust the amount of pressure applied to the ocular surface, as further described below. As described above, certain variations of the eye wall tension control mechanism function as dynamic resistance components.

  The dynamic resistance component may also be configured as a dynamic sleeve. Similar to the slidable cap previously described, the dynamic sleeve may be configured to increase intraocular pressure and eye wall tension prior to needle injection. However, the dynamic sleeve can be operated manually, thereby adjusting the amount of pressure applied on the surface of the eye (and thus the amount of eye wall tension). Having the ability to manually adjust the applied pressure may allow the injector (user) to have improved control of the injection site placement and injection angle, and also on the surface of the eye prior to needle deployment. Increase the user's ability to stably install the device. In general, the dynamic sleeve allows the user to accurately place the device tip at a target site on the surface of the eye and to press the device tip firmly against the eye wall to increase wall tension and intraocular pressure. Designed to be The dynamic sleeve may be used to increase intraocular pressure to a predetermined level, as described above, prior to the start of sleeve movement and needle deployment. It should be understood that the terms “dynamic sleeve”, “sleeve”, “dynamic sleeve resistance control mechanism”, and “sleeve resistance mechanism” are used interchangeably throughout. The dynamic sleeve generally facilitates exposure of the needle when the user exerts a pulling force (eg, retraction) on the sleeve, and the eye wall to slide the sleeve back to expose the needle. Configured to be able to reduce the amount of pressure that needs to be applied to (up to 0 Newton) ("N" refers to the force unit "Newton"). The dynamic sleeve may also prevent this movement against the needle exposure when the user exerts a pushing force on the sleeve (e.g., advancement), and the device tip is It may be configured to allow an increased pressure to be applied to the eye wall.

  Some variations of the dynamic sleeve provide a variable force that follows a U-shaped curve, as further described in Example 1 and FIG. Here, maximum resistance is encountered at the beginning and end of dynamic sleeve movement along the housing, with reduced resistance between the start and end of the dynamic sleeve movement. In use, this translates to having an initial high resistance phase (during initial placement on the eye wall) followed by a decrease in resistance to sleeve movement during advancement of the needle into the eye cavity. When the needle is fully deployed, the dynamic sleeve is typically at the end of its travel path and again encounters increased resistance. This increase in resistance forces minimizes the risk that the sleeve will stop smoothly (instead of a sudden sudden stop at the end point) and transmit a damaging amount of force to the inert eye wall (then Minimizing the risk of causing discomfort or damage to the eyes). Here, the exemplary dynamic sleeve may be configured to taper at the proximal and distal ends. Referring to the cross-sectional view of FIG. 42, the integrated infusion device (42) includes a housing (44), a resistance band (46) that totally or partially surrounds the housing, and a slide on the housing (44). And a dynamic sleeve (48) that can be movably advanced and retracted. The dynamic sleeve (48) has a proximal end (50) that is tapered and a distal end (not shown). The tapered end may provide higher traction friction at the beginning and end of the dynamic sleeve travel path along the device housing (44) (at the beginning or end of needle deployment). The taper at the proximal end (50), when in contact with the resistance band (46), provides higher traction friction and resistance at the beginning of dynamic sleeve movement. The thickness of the resistance band (46) may be varied to adjust the amount of resistance desired. Upon reaching the wider middle segment (52), lower traction friction and lower drag movement are encountered, and then at the end of needle deployment as the taper at the distal end of the dynamic sleeve is reached. Higher traction and higher resistance follow. As the dynamic sleeve gradually tapers at the distal end, additional traction friction is generated against the device housing until it gradually stops completely. Instead of being tapered at both ends, in some variations, one of the proximal and distal ends of the dynamic sleeve may be tapered.

  Variable traction friction may also be provided by components such as a round raised band or ridge on the outer surface of the device tip. These components may also provide opposing traction friction when brought close to another circular raised band or ridge (inner band or ridge) on the inner surface of the movable dynamic sleeve. Good. When the outer and inner bands or ridges are in contact with each other before the dynamic sleeve begins to move, they produce high traction friction and high resistance to dynamic sleeve movement. Once the dynamic sleeve begins to move, the raised band on the outside of the device housing moves beyond the raised band on the inside of the dynamic sleeve, which rapidly reduces resistance to dynamic sleeve movement. Thus, it can result in reduced pressure on the eye wall by the device tip. The raised interlock band or ridge shape generally determines the shape of the drag reduction. For example, the resistance reduction may follow a sinusoidal outline.

  In another variation, when the dynamic sleeve begins to move to expose the needle tip, the dynamic sleeve moves from its highest point before needle deployment (when the dynamic sleeve completely covers the needle). A force that continuously decreases to its lowest point may be generated. Here, the force remains low until the end of the dynamic sleeve completes movement and needle deployment. This resistance reduction pattern may follow a sinusoidal curve.

  The slidable movement of the dynamic sleeve may generate a force in the range of 0N to about 2N between itself and the housing. In some cases, the slidable movement of the dynamic sleeve generates a force in the range of about 0.1 N to about 1 N between itself and the housing.

(Measurement component)
The devices described herein may include a measurement component that may be useful in determining the location of an intraocular injection site on the surface of the eye. An integrated device generally includes a measurement component. The measurement component may be fixedly attached to the eyepiece surface or removably attached. As previously described, the measurement component may be raised above the surface of the eye to prevent the eyelid from contacting the sterile eyepiece at the tip of the device (FIGS. 2A-2B and 8). Certain configurations of measurement components may also help minimize the risk of accidental contamination of sterile drug dispensing members (conduits) such as injection needles. Such contamination may be due to a variety of causes, such as a sterile needle that inadvertently contacts the eyelids or other non-sterile surfaces. The measurement component may also be colored in a manner that provides a color contrast to the surface of the eye, including the conjunctiva, sclera, and iris.

  In general, the measurement component allows the intraocular injection site to be placed more precisely at a specific distance from and behind or in front of the cornea-scleral junction called the “edge” . In some variations, the measurement component provides placement of an intraocular injection site from the edge and about 1 mm to about 5 mm, about 2 mm to about 4.5 mm, or about 3 mm to about 4 mm behind the edge. Also good. In another variation, the measurement component may provide placement of an intraocular injection site about 2 mm to about 5 mm behind the edge, or about 3.5 mm behind the edge. In other variations, the measurement component provides placement of an intraocular injection site from the edge and within about 3 mm or about 2 mm of the edge or from the edge and about 0.1 mm to about 2 mm in front of the edge. May be. In one variation, the measurement component provides an intraocular injection site placement between about 1 mm forward of the edge and about 6 mm behind the edge. In another variation, the measurement component provides for placement of the inner injection site about 3 mm to 4 mm behind the edge.

  The measurement component may have any suitable configuration. For example, the measurement component may be located on one side of the ocular surface, or on more than one side of the ocular surface (eg, FIGS. 9, 10, and 11). Here, when the tip of the measurement component is placed immediately next to the corneal sclera edge, the site of intraocular needle injection is at a certain distance from the edge, eg, about 3 mm to about 4 mm behind the edge. Placed in.

  In alternative variations, the measurement component comprises one or more members (eg, FIGS. 9, 10, and 11). These members may extend radially from the eyepiece surface. Having more than one member with the measurement component means that the distance between the edge and the injection site is perpendicular to the edge and when the measurement means comprises a single member, and It may be beneficial to ensure that it is measured in a non-tangential direction. When the tips of all members comprising the measurement component are aligned along the corneal sclera edge, the site of intraocular needle injection is at a specific distance from the edge, such as about 3 mm to about 4 mm behind the edge. Arranged.

  More specifically, as shown in FIG. 8, a device tip having an ocular surface includes a measurement component (80) that allows determination of an injection site at a distance from the corneal sclera edge. Prepare. As described above, in one variation, the measurement component is located on one side of the device tip. In another variation, more than one measurement component is located on more than one side of the device tip. In a further variation, the tip of the measurement component may be raised, bent, etc., so that the eyelid slides on the measurement component and accidentally contacts the dispensing member (conduit) of the device. To prevent. Also, in FIG. 8, the dispensing member (conduit) is shown as being completely shielded inside the device tip.

  FIG. 9 provides further details regarding another variation of the measurement component. Here, the device tip comprises an annular eyepiece (90) and a measurement component (91) that allows the determination of the injection site at a distance from the corneal sclera edge. The outer circumference of the device tip that contacts the surface of the eye may have, for example, a ring-shaped eye interface, and a dispensing member such as an injection needle may be concealed and protected by the inside of the device tip. In FIG. 9, the measurement component (91) is located on one side of the device tip (FIGS. 9A-9B) or on more than one side of the device tip (FIG. 9C). Thus, when the tip of the measurement component is placed next to the corneal sclera edge, the site of intraocular needle injection is placed at a specific distance from the edge, such as about 3 mm to about 4 mm behind the edge. . Any suitable member of the measurement component may be provided on the device tip, for example attached to the eyepiece. When multiple measurement components are used, they may be disposed around the eyepiece surface in any suitable manner. For example, they may be arranged circumferentially around the eyepiece surface or on one side of the eyepiece surface. They may be evenly or unevenly spaced around the circumference of the eye surface. In other variations, the measurement components may be spaced from the object around the circumference of the eyepiece surface, or asymmetrically spaced. These configurations may be beneficial in allowing the injector to rotate the device along its long axis.

  10A-10C provide additional views of the measurement components similar to those shown in FIGS. 9A-9C. In FIG. 10, the annulus ocular surface (93) has a measurement component (93) that allows the determination of the injection site at a distance to and perpendicular to the corneal sclera margin (94). Is shown. The measurement component is displayed on one side of the device tip or, in another variation, on more than one side of the device tip. Again, the measurement component may comprise one or more members. Having more than one member with a measurement component means that the distance between the edge and the injection site is perpendicular to the edge, as is the case when the measurement component comprises a single member. And may be beneficial to ensure that it is measured non-tangentially. When the tips of all members comprising the measurement component are aligned along the corneal sclera edge, the site of intraocular needle injection is at a specific distance from the edge, such as about 3 mm to about 4 mm behind the edge. Arranged.

  More than one measurement component is also shown in FIGS. 11A-11D. Here, the measurement component (95) is displayed as extending from the common attachment point (96) on the eyepiece. When the tips of all members comprising the measurement component are aligned along the corneal sclera edge, the site of intraocular needle injection is a specific distance from the edge, such as about 3 mm to about 4 mm behind the edge. Placed and placed.

  Alternatively, the measurement component may be configured as one or more flexible measurement strips. Flexible materials that may be used to make the measurement strip include flexible polymers such as silicone. As shown in FIG. 44A, the measurement strip (800) can be moved from the device tip (802), usually the eyepiece surface (804), so that the distance between the edge and the injection site can be measured perpendicular to the edge. ) May extend from the side. A position indicator component (806) may be employed to ensure that the measurement strip (800) is being used properly. For example, as shown in FIG. 44B, when the position indicator component is substantially tensioned (as an angle of 90 degrees is formed between the measurement strip and the device housing (808)). ) The correct placement of the measurement strip (800) may be determined. In contrast, a loose position indicator component (as shown in FIG. 44C) indicates an incorrect installation. The position indicator component may be a code. In one variation, the integrated device comprises at least three measurement strips. In another variation, the integrated device includes at least four measurement strips. When multiple measurement strips are used, they may be configured in any suitable manner around the tip of the integrated device (of the ocular surface, spaced evenly around the circumference of the ocular surface) Arranged symmetrically or asymmetrically around the circumference). For example, as shown in FIG. 44D, the measurement strip spans the desired 90 degree angle (45 degrees plus 45 degrees between the furthest strips) of the control lever without having to reposition the user's hand. It may be configured to allow 90 degree rotation.

  In some variations, the measurement component may be configured as a marking tip member (97). As shown in FIG. 12, the marking tip member (97) at its distal end (closer to the eye) is in interface contact with the eye surface and is visible thereon when pressed against the conjunctival surface. The mark (98) is left (for example, FIG. 13). The far end of the marker is such that intraocular injection is performed through the safety area of the eye against the corneal scleral margin (99), such as about 3 mm to about 4 mm behind the edge, covering the flat area of the ciliary body of the eye Enable. The marking tip diameter may range from about 1 mm to about 8 mm, or from about 2 mm to about 5 mm, or from about 2.3 mm to about 2.4 mm (eg, FIG. 12).

(conduit)
The intraocular drug delivery devices described herein may include any suitable conduit (or dispensing member) for accessing the intraocular space and delivering the active agent therein. The conduit may have any suitable configuration, but generally has a proximal end, a distal end, and a lumen extending therethrough. In their first undeployed (pre-deployed) state, the conduit is generally present in the housing. In their second deployed state, i.e., after activation of the actuation mechanism, the conduit or portion thereof typically extends from the housing. By “proximal end” is meant the end closest to the user's hand when the device is placed against the surface of the eye and opposite the end near the eye.

  The distal end of the conduit may generally be an ocular surface, eg, sharp, beveled, or otherwise capable of penetrating the sclera. The conduit employed may be any suitable gauge, such as about 25 gauge, about 26 gauge, about 27 gauge, about 28 gauge, about 29 gauge, about 30 gauge, about 31 gauge, about 32 gauge, about 33 gauge, It may be about 34 gauge, about 35 gauge, about 36 gauge, about 37 gauge, about 38 gauge, or about 39 gauge. The thickness of the conduit may also have any suitable wall thickness. For example, in addition to the normal wall (RW) thickness, the wall thickness of the conduit may be designated as thin wall (TW), ultra / ultra thin wall (XTW / UTW), or ultra ultra thin wall (XXTW). . These designations are well known to those skilled in the art. For example, the conduit may be a fine gauge cannula or needle. In some variations, the conduit may have a gauge between about 25 and about 39. In other variations, the conduit may have a gauge between about 27 and about 35. In a further variation, the conduit may have a gauge between about 30 and about 33.

  The conduit may have a sharp pointed tip (FIGS. 14B-14C and 15A1-15A2) rather than a rounded tip (FIG. 14A) like a conventional needle. Pointed needle tips are at their focal point to the tip from about 5 degrees to about 45 degrees (Figure 14B), from about 5 degrees to about 30 degrees, from about 13 degrees to about 20 degrees, or about 10 degrees. May be formed by an outer surface that is straight at their focal point forming a bevel angle that may range from up to about 23 degrees (FIG. 14C).

  The sharp pointed needle tip is the primary structural covering of the eye and may provide improved penetration of the needle through fibrous, fibrous scleral tissue consisting of a strong collagen fiber network. Thus, such a needle tip may produce less resistance during its penetration through the eye wall and thus reduce the impact force transmitted to intraocular structures such as the retina and the lens, , Causing less damage to intraocular structures during the intraocular injection process (compared to conventional needles).

  In addition, such a narrow bevel angle may allow the needle to cause less sensation when penetrating the eye wall (the outer envelope of the eye wall is particularly tight within the conjunctiva and cornea) It is abundantly innervated with sensory nerve fiber endings located), which can be a problem when intraocular injection is involved compared to other less sensitive sites.

  A narrow bevel angle may also allow for a longer bevel length and a larger bevel opening, and thus a larger opening at the distal end of the injection needle. In such a configuration, the force of drug injection into the ocular cavity may be reduced, and therefore intraocular due to the forced flow of the injected substance, which may occur with conventional short-graded needles. Reduce the possibility of tissue damage.

  In some variations, the conduit is an injection needle having one or more planes and one or more side cut surfaces, as illustrated in FIGS. Examples include a needle shaft with multiple surfaces separated by sharp ridges (FIGS. 16A-16C), and a needle tip with sharp side cuts located on either side of the beveled surface at about 90 degrees from the beveled surface. including. The conduit may also be beveled on both sides, i.e., having two bevels facing each other at approximately 180 degrees from the opposite sides of the conduit. The conduit may also be coated (eg, with silicone, PTFE, etc.) to facilitate its penetration through the eye wall (FIG. 17).

  In other variations, the conduit is configured to be wholly or partially flat in at least one dimension, as shown in the cross-sectional view of FIG. 18C taken along line AA of FIG. 18A. May be. For example, the conduit may be flat in the anterior-posterior dimension (from the beveled side of the needle to the opposite side). In one variation, both the outer and inner surfaces of the needle are flat and represent oval in cross section. In another variation, the inner surface of the needle is round and represents a circle in cross-section while the outer surface of the needle allows its easier penetration through the fibrous sclera or corneal tissue of the eye wall It is flat. In another variation, more than one outer surface of one of the needles is flat to allow its easier penetration through the fibrous eye wall, while the inner opening of the needle is circular Or any shape including an oval shape may be sufficient.

  As previously described, in its second deployed state, the conduit or needle extends from the housing. The portion of the needle extending from the housing can be referred to as the exposed needle length. Upon activation of the actuating mechanism, the needle moves from a first undeployed state (pre-deployment state) (the needle is completely within the device housing) to the outside of the housing where its length is exposed. This is the second deployment configuration. This exposed length may range from about 1 mm to about 25 mm, from about 2 mm to about 15 mm, or from about 3.5 mm to about 10 mm. These exposed needle lengths allow full intraocular penetration through the sclera, choroid, and ciliary body into the vitreous cavity while minimizing the risk of intraocular damage. Also good. In some variations, the length of the exposed needle ranges from about 1 mm to about 5 mm, or from about 1 mm to about 4 mm, or from about 1 mm to about 3 mm. Here, the length of the exposed needle may allow full intraocular penetration through the cornea into the anterior chamber while minimizing the risk of intraocular damage.

  In some variations, the device may include an exposure control mechanism (9) for the dispensing member (11) (conduit) (FIGS. 19 and 20). The exposure control mechanism (9) generally allows setting the maximum length of the dispensing member during dispensing member deployment. In one variation, the exposure control mechanism operates by providing an anti-reverse device for the needle protection member (13). In another variation, the exposure control mechanism (9) may be a rotating ring member with a dialable gauge. Needle exposure can be adjusted in millimeters or fractions of millimeters, such as 1 mm, 1.5 mm, 2 mm, 2.5 mm, 3 mm, and the like. Here, the device may be equipped with a retraction mechanism for controlling the needle retraction into the needle protection member. Such a needle retraction mechanism may be a spring operated type (FIG. 20).

  The device may also include a removable distal (toward the eye) member that covers and protects the conduit (eg, the front cover (15) of FIG. 21). In one variation, the device also has a removable proximal (such as comprising a loading dock mechanism (17) (eg, back cover (19) of FIG. 21)) that covers and protects the proximal portion of the device. It may include a member (away from the eye).

(Reservoir)
The reservoir is generally configured in any suitable manner as long as it is contained within the housing and is capable of delivering the active agent to the intraocular space using the actuation mechanism described herein. May be. The reservoir may hold any suitable drug or formulation, or combination of drugs or formulations, in the intraocular space, eg, the vitreous space. It should be understood that the terms “agent” and “agent” are used interchangeably herein throughout. In one variation, the drug reservoir does not contain silicone oil (lack of one of the silicone oils or derivatives thereof) and is internally covered or lubricated with silicone oil or derivatives or modifications thereof. Make sure that the silicone oil does not enter the inside of the eye and cause floating or increased intraocular pressure. In another variation, the drug reservoir does not contain any lubricant or sealant, and is not covered or lubricated with any lubrication or sealing material, and the lubrication or sealing material is inside the eye. Enter and ensure that it does not cause flying mosquito disease or increased intraocular pressure.

In some variations, the reservoir is a cyclic olefin resin, Zeonex® cycloolefin polymer (ZEON Corporation, Tokyo, Japan) or Crystal Zenith® olefin polymer (Daikyo Seiko, Ltd., Tokyo, Japan), and cyclic olefin ethylene copolymers, cyclic olefin ethylene copolymers, polyethylene terephthalate resins, including commercially available products such as APEL ^™ cycloolefin copolymer (COC) (Mitsui Chemicals, Inc., Tokyo, Japan) , Polystyrene resin, polybutylene terephthalate resin, and combinations thereof. In one variation, it has high transparency, high heat resistance, and minimal chemical interaction with pharmaceuticals such as proteins, protein fragments, polypeptides, or chimeric molecules including antibodies, receptors, or binding proteins It may be beneficial to use cyclic olefin-based resins and cyclic olefin ethylene copolymers with little or no.

  Exemplary agents are anti-inflammatory drugs (eg, steroidal and non-steroidal), anti-infectives (eg, antibiotics, antifungals, anthelmintics, antivirals, and antiseptics), cholinergic antagonists and agonists , Adrenergic antagonists and agonists, antiglaucoma, neuroprotective, cataract prevention or treatment, antioxidant, antihistamine, antiplatelet, anticoagulant, antithrombotic, antiscarring, antiproliferative Antitumor agents, complement inhibitors (eg, anti-C5 agents including anti-C5a and anti-C5b agents), vitamins (eg, vitamin B and its derivatives, vitamin A, dexpantenol, retinoic acid), growth factors, growth Agents that inhibit factors, gene therapy vectors, chemotherapeutic agents, protein kinase inhibitors, tyrosine kinase inhibitors, PEGF (pigment epidermal growth factor), small interfering RNA Their analogs, derivatives, complexes, and modifications thereof, as well as may be selected from the class of such combination thereof.

Non-limiting specific examples of agents that may be used alone or as part of a combination drug therapy include Lucentis ^™ (Ranibizumab), Avastin ^™ (Bevacizumab), Macugen ^™ (Pegaptanib), steroids such as Dexamethasone, dexamethasone sodium phosphate, triamcinolone, triamcinolone acetonide, and fluocinolone, taxol-like drug, integrin or anti-integrin agent, vascular endothelial growth factor (VEGF) trap (aflibercept), annecortab acetate (Retaane), and limus Group compounds. Non-limiting examples of components of the Limus family compounds include sirolimus (rapamycin) and its water-soluble analogs SDZ-RAD, tacrolimus, everolimus, pimecrolimus, and zotarolimus, and analogs, derivatives, complexes, salts, And modifications, and combinations thereof.

  A local anesthetic may also be included in the reservoir. For example, lidocaine, proparacaine, prilocaine, tetracaine, betacaine, benzocaine, ELA-Max®, EMLA® (eutectic mixture of local anesthetics), and combinations thereof may be used.

  The reservoirs and devices described herein may be suitable for intraocular administration of very small volumes of solutions, suspensions, gels, or semi-solid materials. For example, a volume of between about 1 μl to about 200 μl, or between about 10 μl to about 150 μl, or between about 20 μl to about 100 μl may be delivered. To that end, the device generally has a very small “dead space”, which allows a very small volume of intraocular administration.

  The device reservoir may be preloaded during the manufacturing process, as described further below, or manually loaded prior to intraocular injection.

(Medicine loader)
A loading member may be employed when the drug or formulation is loaded into the reservoir of the device prior to intraocular injection. The loading member may be removably attached to the distal end of the housing. For example, the loading member may function as a loading dock that quantitatively controls the volume of liquid, semi-liquid, gelatinous, or suspended drug loaded into the device. For example, the loading member may include a dial mechanism (21) that allows the operator to preset a specific volume of drug to be loaded into the device (FIGS. 21 and 22). Loading may occur with an accuracy ranging from about 0.01 μl to about 100 μl, or from about 0.1 μl to 10 μl. Such a loading member can store liquid, semi-liquid, gelatinous, or suspended drug in the device at a specific volume below the capacity of the drug storage container, allowing air-free loading of the drug into the device. It may be possible to load the part. This is beneficial because the air injected into the eye provides the sensation of seeing "float" by the patient, which can be uncomfortable and disturbing to the patient, especially during driving or other similar activities. Also good.

  As shown in FIG. 22, the drug loading mechanism (23) has a wide base member (25) for upright loading of the reservoir (27) through its proximal (further away from the eye) end (29). Including. Also shown are exemplary front (31) and back (33) covers and a dialable control mechanism (21) for setting the loading and / or infusion volume. In other variations, the device comprises a loading mechanism, such as a loading dock (35A), where the dock (35A) is in interface contact with a drug storage container (FIGS. 25A-25B) such as a vial known to those skilled in the art, The vial stopper is penetrated to gain access to the medication contained inside the vial so that the medication can be loaded into the device reservoir. In FIGS. 25A-25B, the docking mechanism is located in a dependent position such that the drug vial (37) is placed directly above the dock so that the drug moves downward from the vial in the direction of gravity.

  In one variation, the dock mechanism comprises a needle or sharp cannula with an opening or fenestration (39) at its base. The opening or fenestration is placed directly adjacent to the inner surface of the vial stopper when the loading dock penetrates into the drug vial while in the desired loading position, which is then into the device. Allows airless loading as well as complete drug removal from the storage container. Airless drug loading may be beneficial because it may prevent the patient from seeing small intraocular bubbles or “floats”. Complete drug removal may also be beneficial considering the low drug volume and the expensive drugs typically used.

  In other variations, for example, when the device has a flat side (FIGS. 24A-24D) or has a flat front or back (FIG. 22), the loading mechanism is positioned 180 degrees from the plane. including. This makes the loading dock straight up, which allows its penetration into the drug container in a subordinate position, which in turn will deliver airless drug delivery into the device as well as in the storage container Allows complete drug removal from the storage container and its loading into the device without drug placement or loss.

  In a further variation, as shown in FIGS. 33A-33B, an access port (144) that allows medication from the storage container (146) to be loaded into the reservoir (122) includes a needle assembly. (125) may be provided at the distal end. Access port (144) may be located at any suitable location on needle assembly (125) or housing (102). For example, if desired, the access port may be located even on the front wall or eyepiece surface (not shown) of the housing so that drug loading occurs from the front of the device. Access port (144) may be made of a material, such as silicone, that allows sealable penetration by a sharp conduit. One or more membranes (148) may also be provided, for example, in the eyepiece surface (108) to seal the interior compartment of the housing against air leakage and / or external recent contamination. One or more small openings (150) may also be provided in the wall of the housing (102) to help control the outflow of air from the housing (102). The number and diameter of the openings (150) may be varied to control the rate of needle deployment (and needle assembly).

  In some variations, for example, when a pneumatic actuation mechanism is used, the drug loading may be controlled by the drug loading position. For example, as shown in FIG. 38, the device (400) may include a drug loading position (402) having a proximal end (404) and a distal end (406). The distal end (406) is adapted to include a threaded portion (408). Thus, during loading of drug from the container (410) through the adapter (412) and access port (414), the drug loading position (402) rotates to create a negative pressure within the reservoir (416). Can be pulled out. This negative pressure then draws the drug through the needle (418) and into the reservoir (416). A container (420) may also be provided at the distal end of the device to hold the initially loaded drug prior to transfer into the reservoir (416).

(Operating mechanism)
The devices described herein generally include an actuation mechanism within the housing that deploys a conduit from the housing and enables delivery of the drug from the device into the intraocular space. In other variations, the conduit is deployed by an actuation mechanism contained within a separate cartridge that can be removably attached to the device housing using, for example, a snap fit or other interlocking element. Is done. The actuation mechanism may have any suitable configuration as long as it provides accurate and atraumatic controlled delivery of the drug into the intraocular space. For example, the actuation mechanism may be controlled by intraocular injection at a rate in the range of about 1 μl / second to about 1 ml / second, about 5 μl / second to about 200 μl / second, or about 10 μl / second to about 100 μl / second. The drug or formulation may be delivered into it. The actuation mechanism is generally strong enough to penetrate the eye wall with the conjunctiva, sclera, and ciliary flat area, but with a needle deployment that is less than the force that causes damage to the intraocular structure due to high velocity impact You may provide the power of This force is due to several physical factors including, but not limited to, the needle gauge utilized, the speed / rate of needle deployment at the point of contact between the needle tip and the eye wall that determines the impact force. Dependent. An exemplary range of forces that may be generated by the actuation mechanism is from about 0.1 N (Newton) to about 1.0 N (Newton). The speed of needle deployment may also range between about 0.05 seconds and about 5 seconds.

  In some variations, the actuation mechanism is a single spring mechanism. In another variation, the actuation mechanism is a two spring mechanism. In a further variation, the actuation mechanism is pneumatic, for example employing a negative pressure such as a vacuum or a positive pressure driven mechanism. In a further variation, the actuation mechanism is magnetically or electrically driven, for example by a piezoelectric or magnetic rail mechanism. These types of actuation mechanisms include the rate and force of drug injection (eg, controlled by the first spring member in a two-spring variation) and the speed and force of dispensing member deployment (eg, a two-spring variation). It may be configured to allow independent control (in the example controlled by the second spring member). An exemplary two spring mechanism is shown in FIGS.

  FIG. 28 also displays an exemplary integrated intraocular drug delivery device with a two-spring actuation mechanism. In FIG. 28, the device (100) includes a housing (102) having a proximal end (104) and a distal end (106). The eyepiece surface (108) is attached to the distal end (106). The measurement component (110) is attached to one side of the eyepiece (108). As described further below, the trigger (112) operably coupled to the housing (102) deploys a pin (118) through the opening (120) of the housing (102), thereby In conjunction with the first spring (114) and the second spring (116) of the actuation mechanism to deliver the drug from the reservoir (122). The first spring (114), the second spring (116), the pin (118), the opening (120), and the reservoir (122) are better shown in FIG. Also in FIG. 29, a conduit, such as a needle (124), is displayed in the housing in its first undeployed state. Needle (124) is configured as part of assembly (125) such that movement of the assembly results in corresponding movement of needle (124). A stop (115) connected to the distal end of the first spring (114) and the proximal end of the second spring (116) is provided at the proximal end (127) of the assembly (125). . The springs, as well as the components of the device, may be connected via medical grade adhesive, friction or snap fit, and the like.

  In FIG. 30, the second spring (116) is operably connected to the plunger (132) by a friction fit within the compartment (134) of the plunger (132). In the pre-activation state, as shown in FIG. 29, the plunger (132) and the second spring (116) are held in place by the pin (118). The pin (118) is removably engaged with the plunger (132) in the plunger groove (138) and causes the plunger (132) to be in place through a friction fit to the plunger groove (138) and the housing (102). Lock.

  Activation of the first spring (114) of the actuating mechanism by activating the trigger deploys the needle (124) into the intraocular space, i.e., the needle (124) is in its first undeployed state ( 29) to its second deployed state (FIG. 30). Referring to FIGS. 30 and 31A-31C, activation of the first spring (114) occurs by depressing the trigger (112), for example by one or two fingers that also depress the button (126). As shown in FIGS. 31A and 31B, the button (126) is accompanied by a button groove (128) that allows the button (126) to align with the channel (130) in the housing (102). Composed. Once aligned with channel (130), button (126) may be slidably advanced along channel (130). The speed of movement along channel (130) may be manually controlled by the user, automatically controlled by the force of the spring expansion, or a combination of both. This movement of button (126) allows expansion of first spring (114) relative to stop (115) so that needle assembly (125) and needle (124) can be deployed. The channel in the housing may have any suitable configuration. For example, as shown in FIG. 31C, the channel (130) is within the housing to allow needle rotation or helical movement during advancement that may facilitate needle penetration through the eye wall. It may be cut in a spiral shape.

  Activation of the first spring (114) typically results in activation of the second spring (116) to deliver the drug out of the device and into the intraocular space. For example, as shown in FIG. 30, the extension of the first spring (114) relative to the stop (115) that is also connected to the proximal end of the second spring (116) causes the assembly (125) to be Operate to expand the second spring (116) for advancement in (102). As illustrated in FIGS. 32A-32C, when the pin (118) removably engaged with the plunger (132) reaches the opening (120), they are released through the opening (120). Deployed. The release of the pin (118) from the device then allows free expansion of the second spring (116) relative to the plunger (132), thereby pushing out the reservoir (122) and the existing drug from the device. The opening (120) may be covered by a membrane or seal (140) that can be penetrated by the pin (118) to provide a visual indication that the drug has been delivered.

  A two-spring actuation mechanism as shown in FIGS. 41A-41B may also be used. Referring to FIG. 41A, the integrated device (600) includes an actuation mechanism comprising a first spring (602) and a second spring (604). In use, when a trigger (606), eg, a lever, is depressed, the first spring (602) is released to advance the shaft (608) in the direction of the arrow, which is then the device (600 ) To advance the needle (610) out of the tip. Continued advancement of the shaft (608) advances the infusion sleeve (612) and top seal (614) so that medication in the reservoir (616) may be delivered through the needle (610). Referring to FIG. 41B, once the drug is injected, the tab (618) removably engages the housing opening (620), thereby releasing the second spring (604), which is then The shaft (608) is moved backward to retract the needle (610) (not shown).

  In some variations, a single spring actuation mechanism is employed, as shown in FIGS. When a single spring is used, the actuation mechanism is configured much like the two-spring mechanism described above, except that the second spring is removed. Thus, as shown in FIG. 36, in its pre-activation state, the device (300) having a single spring (302) is depressed by pressing the trigger (304), for example, one button (306). Or it can be activated by two fingers. The button (306) is configured with a button groove (308) that allows the button (306) to align with a channel (not shown) in the housing (310). Once aligned with the channel, button (306) may be slidably advanced along the channel. This movement of button (306) allows expansion of spring (302) relative to plunger (312) so that needle assembly (314) and needle (316) can be deployed. When the pins (318) removably engaged with the plunger (312) reach the opening (320) in the housing (310), they are deployed out through the opening (320). The release of the pin (318) from the device then allows free expansion of the spring (302) relative to the plunger (312), thereby pushing out the reservoir (322) and the existing drug from the device. Although not shown here, the opening (320) may be covered by a membrane or seal that can be penetrated by the pin (318) to provide a visual indication that the drug has been delivered.

  A pneumatic actuation mechanism may also be employed. In one variation, as shown in FIGS. 34 and 35A and 35B, the pneumatic actuation mechanism is similar to that described for the single and dual spring mechanisms and includes a plunger, a pin, and a housing opening. including. However, instead of using a spring to deploy the needle assembly and plunger, a piston is used to slidably advance the needle assembly within the housing. For example, in FIG. 34, a device having a pneumatic actuation mechanism (200) includes a piston (202) and a trigger (204). The piston (202) is used to compress air into the housing (206) of the device (202). If desired, the amount of compressed air that the piston contains in the device may be controlled by a dial or other mechanism (not shown). The proximal end of the housing is also configured with, for example, a flange, wrinkle, or other containment structure that allows translation of the piston (202) into the housing but not out of the housing May be. When the trigger (208) is depressed, a pair of locking pins (210) is also depressed, thereby allowing the compressed air generated by the piston (202) to push the needle assembly (212) forward. This movement of the needle assembly (212) deploys the needle (214) out of the device (FIG. 35B). As previously described, a pin (216) similar to that described above is also provided that locks the plunger (218) in place. Upon release from the device out of the opening (220) of the housing (206) due to the forward movement of the needle assembly (212), the compressed air moves the plunger (218) further forward, thereby leaving the device. The medicine existing together with the reservoir (222) is pushed out. A rotation pin (224) may also be included that allows rotation of the needle assembly (212) relative to the housing (206) upon release by sliding the needle assembly (212).

  As described above, the trigger may be coupled to the housing and configured to activate the actuation mechanism. In one variation, the trigger is placed at the tip of the device at the eye interface so that the finger can be activated by the fingertip while the device is placed over the surface area of the desired eye with the finger of the same hand. Located on the side of an adjacent device housing (eg, the distance between the trigger and the device tip may range from 5 mm to 50 mm, from 10 mm to 25 mm, or from 15 mm to 20 mm) Good). In another variation, activating a trigger at the tip of the second or third finger of the same hand that places the device on the surface of the eye when the eyepiece is placed on the surface of the eye perpendicular to the edge The trigger is located on the side of the device housing at 90 degrees to the measurement component.

  Some variations of the device may include a control lever for initiating plunger movement. In these cases, the control lever may mechanically actuate the plunger, for example, by a spring actuation similar to that described above. In other variations, actuation of the plunger may occur through a combination of mechanical and manual features. For example, the start of plunger movement may be assisted by a manual force applied on the control lever, while a spring-actuated mechanism for generating mechanical force also moves the plunger forward inside the device. Adopted for injecting drugs. In the case where the control lever is connected to the plunger, the movement of the plunger and the start of drug injection are controlled by manual components, while the speed of fluid injection is controlled by mechanical force. Here, reduced manual force may be applied to the plunger by its combination with unidirectional mechanical force, thus improving the stability of the device on the eye surface at the precise injection site.

  The control lever may be placed between 10 mm and 50 mm from the tip of the device in interface contact with the eye surface, or between 20 mm and 40 mm from the tip of the device. Installation of such a control lever may allow atraumatic and accurate operation of the device with one hand.

  As illustrated in FIGS. 43A-43D, an exemplary integrated device (700) includes a housing (702), a dynamic sleeve (704) slidable thereon, and an eyepiece (706). A plunger (708) and a control lever (710) for manually actuating the plunger (708) to inject the drug through the needle (712). An enlarged cross-sectional view of the eyepiece (706), dynamic sleeve (704), plunger (708), and needle (712) shown in FIG. 43A is shown in FIG. 43B. In use, after placing the eyepiece surface (706) over the eye, the applied pressure automatically slides the dynamic sleeve (704) backwards (in the direction of the arrow) to expose the needle, It may allow penetration of the needle through the eye wall. The control lever (710) may then be manually slidably advanced (in the direction of the arrow in FIG. 43C) to advance the plunger (708). When the injection of drug through the needle (712) is complete, the dynamic sleeve (704) may be manually slidably advanced over the needle, as shown in FIG. 43D.

  The dynamic sleeve can be slidably advanced or retracted manually by a fine mobility control mechanism, also called a mobility control mechanism. In these cases, the dynamic sleeve may comprise a high traction friction surface located on the outer surface of the sleeve that may assist movement of the sleeve by the fingertip. In one variation, the high traction friction surface may be engraved into a serrated pattern or contain markings. In other variations, as shown in FIG. 45A, a platform or pad (eg, fingertip pad) (900) is attached to the outer surface of the sleeve (902) to help manually advance or retract the sleeve. May be. The platform or pad may also include a high traction friction surface (904), whose perspective, side, and top views are illustrated in FIGS. 45B, 45C, and 45D, respectively. The platform or pad (900) typically includes a base (912) for attachment to a sleeve (902). The base (912) may be of any suitable configuration. For example, the platform or pad base may be configured as a cylinder (FIG. 45H) or with a narrowed portion (smaller diameter portion) such as a dumbbell or apple core shape (FIG. 45I).

  Some variations of the devices described herein include a grip having a retracting slot or channel that operates in combination with a dynamic resistance component to inject a drug into the eye. Referring to FIG. 45A, the grip (906) may be a component that is coupled (usually fixedly attached) to the device housing (908) at the proximal end (912) of the sleeve (902). . The grip (906) may be configured to include a retracting slot (910) in its wall. In use, the pad or platform base (912) is moved into the slot (910) when the sleeve (902) is retracted, as indicated by the direction of the arrow in FIG. 45J. The retraction slot (910) has a keyhole shape as a channel with a uniform width (Fig. 45F) or with a narrowed portion (Fig. 45G) or an enlarged portion (Fig. 45E) at the proximal or distal end of the slot. It may be configured as a channel with configuration. The retreat slot may provide sensory feedback when, for example, the retreat end point is reached. The platform or pad base configuration may be selected to provide a friction fit with the slot. For example, when the slot has a narrowed portion, the base may also have a narrowed portion.

  When grips are employed, the device may also include a locking mechanism. In one variation, when the end of sleeve retraction and needle exposure / deployment is reached, the wide portion of the sleeve slot is divided into the wide portion of the grip slot, and the opening of the housing and the opening of the plunger shaft. Allowing the platform base to be inserted into the plunger shaft so as to lock against the platform which is aligned with and becomes an actuating lever for manual drug injection. The narrow portion of the base enters the narrow portion of the sleeve slot, which releases the platform relative to the sleeve and allows its movement toward the device tip. In another variation, when the platform base reaches the end of the retracting slot, it may be pushed into the opening of the plunger shaft and become a locking pin connecting the platform and the plunger. When it is depressed, the narrow portion enters the keyhole slot of the sleeve, becomes movable within the slot, and moves toward the tip of the sleeve (releasing the platform base and sleeve).

  A mobility control mechanism may be beneficial when the user desires to control the amount of pressure exerted by the device tip on the surface of the eye to deploy the needle during its intraocular penetration. With the mobility control mechanism, the user may use the fingertip to reduce or increase the counteracting force that adjusts sleeve movement and needle exposure.

  For example, if the user exerts a pulling force on the high traction friction surface (ie, pulling the high traction friction surface of the sleeve away from the tip of the device), this movement facilitates needle exposure and causes the sleeve to slide backwards. The amount of pressure that needs to be applied to the eye wall to expose the needle may be reduced (to 0 Newton). In another variation, if the user exerts a pushing force (ie, pushes the high traction friction surface of the sleeve toward the tip of the device), this movement may be hindered against the needle exposure, which is the sleeve The device tip may allow increased pressure to be applied to the eye wall prior to initiation of movement and needle exposure.

  In use, the platform or pad may be slid by the second or third finger. Again, this allows the injector to manually modulate sleeve resistance and movement along the device tip. For example, when the device tip is placed on the surface of the eye (and the needle needs to remain fully covered) by pushing the pad and thus the sleeve forward with the fingertip, the injector Provides some resistance at the start of the procedure. The injector then releases the fingertip from the sleeve pad to allow needle deployment and its transscleral penetration. Some variations of the device may also include a step or an annular ridge at the end of the sleeve path to automatically induce spring-operated plunger movement after the sleeve is pulled back over this step. . The fingertip pad can be used to pull the sleeve back over the step at the end of needle deployment to activate plunger movement and drug injection.

  When the platform or pad is utilized, it reduces the amount of pressure that the device exerts on the eyeball before the sleeve begins to move to expose the needle, and thus the amount of pressure applied per patient. Customization may be possible.

  In another aspect, the dynamic sleeve may provide gradual needle exposure as it penetrates the eye wall so that when the maximum resistance is encountered at the surface of the eye, the needle is exposed no more than 1 mm. Here, the rest of the needle is located inside the sleeve, with at least its distal unexposed point or longer segment protected inside the narrow outlet or tube. Such a sleeve design can minimize the risk of needle bending as compared to conventional syringes with long exposed needles. This design may allow the use of smaller cage needles without the increased risk of bending as they penetrate the eye wall. A smaller needle gauge can be more comfortable and less traumatic during its intraocular penetration.

(II. Method)
A method for using an integrated intraocular drug delivery device is also described herein. In general, the method includes placing an eyepiece surface of the device on the surface of the eye, applying pressure to the eye surface at the target injection site using the eyepiece surface, and activating an actuation mechanism. Delivering an active agent from a reservoir of the device into the eye. The installing, applying, and delivering steps are typically completed with one hand.

  Application of pressure to the surface of the eye using the ocular surface may also be used to generate intraocular pressure ranging between 15 mmHg and 120 mmHg, between 20 mmHg and 90 mmHg, or between 25 mmHg and 60 mmHg. . As mentioned above, the generation of intraocular pressure prior to the dispensing member (conduit) deployment can reduce the flexibility of the sclera, which in turn facilitates penetration of the conduit through the sclera and during the infusion procedure. May reduce discomfort on the surface of the eye through the eye wall and / or prevent repulsion of the device. Intraocular pressure control is performed manually using components such as pressure relief valves, pressure sensors, accumulators, pressure sensors, or slidable caps with locking mechanisms and / or ridges as previously described. Or may be generated or maintained automatically.

  The use of the device according to the described method may reduce pain associated with needle penetration through various coverings of the eye wall, such as the conjunctiva, which are heavily innervated at pain nerve endings. The anesthetic effect at the injection site during the intraocular injection procedure may be provided by applying mechanical pressure to the conjunctiva and the eye wall before and / or during needle injection. The application of mechanical pressure to the eye wall also transiently increases the intraocular pressure to increase the hardness of the eye wall (and reduce its elasticity), thereby preventing needle penetration through the sclera. Can promote. Furthermore, application of mechanical pressure to the eye wall may displace intraocular fluid in the eye to create a potential space for the drug injected by the device.

  The device may be used to treat any suitable ocular condition. Exemplary ocular symptoms include, but are not limited to, any type of retinal or macular edema, and diseases associated with retinal or macular edema, such as age-related macular degeneration, diabetic macular edema, cystic macular edema, And postoperative macular edema, CRVO (central retinal vein occlusion), BRVO (retinal vein branch occlusion), CRAO (central retinal artery occlusion), BRAO (retinal artery branch occlusion), ROP (retinopathy of prematurity), etc. Includes retinal vaso-occlusive disease, neovascular glaucoma, uveitis, central serous chorioretinopathy, and diabetic retinopathy.

  When dexamethasone sodium phosphate solution is used to treat ocular conditions, the dose of dexamethasone sodium phosphate that may be administered to the eye by each individual infusion device is between about 0.05 mg and about 5.0 mg Between about 0.1 mg and about 2.0 mg, or between about 0.4 mg and about 1.2 mg.

  In some variations, a local anesthetic is applied on the surface of the eye prior to placing the device on the eye. Any suitable local anesthetic may be used. Exemplary local anesthetics include, but are not limited to, lidocaine, proparacaine, prilocaine, tetracaine, betacaine, benzocaine, bupivacaine, ELA-Max®, EMLA® (eutectic mixture of local anesthetics) ), And combinations thereof. In one variation, the local anesthetic includes lidocaine. When lidocaine is used, it may be provided at a concentration ranging from about 1% to about 10%, from about 1.5% to about 7%, or from about 2% to about 5%. In another variation, the local anesthetic is mixed with phenylephrine or another agent that enhances or / and prolongs the anesthetic effect of the pharmaceutical formulation. The local anesthetic may be provided in any suitable form. For example, it may be provided as a solution, gel, ointment, etc.

  A disinfectant may also be applied on the eye surface prior to placing the device on the eye. Examples of suitable disinfectants include, but are not limited to, iodine, povidone iodine (betadine®), chlorhexidine, soaps, antibiotics, salts and derivatives thereof, and combinations thereof. The disinfectant may or may not be applied in combination with a local anesthetic. When the disinfectant comprises povidone iodine (Betadin®), the concentration of povidone iodine is from about 1% to about 10%, from about 2.5% to about 7.5%, or from about 4% to about 6%. %.

  During the drug delivery process, the devices described herein may be configured such that the injection needle enters the eye at a right angle that is perpendicular to the eye wall (sclera). In other cases, the device may be configured such that the injection needle enters through the cornea into the anterior chamber parallel to the iris surface.

(III. System and Kit)
Systems and kits that include intraocular drug delivery devices are also described herein. The kit may include one or more integrated drug delivery devices. Such a device may be preloaded with an active agent. When multiple preloaded devices are included, they are packaged separately and contain the same or different active agents, and may contain the same or different doses of active agent.

  The system and kit may also include one or more separately packaged devices that are manually loaded. If the device is manually loaded prior to use, one or more separately packaged active agents may be incorporated into the kit. As with the preloaded device system or kit, the one or more separately packaged active agents in the systems and kits herein may be the same or different, each separate The dose provided by the active agent packaged in can be the same or different.

  Of course, the systems and kits may include any combination of preloaded devices, devices for manual loading, and active agents. It should also be understood that instructions for use of the device are also included. In some variations, one or more separately packaged measurement components may be provided in systems and kits for removably attaching to a device. Local anesthetics and / or disinfectants may also be included.

(IV. Examples)
The following examples serve to more fully describe the manner of using the intraocular injection device described above. It is understood that this example in no way serves to limit the scope of the invention, but rather is presented for illustrative purposes.

Example 1: Resistance generated by a dynamic sleeve
An intraocular injection device with a 30 gauge needle covered by a dynamic sleeve (a double-tapered design with each end of the sleeve tapered) is fixed on an Imada tensile test bench and measured for Imada 10N force at a speed of 10 mm / min. Moved relative to the vessel. The resistance was measured while the sleeve was pushed back to expose the needle, simulating the movement of the sleeve in practice. This generated a “U” shaped force drawn against the sleeve displacement curve, as shown in FIG. The resistance at the beginning and end of the sleeve travel path was greater than the resistance at the middle of the path. In FIG. 46, the illustrated range of resistance force generated may be between 0 Newtons and about 2 Newtons, between about 0.1 Newtons and about 1.0 Newtons.

  In one case, the initial resistance of the sleeve path was equal to the force required for a 30 or 31 gauge needle to penetrate the human sclera (e.g., 0.2 Newton and 0.5 Newton). Between). When the use of a higher resistance sleeve was employed, the initial resistance of the sleeve path was greater than the force required for a 30 or 31 gauge needle to penetrate the human sclera ( For example, 1 Newton or more). However, the force was comfortable enough for the patient and low enough to avoid potential damage to the eye (eg, avoiding an increase in intraocular pressure above 60 mmHg). In the middle part of the sleeve travel path, the force approached 0 Newton.

Claims (51)

An integrated device for intraocular drug delivery comprising:
The integrated device is:
A housing sized and shaped to operate with one hand, the housing having a proximal end and a distal end;
An atraumatic ocular surface at the distal end of the housing;
A measurement component; and
A conduit at least partially within the housing, the conduit having a proximal end, a distal end, and a lumen therethrough;
An actuation mechanism contained within the housing, the actuation mechanism being operatively connected to a reservoir for holding the conduit and an active agent;
A trigger coupled to the housing, the trigger configured to activate the actuation mechanism;
A dynamic resistance component coupled to the housing;
The dynamic resistance component includes a dynamic sleeve having a distal end, the dynamic resistance component being movable between a first configuration and a second configuration, the first configuration The conduit extends distally beyond the distal end of the dynamic sleeve for intraocular injection, and in the second configuration, the conduit is entirely within the dynamic sleeve. Retracted distally, proximally within the housing,
An integrated device, wherein the housing, the conduit and the dynamic sleeve are incorporated into a single integrated device.   The integrated device of claim 1, wherein the dynamic resistance component includes a slidable element coupled to the housing.   The integrated device of claim 2, wherein the dynamic sleeve has a proximal end and an inner surface.   The integrated device of claim 3, wherein the proximal and distal ends of the dynamic sleeve are tapered. Before kidou manner sleeve and the housing, generates a force of less than 2N, integrated device according to claim 4. Before kidou manner sleeve and the housing, generates a force between 0.1N and 1N, integrated device according to claim 4.   The integrated device of claim 3, wherein the inner surface of the dynamic sleeve includes one or more traction friction surfaces.   The integrated device of claim 7, wherein the housing includes one or more traction friction surfaces.   9. The integrated device of claim 8, wherein the dynamic sleeve and the one or more traction friction surfaces of the housing generate a force of 2N or less.   The integrated device of claim 8, wherein the dynamic sleeve and the one or more traction friction surfaces of the housing generate a force between 0.1 N and 1.0 N.   The integrated device of claim 3, wherein the dynamic sleeve further comprises a fine sleeve mobility control component.   The integrated device of claim 1, wherein the eyepiece includes a ring, a flange, or a combination thereof.   The integrated device of claim 12, wherein the eyepiece includes a ring.   14. An integrated device according to claim 13, wherein the ring has a diameter between 0.3 mm and 8 mm.   The integrated device of claim 1, wherein the eyepiece surface is flat, convex, or concave.   The integrated device of claim 1, wherein the eyepiece includes one or more traction friction elements.   The integrated device of claim 1, wherein the ocular surface includes an adhesive component.   The integrated device of claim 17, wherein the adhesive component includes a suction mechanism.   The eyepiece surface is a material selected from the group consisting of nylon fiber, cotton fiber, hydrogel, spongy material, expanded styrene, other foams, silicone, plastic, polypropylene, polyethylene, polytetrafluoroethylene, and combinations thereof. The integrated device of claim 1, comprising:   The integrated device of claim 1, wherein the actuation mechanism comprises a manual actuation mechanism.   21. The integrated device of claim 20, wherein the manual actuation mechanism includes a control lever for slidable advancement of a plunger.   The integrated device of claim 1, wherein the actuation mechanism comprises an automatic actuation mechanism.   23. The integrated device of claim 22, wherein the automatic actuation mechanism includes a spring loaded actuation mechanism.   24. The integrated device of claim 23, wherein the spring loaded actuation mechanism is configured to deliver the active agent into the intraocular space at a rate ranging from 1 [mu] l / sec to 1 ml / sec.   25. The integrated device of claim 24, wherein the spring loaded actuation mechanism delivers the active agent into the intraocular space at a rate ranging from 10 [mu] l / sec to 100 [mu] l / sec.   24. The integrated device of claim 23, wherein the spring loaded actuation mechanism generates a force from 0.1N to 1.0N.   24. The integrated device of claim 23, wherein the spring load actuation mechanism includes a first spring and a second spring.   28. The integrated device of claim 27, wherein the second spring is configured to deploy a plunger and to control the delivery rate of the active agent.   28. The method of claim 27, wherein the first spring is configured to move the conduit from a first undeployed state to a second deployed state and to control the speed and force of deployment of the conduit. Integrated device as described.   The integrated device of claim 1, wherein the actuation mechanism is a partially automated actuation mechanism.   31. The integrated device of claim 30, wherein the partially automated actuation mechanism includes a control lever for slidable advancement of a plunger.   32. The integrated device of claim 30, wherein the partially automated actuation mechanism comprises a spring loaded actuation mechanism.   35. The integrated device of claim 32, wherein the spring loaded actuation mechanism is configured to deliver the active agent into the intraocular space at a rate in the range of 1 [mu] l / sec to 1 ml / sec.   33. The integrated device of claim 32, wherein the spring loaded actuation mechanism delivers the active agent into the intraocular space at a rate in the range of 10 [mu] l / sec to 100 [mu] l / sec.   33. The integrated device of claim 32, wherein the spring loaded actuation mechanism generates a force from 0.1N to 1.0N.   33. The integrated device of claim 32, wherein the spring load actuation mechanism includes a first spring and a second spring.   38. The integrated device of claim 36, wherein the second spring is configured to deploy a plunger and to control the delivery rate of the active agent.   The first spring is configured to move the conduit from a first undeployed state to a second deployed state and to control the speed and force of deployment of the conduit. Integrated device as described.   The integrated device of claim 1, wherein the actuation mechanism is a pneumatic actuation mechanism.   The active agents include steroidal anti-inflammatory drugs, non-steroidal anti-inflammatory drugs, anti-infective drugs, anti-allergen drugs, choline antagonists and agonists, adrenergic antagonists and agonists, anti-glaucoma drugs, neuroprotective drugs, cataract prevention Or therapeutic agents, antiproliferative agents, antitumor agents, complement inhibitors, vitamins, growth factors, agents that inhibit growth factors, gene therapy vectors, chemotherapeutic agents, protein kinase inhibitors, small interfering RNA, they The integrated device of claim 1, wherein the integrated device is selected from the group consisting of analogs, derivatives, and modifications, and combinations thereof.   The active agent is selected from the group consisting of ranibizumab, bevacizumab, pegaptanib, dexamethasone, dexamethasone sodium phosphate, triamcinolone, triamcinolone acetonide, fluocinolone, taxol-like drug, aflircept, anecoltab acetate, and the Limus family compound. The integrated device according to Item 1.   The Limus family compounds include sirolimus, SDZ-RAD, tacrolimus, everolimus, pimecrolimus, zotarolimus, CCI-779, AP23841, and ABT-578, their analogs, derivatives, complexes, salts, and modifications, and their 42. The integrated device of claim 41, selected from the group consisting of combinations.   The integrated device according to claim 1, wherein the storage unit is made of a cyclic olefin-based resin.   41. The integrated device of claim 40, wherein the reservoir is devoid of one of silicone oil or derivatives thereof.   The integrated device of claim 1, wherein the measurement component is attached to the eyepiece surface.   The integrated device of claim 1, wherein the measurement component includes one or more radially extending members.   48. The integrated device of claim 46, wherein the one or more radially extending members include a raised distal tip.   48. The integrated device of claim 46, wherein the one or more radially extending members are flexible.   49. The integrated device of claim 48, wherein the measurement component includes a position indicator component.   The integrated device of claim 1, wherein the reservoir is preloaded with the active agent.   The integrated device of claim 3, wherein one of the proximal and distal ends of the dynamic sleeve is tapered.

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