CN103037802B - Equipment and method for intraocular drug delivery - Google Patents

Abstract

The present invention relates to a kind of equipment for being delivered in eye by pharmaceutical formulation.Equipment can be integrated to include feature, and described feature allows with a hand safety and hurtless measure ground operation equipment.Such as, can be performed with one hand: on eyes, equipment is accurately placed, including correctly adjusting angle, and pharmaceutical formulation is injected in eye.Equipment may also include the safety feature of improvement.Such as, equipment can include actuating mechanism, and described actuating mechanism controls speed and the degree of depth being injected in eye.Some equipment includes that dynamic stop member, described dynamic stop member can adjust the amount applying the pressure to ocular.There is also described herein correlation technique and include the system of this equipment.

Description

Equipment and method for intraocular drug delivery

Cross-Reference to Related Applications

This application claims the U.S.Provisional Serial 61/341,582 in submission on March 31st, 2010, Yi Jiyu The priority of the U.S.Provisional Serial 61/384,636 that on September 20th, 2010 submits to, each described application is by quoting Entirety is incorporated into herein.

Technical field

As herein described it be structured to safety and accurately deliver pharmaceutical formulation to the equipment in eye.Especially, this equipment Can integrated various features, described feature allows easy manipulation to equipment, and can be conducive to equipment location in ocular And beneficially hurtless measure ground injection drug composition formula within the eye.There is also described herein and utilize this equipment to deliver pharmaceutical formulation within the eye System and method.

Background technology

Eyes are to include the most multipart complex organ, and described many parts make to achieve the process seen.Visual quality Depend on situation and the cooperative ability of these parts of each body component.Such as, vision can be by the shadow of these situations Ringing, described situation have impact on crystalline lens (such as cataract), retina (such as cytomegaloviral retinitis) or macula lutea (such as macular degeneration).Local and the pharmaceutical formulation of whole body have been developed that to treat these and other eye condition, but often One has its defect.Such as, typically, apply to the local treatment in ocular and there is the shorter time of staying, because tear stream They are gone out eyes.Additionally, if it is expected that target be positioned at back room, then due to by cornea and sclera and other structure The natural cover for defense presented, is restricted to intraocular delivery medicine.As for whole body therapeutic, it usually needs the medicine of high dose with Intraocular reaches curative level, which increases the risk of harmful side effect.

Alternatively, intravitreal injection has been performed to deliver pharmaceutical formulation partly to intraocular.Owing to being used for treating urgency Property macular degeneration (AMD) anti-vascular endothelial growth factor medicament supply increase, utilize intravitreal injection to become more Generally.Through FDA(Food and Drug Administration) approval for intravitreal injection with treatment AMD medicament include Lucentis (Genetech company, city of San Francisco, south, California) and Pei Jianibu sodium ( Eyetech drugmaker, New York, New York).Additionally, bevacizumab in vitreum (Genentech is public Department, city of San Francisco, south, California) have been widely used for the application outside medicine approval indicates to treat the new green blood of choroid Pipe.There is also the interest of growth in terms of developing new drug thing, described novel drugs in being directly delivered to vitreum to treat Macular edema, retinal vein obstruction and vitreous hemorrhage.

Currently, commercially available intravitreal injection equipment lacks many useful features in the following areas: make injection site reveal Go out, make equipment stable against sclera and/or control angle and the degree of depth of injection.Many at patent document (such as WO 2008/ 084064 and the U.S. 2007/0005016) described in equipment be also the part of multiple component system, described multiple component system group Fill and use the most time-consuming.The process time of the increase that these equipment are adjoint can transfer to increase the risk of complication. Further, it is necessary to the many parts of operation itself can increase because user's error causes the risk of complication.The one of intraocular injection is tight Weight complication is intraocular infection, and referred to as entophthamia, described entophthamia is owing to the entrance of causal organism is (such as from ocular Enter the bacterium of ocular environment), or the wound (such as cornea or conjunctiva wear and tear) of ocular tissue.

Therefore, the new equipment being used for performing intravitreal injection is in need.Simplify injection process and reduce complication The equipment meeting ergonomics of risk is useful.Accurately and hurtless measure ground by medicine (such as liquid, semisolid or Medicine with suspension as substrate) equipment that is injected in eye is also useful.

Summary of the invention

Described herein is for delivering pharmaceutical formulation to equipment, method and the system in eye.This equipment can be integrated 's." integrated " refers to various feature and is combined in individual equipment, and described various features can be conducive to such as with peace Entirely, aseptic and accurate mode delivers pharmaceutical formulation in eye.Such as, these features can be integrated in individual equipment: Described feature can assist correctly to be placed on desired ocular position, helps location equipment thus arrive eye at a proper angle Interior space, once equipment positions, assists in keeping equipment terminal stabilization without moving in ocular during whole drug injection Dynamic or slide, adjust or control intraocular pressure, and/or help by such as because of drug injection power or contact or pierce through wall of eyeball from Body and the wound that causes is down to minimum.More particularly, integrated equipment can be used for by due to destination organization directly contact or The wound transmitted by the indirect force of another tissue (such as wall of eyeball or vitreous gel) and cause be down to minimum it can also be used to By corneal, conjunctiva, episclera, sclera and intraocular structure (include but not limited to retina, choroid, ciliary body and Crystalline lens, and blood vessel) and the neural wound that is associated with these structures be down to minimum.May also include such feature: Described feature can advantageously reduce the risk of intraocular infection inflammation (such as entophthamia) and can reduce pain.Should be understood that Pharmaceutical formulation can be delivered to any suitable target location of intraocular, such as anterior chamber or back room.Additionally, pharmaceutical formulation can include appointing What suitable activating agent also can take any suitable form.Such as, pharmaceutical formulation can be solid, semisolid, liquid, etc. Deng.Pharmaceutical formulation is also adapted for the release of any suitable type.Such as, it may be adapted at once to discharge, controlled release, delays to release Put, persistently discharge or the mode release bioactive agent of pill release.

It is easy to one it is said that in general, equipment as herein described includes that housing, the size and dimension of described housing determine into Hand operates.Typically, housing has proximally and distally, and the eye contact surface at housing distal.It is in state before it is disposed Conduit be usually located in housing.Conduit is in its deployable state in enclosure interior at least in part.In some cases, lead Pipe is slidably attached to housing.Conduit is generally of near-end, far-end and the inner chamber extended by it.Can within housing Including actuating mechanism, described actuating mechanism may be operably coupled to conduit and for accommodating the reservoir of activating agent.Trigger is same Sample can be linked to housing and be configured to activate actuating mechanism.In a modification, trigger is positioned on the sidepiece of apparatus casing, (distance between trigger and equipment end is between 5mm to 50mm, 10mm to 25mm for equipment end at neighbouring eye contact surface Between or 15mm to 20mm between scope), thus can be by finger tip easy actuation trigger simultaneously with the finger of the same hand Equipment is positioned on desired ocular position.In another modification, trigger is positioned on the sidepiece of apparatus casing and measurement portion Part becomes 90 degree, thus when equipment end be placed on be perpendicular to corneal limbus in ocular time, available equipment is positioned in ocular The second of the same hand or the fingertip activation trigger of the 3rd finger.In a modification, measure parts and be attached to eye contact Face.In some variations, medicine filling mechanism is also included.

Actuating mechanism can be manual, automatic or part is automatic.In a modification, actuating mechanism is spring The actuating mechanism loaded.Here, this mechanism can include single spring or two springs.In another modification, actuating mechanism is gas Dynamic actuating mechanism.

Can be achieved and further by including the dynamic stop member of injection device is made applying pressure to ocular Become more meticulous.Dynamically stop member can include the slidable element being linked to housing.In some variations, slidable element includes moving State sleeve pipe, described dynamic sleeve pipe is configured to regulation and applies the amount of the pressure to ocular.In other modification, dynamic stop member structure Cause wall of eyeball tension control mechanism.

In use, within equipment is by so delivering the medicament to intraocular space: the eye of integrated equipment is contacted Face is positioned in ocular (wherein equipment also includes the reservoir for accommodating activating agent and actuating mechanism), and in targeted injection portion Utilize eye contact surface that ocular applies pressure at Wei, and by actuating mechanism is activated, activating agent is delivered from reservoir subsequently To eye.Location, force and the step delivered are completed by a hand.In some cases, equipment is being placed on eye it Forward direction ocular application local anaesthesia.Also can be to ocular application disinfectant before equipment is placed on eye.

Utilize eye contact surface to ocular apply pressure can also be formed between 15mm Hg to 120mm Hg, 20mm Hg extremely The intraocular pressure of the scope between 90mm Hg or between 25mm Hg to 60mm Hg.As described further below, dividing Form intraocular pressure before joining the deployment of element (conduit) and the pliability of sclera can be reduced, this then conduit can be easy to and pierce through Gong Film, reduces conduit during injection process and pierces through the adjoint sense of discomfort of wall of eyeball and/or prevent the backlash of equipment.

Drug delivery device, its parts and/or various activating agent can be arranged at system or one-tenth as single package parts In set articles for use.System or kit can include one or more equipment and one or more activating agents.Equipment can be pre- Filling or be configured for the filling of manual medicine.When including multiple actives, identical or different activating agent can be used. It is used as the activating agent of identical or different dosage.System or kit generally include operation instruction.They may also include fiber crops Liquor-saturated dose and/or disinfectant.

Accompanying drawing explanation

Figure 1A to Figure 1B illustrates the front view of exemplary eye contact surface.

Fig. 2 A to Fig. 2 C illustrates the side view of other exemplary eye contact surface, including measuring parts.

Fig. 3 A1 to Fig. 3 A3 and Fig. 3 B1 to Fig. 3 B3 illustrates the side view of other exemplary eye contact surface.

Fig. 4 A and Fig. 4 B1 to Fig. 4 B2 illustrates stereogram and the front view of exemplary flanged contact surface.

Fig. 5 A1 to Fig. 5 A2 and Fig. 5 B1 to Fig. 5 B2 illustrates the side view of exemplary flat He convex eye contact surface and stands Body figure.

Fig. 6 A1 to Fig. 6 A2 and Fig. 6 B1 to Fig. 6 B2 illustrates the side view of exemplary soft or semisolid eye contact surface And front view.

Fig. 7 A1 to Fig. 7 A2, Fig. 7 B1 to Fig. 7 B2, Fig. 7 C1 to Fig. 7 C2 and Fig. 7 D to Fig. 7 E illustrate other exemplary Eye contact surface, including the eye contact surface with high attachment friction interface.

Fig. 8 illustrates how exemplary measurement parts play the work making eyelid retract and measuring a certain distance away from corneal limbus With.

Fig. 9 A to Fig. 9 C illustrates the exemplary layout measuring parts around eye contact surface.

Figure 10 A to Figure 10 C illustrate other exemplary measurement parts and they how to play and measure a certain away from corneal limbus The effect of distance.

Figure 11 A to Figure 11 D illustrates other exemplary measurement parts.

Figure 12 illustrates the exemplary apparatus including marking end component.

Figure 13 illustrates the mark done in ocular by exemplary mark end component can how to be used for equipment to be positioned Targeted injection position.

Figure 14 A to Figure 14 C illustrates the stereogram of exemplary sharp-pointed conduit.

Figure 15 A1 to Figure 15 A2 illustrates the side view of exemplary ramp angles.

Figure 16 A to Figure 16 D illustrates the sectional view of exemplary conduit geometric shape.

Figure 17 illustrates the sectional view of other exemplary conduit geometric shape.

Figure 18 A to Figure 18 C illustrates side view and the sectional view (A-A along the line intercepting) of the exemplary conduit through flattening.

Figure 19 illustrates for controlling the exemplary mechanism that conduit exposes.

Figure 20 gives another exemplary conduit and exposes controlling organization.

Figure 21 illustrates the exemplary apparatus with protecgulum and bonnet.

Figure 22 illustrates how to utilize exemplary medicine filling element to make equipment fill pharmaceutical formulation.

Figure 23 A to Figure 23 C illustrates other example of medicine filling element.

Figure 24 A to Figure 24 D illustrates the medicine filling element of exemplary band fenestra.

Figure 25 A to Figure 25 B illustrates the exemplary band fenestra medicine filling element with drug source handing-over.

Figure 26 A to Figure 26 C illustrates the cut-away side view of exemplary dual spring actuation mechanism.

Figure 27 is the cut-away side view of another exemplary dual spring actuation mechanism.

Figure 28 illustrates that the stereogram of equipment, described equipment include another example of dual spring actuation mechanism, described dual spring Actuating mechanism is in state before it activates.

Figure 29 is the equipment shown in Figure 28 and the sectional view of dual spring actuation mechanism.

Figure 30 is the sectional view after dual spring actuation mechanism activated of the equipment shown in Figure 28.

Figure 31 A to Figure 31 C illustrates that the trigger in Figure 28 is the most spring-actuated with portion by the first of dual spring actuation mechanism Administration's conduit.

The enlarged drawing of Figure 32 A to Figure 32 C shows how the release of the stop pin in Figure 28 is played dual spring actuation machine Second spring-actuated effect of structure.

Figure 33 A to Figure 33 B illustrates the equipment of Figure 28 and has exemplary filler.

Figure 34 is the stereogram of the exemplary apparatus with pneumatic actuating mechanism.

Figure 35 A to Figure 35 B gives the sectional view of equipment shown in Figure 34.Figure 35 A illustrates and is in the gas activating front state Dynamic actuating mechanism.Figure 35 B is shown in the pneumatic actuating mechanism after deployment catheter.

Figure 36 is the sectional view of the exemplary apparatus of the actuating mechanism including single spring.

Figure 37 is the sectional view of equipment shown in Figure 36, and it is shown in the single spring-actuated mechanism after deployment catheter.

Figure 38 is the cut-away side view of exemplary medicine filling piston.

Figure 39 A to Figure 39 I illustrates the various views of exemplary apparatus end.

Figure 40 illustrates the exemplary apparatus with sliding cap.

Figure 41 A to Figure 41 B provides the sectional view of another exemplary apparatus with dual spring actuation mechanism.

Figure 42 illustrates the amplification view of exemplary dynamic sleeve pipe.

Figure 43 A to Figure 43 D illustrates moving ahead and the example method of drug injection of distribution member.

Figure 44 A to Figure 44 D illustrates exemplary register guide parts.

Figure 45 A to Figure 45 J illustrates the various aspects of exemplary fine sleeve pipe mobile control unit.

Figure 46 is to describe according to a modification, the diagram of the amount of resistance that produced by dynamic sleeve pipe.

Detailed description of the invention

As herein described be handheld device for such as pharmaceutical formulation being delivered in eye by injection, method, with And system.Equipment can by integrated for various features (combination) to individual equipment, described feature can be conducive to such as with safety, Pharmaceutical formulation is delivered in eye by aseptic and accurate mode.Therefore, such feature can be integrated in individual equipment: can Auxiliary correctly place on eye, help location thus at a proper angle arrive intraocular space, regulate or control intraocular pressure, And/or help the wound of sclera and intraocular structure is down to (such as causing because of the power of injection or puncture sclera self) Low.Equipment can wholly or partially be configured to disposably.

I. equipment

It is easy to use it is said that in general, integrated equipment as herein described includes that housing, the size and dimension of described housing determine into One hand operation.Typically, housing has the eye contact surface proximally and distally and at housing distal.Before being in its deployment The conduit of state can be located in housing.Conduit is in its deployable state in enclosure interior at least in part.In some cases, Conduit is slidably attached to housing.Additionally, conduit is generally of near-end, far-end and the inner chamber extended by it.At housing In can include that actuating mechanism, described actuating mechanism may be operably coupled to conduit and for accommodating the reservoir of activating agent.

Can by the combination of any suitable biocompatible materials or biocompatible materials formed equipment or it one Part.Such as, one or more biocompatible polymers can be used for making such as apparatus casing, eye contact surface, measure parts, Etc..Exemplary biocompatibility and can not including but not limited to by Biodegradable material: methyl methacrylate (MMA), poly- Methyl methacrylate (PMMA), polyethyl methacrylate (PEM) and other acrylic acid based polymer；Polyolefin, such as Polypropylene and polyethylene；Vinylacetate；Polyvinyl chloride；Polyurethane；Polyvinylpyrrolidone；2-Pyrrolidone；Polypropylene Nitrile-butadiene；Merlon；Polyamide；Fluoropolymer, such as polytetrafluoroethylene (PTFE) is (such as Teflon^TMPolymer)；Polyphenyl second Alkene；Styrene-acrylonitrile；Cellulose acetate;Acrylonitrile-butadiene-styrene (ABS)；Polymethylpentene；Polysulfones；Polyester；Polyamides is sub- Amine；Natural rubber；Oppanol；Polymethylstyrene；Silicones；And their copolymer and mixture.

In some variations, equipment or equipment a part (such as medicament reservoir, plunger, housing, eye contact surface or Measure parts) it is made up of the material comprising cyclenes system resin.Exemplary cyclenes resin includes but not limited to: such asCyclic olefin polymer (ZEON company, Tokyo, Japan) or CrystalOlefin polymer (assists greatly essence Work Co., Ltd., Tokyo, Japan) and APEL^TMCyclic olefine copolymer (COC) (Mitsui Chemicals, Inc, Tokyo, Japan) Commercially available prod, cyclenes-ethylene copolymer, PET series resin, polystyrene resin, poly terephthalic acid Butanediol ester resin and combinations thereof.In a modification, using cyclenes system resin and cyclenes-ethylene copolymer is to have Profit, described cyclenes system resin and cyclenes-ethylene copolymer have the high grade of transparency, high-fire resistance and with pharmacology product (such as Protein, protein fragments, polypeptide or include antibody, acceptor or protein-bonded chimeric molecule) minimum or even do not have chemistry anti- Should.

Cycloolefine polymer or its hydrogenation product can be the open loop homopolymers of cycloolefin monomers, the ring-opening copolymer of cycloolefin monomers With other monomer, the addition homopolymers of cycloolefin monomers, the addition copolymer of cycloolefin monomers and other monomer and this homopolymers Or the hydrogenation product of copolymer.Above cycloolefin monomers can include that cycloolefin monomer and polycyclic olefin monomer (include dicyclo Higher cycle compound).The example being suitable to produce the cycloolefin monomer of the homopolymers of cycloolefin monomers or copolymer is such as ring The cycloolefin monomer of amylene, cyclopentadiene, cyclic ethylene, methyl cyclic ethylene and cyclo-octene；They containing 1 to 3 lower alkyl The lower alkyl derived thing of base (such as methyl and/or ethyl) alternatively base；And their acrylate derivative.

The example of polycyclic olefin monomer be dicyclopentadiene, 2,3-dihydro cyclopentadiene, dicyclo [2,2,1]-hept-2-ene" and Its derivative, three rings [4,3,0,1^2,5]-3-decene and derivative, three rings [4,4,0,1^2,5]-3-endecatylene and derivative Thing, Fourth Ring [4,4,0,1^2,5,0^7,10]-3-dodecylene and derivative, five rings [6,5,1,1^3,6,0^2,7,0^9,13]-4-15 carbon Alkene and derivative thereof, five rings [7,4,0,1^2,5,0,0^8,13,1^9,12]-3-15 carbene and derivative thereof and six rings [6,6,1,1^3,6, 1^10,13,0^2,7,0^9,14]-4-heptadecene and derivative thereof.The example of dicyclo [2,2,1]-hept-2-ene" derivative includes 5-first Base-dicyclo [2,2,1]-hept-2-ene", 5-methoxyl group-dicyclo [2,2,1]-hept-2-ene", 5-ethylidene-dicyclo [2,2,1]-hept- 2-alkene, 5-phenyl-dicyclo [2,2,1]-hept-2-ene" and 6-methoxycarbonyl-dicyclo [2,2,1]-hept-2-ene".Three rings [4, 3,0,1^2,5] example of-3-decene derivative includes 2-methyl-three ring [4,3,0,1^2,5]-3-decene and 5-methyl-three ring [4, 3,0,1^2,5]-3-decene.Fourth Ring [4,4,0,1^2,5] example of-3-undecylenic derivatives include 10-methyl-Fourth Ring [4,4,0, 1^2,5]-3-endecatylene, and three rings [4,3,0,1^2,5] example of-3-decene derivative includes 5-methyl-three ring [4,3,0,1^{2 ,5}]-3-decene.

Fourth Ring [4,4,0,1^2,5,0^7,10] example of-3-dodecylene derivative includes 8-ethylidene-Fourth Ring [4,4,0,1^{2 ,5},0^7,10]-3-dodecylene, 8-methyl-Fourth Ring [4,4,0,1^2,5,0^7,10]-3-dodecylene, 9-methyl-8-methoxyl group-carbonyl Base-Fourth Ring [4,4,0,1^2,5,0^7,10]-3-dodecylene, 5,10-dimethyl-Fourth Ring [4,4,0,1^2,5,0^7,10]-3-12 carbon Alkene.Six rings [6,6,1,1^3,6,1^10,13,0^2,7,0^9,14] example of-4-heptadecene derivative include 12-methyl-six ring [6,6, 1,1^3,6,1^10,13,0^2,7,0^9,14]-4-heptadecene and 1,6-dimethyl-six ring [6,6,1,1^3,6,1^10,13,0^2,7,0^9,14]-4- Heptadecene.One example of cycloolefine polymer is addition homopolymers or at least one cycloolefin monomers of at least one cycloolefin monomers With at least one other olefinic monomer (such as, ethene, propylene, 4-methylpentene-1, cyclopentene, cyclo-octene, butadiene, isoamyl Diene, styrene, or the like) addition copolymer.Can by such as while utilizing known catalyst by above-mentioned list Body is polymerized and obtains this homopolymers or copolymer, and described catalyst soluble is in varsol and by vfanadium compound or the like And organo-aluminum compound or the like composition (Japanese patent application open (Kokai) number HEI 6-157672, Japan Patent Shen (Kokai) number HEI 5-43663 please be disclose).

Another example of cycloolefine polymer is open loop homopolymers or the ring-opening copolymer of above-mentioned monomer of above-mentioned monomer.It can By such as by above-mentioned monomer homopolymerization or above-mentioned monomer copolymerization being obtained, described catalysis while utilizing known catalyst Agent for example, (1) is by urging that the halide of platinum group metal (such as ruthenium, rhodium, palladium, osmium or platinum) or nitrate and reducing agent form Agent or (2) are organic by the metal in one of I to IV race of the compound of transition metal (such as titanium, molybdenum or tungsten) and periodic table (Japanese patent application is open for the catalyst that metallic compound (such as organo-aluminum compound or organo-tin compound) forms (Kokai) number HEI 6-157672, open (Kokai) number HEI5-43663 of Japanese patent application).

Homopolymers or copolymer can contain unsaturated bond.Available known hydrogenation catalyst is by homopolymers or copolymer hydrogen Change.The example of hydrogenation catalyst includes (1) Ziegler-type homogeneous catalyst, each of described Ziegler-type homogeneous catalyst by The organo-metallic compound composition of the acylate of titanium, cobalt, nickel or the like and lithium, aluminium or the like, (2) supported catalyst Agent, each of described loaded catalyst is by carrier (such as carbon or aluminum oxide) and the platinum that is carried on carrier (such as Palladium or ruthenium) composition, and (3) each catalyst being made up of the compound of one of above-mentioned platinum group metal (Japanese patent application public affairs Open (Kokai) number HEI 6-157672).

In some cases, a part (such as medicament reservoir) for equipment or equipment is made up of the material comprising rubber. Suitably the example of elastomeric material include butyl rubber (such as butyl rubber, chlorinated scoline, brombutyl and Divinylbenzene copolymerization butyl rubber)；Conjugated diene rubber is (such as polyisoprene rubber (high to low cis-1,4 keys), poly- Butadiene rubber (high to low cis-1,4 keys) and styrene butadiene copolymers rubber)；And Ethylene-Propylene-Diene three Unit's copolymer rubber (EPDM).Also can use cross-linking elastomeric material, and can be by above-mentioned elastomeric material (is such as handed over additive Connection agent, filler and/or stiffener, colouring agent or age resister) kneading makes described cross-linking elastomeric material to coming together.

In some cases, biocompatible materials is biodegradable polymer.Suitably biodegradable polymeric The non-limiting example of thing includes cellulose and ester, polyacrylate (TYR derivative or free acid), poly-(beta-hydroxy Ester), polyamide, poly-(amino acid), polyglycerol fatty acid ester, poly-alkylene alkylates, polyoxyalkylene, poly-alkylene succinate, polyacids Acid anhydride, polyanhydride ester, poly-aspartate, PLA, polytetramethylene glycol, poly-(caprolactone), poly-(caprolactone)/PEG copolymer, The derivative Merlon of Merlon, TYR, polybutylcyanoacrylate, poly-dihydro, poly-(dioxanone), poly-p-bis- Oxygen cyclohexanone, poly-(6-caprolactone-dimethyltrimethylene carbonate), poly-(esteramides), polyester, aliphatic polyester, poly-(ether Ester), polyethylene glycol/poly-(ortho esters) copolymer, poly-glutaric acid, poly-(glycolic), poly-(glycolide), poly-(glycolide)/poly-(second Glycol) copolymer, PLA, poly-(lactide-co-caprolactone), poly-(DL-lactide-co-glycolide), poly-(third hand over Ester-co-glycolide)/PEG copolymer, PLA PEG copolymer, polyphosphazene, polyphosphate, poly- Phosphate carbamate (polyphophoester urethanes), poly-(propylene fumaric acid-co-ethylene glycol), poly-(Sanya Methyl carbonic), polytyrosinecarbonates, polyurethane, terpolymer (glycolide lactide or dimethyltrimethylene carbon The copolymer of acid esters) and combinations thereof, mixture or copolymer.

Can add an additive in polymer and polymeric blends to adjust its characteristic as required.Such as, can be by Biocompatibility plasticizer adds to flexible and/or mechanical to increase it at least one of polymer formulators of equipment Intensity, or to provide the color contrast relative to ocular.In other cases, biocompatible filling material can be added (such as Particulate filler, fiber and/or net) to give mechanical strength and/or rigidity to a part for equipment.

Can be by above-mentioned material injection or compression moulding be manufactured equipment as herein described at least in part.

In some cases, equipment includes removably being attached or integrated viewing and/or amplifier element can be to have Profit.Such as, magnifying glass and/or light source (such as LED) can be removably attached to equipment so that equipment end and The visualization of injection site.Visual improvement can help to more accurately and be safely positioned by equipment target location (example Such as corneoscleral junction rear about 3.5mm to 4mm), thus avoid complication (the such as retinal detachment, eyelash of intraocular injection potentially Shape body is hemorrhage) or wound to intra-ocular lens.Magnifying glass can be made up of any suitable material, and such as, it can be by previously retouching Any suitable nonabsorable (degradable) material stated makes, but typically lightweight, set so that it does not affect injection Standby balance.Magnifying glass and/or light source (such as LED) can be disposable.

Housing

The housing of equipment generally includes medicament reservoir and actuating mechanism.When at the first, non-deployable state (shape before Bu Shuing State) time, within conduit can be located at housing.Housing can be any suitable shape, as long as it allows with a grasped and behaviour Make housing.Such as, housing can be in shape tubulose or cylinder, rectangle, square, circular or oval 's.In some variations, housing is tubulose or cylinder, is similar to the cylinder of syringe.In this case, housing has about Length between 1cm to about 15cm, between about 2.5cm to about 10cm or between about 4cm to about 7.5cm.Such as, housing can have Have about 1cm, about 2cm, about 3cm, about 4cm, about 5cm, about 6cm, about 7cm, about 8cm, about 9cm, about 10cm, about 11cm, about 12cm, The length of about 13cm, about 14cm or about 15cm.The surface of housing also can veining, roughening or in some region with other Mode improve (such as with protuberance, ridge dash forward, etc.) to assist user to grasp and/or to operate housing.

Housing can be made up of any suitable material.Such as (and as discussed previously), the parts of equipment can be by any conjunction Suitable biocompatible materials or the combination of biocompatible materials are made.The material making housing can be conducive to include but do not limit In: cyclenes system resin, cyclenes-ethylene copolymer, PET series resin, polystyrene resin, Yi Jiju Ethylene glycol terephthalate resin.In a modification, it can be favourable for using cyclenes system resin and cyclenes-ethylene copolymer , described cyclenes system resin and cyclenes-ethylene copolymer have the high grade of transparency, high-fire resistance and with pharmacology product (such as egg White matter, protein fragments, polypeptide or include antibody, acceptor or protein-bonded chimeric molecule) minimum or even do not have chemistry anti- Should.Other material making housing can be conducive to include but not limited to: fluoropolymer；Thermoplastic (such as polyether-ether-ketone, Polyethylene, polyethylene terephthalate, polyurethane, nylon, etc.)；And silicones.In some variations, housing Can be made of clear material and confirm that catheter deployment and/or medicine deliver with auxiliary.Typically, there is the material of suitable transparency For polymer, described polymer for example, acrylic copolymer, acrylonitrile-butadiene-styrene (ABS) (ABS), Merlon, polyphenyl Ethene, polyvinyl chloride (PVC), glycol-modified-polyethylene terephthalate (PETG) and styrene-acrylonitrile (SAN).Useful acrylic copolymer includes but not limited to: polymethyl methacrylate (PMMA) copolymer and styrene methyl Methyl acrylate (SMMA) copolymer (such as ZylarAcrylic copolymer).

Eye contact surface

Equipment as herein described generally includes hurtless measure eye contact surface at housing distal.In some variations, eye contact Face is securely attached to housing proximal end.In other modification, eye contact surface is removably attached to housing proximal end.Typically, eye Contact surface is aseptic.In some cases, eye contact surface is disposable.During use, the eye that the eye contact surface of equipment is placed On table.

Eye contact surface can be any suitable configuration (such as size, shape, geometric shape, etc.), as long as it allows It is placed in ocular equipment hurtless measure.In some variations, eye contact surface is annular (such as Figure 1A to Figure 1B).When eye connects When contacting surface takes the shape of ring, it can have the about 0.3mm diameter to about 8mm, about 1mm to about 6mm or about 2mm to about 4mm. In other modification, the shape of eye contact surface is oval or circular.

More particularly, as shown in the front view of Figure 1A to Figure 1B, equipment end includes the eye contact surface of annular, at described eye At contact surface, the distance between internal diameter and the external diameter of ring defines wheel rim.In this case, the eye contact surface of annular can construct Become there is wider eye contact surface (10) (wheel rim) and less inside opening (12) (Figure 1A) or there is relatively large inner opening (16) narrower eye contact surface (14) (wheel rim) (Figure 1B).Distribution member (conduit) can be to be hidden in inside and by equipment end The entry needle of protection.Also can arrange film, described film extends across inside opening, and can flush with eye contact surface or recess at injection Among the equipment terminus lumen that pin is positioned at.

As shown in Figure 39 A to 39B, under quiescent condition, the end of distribution member can be relative to including setting of a contact surface The end of standby housing is recessed, thus when equipment end is arranged to contact with any surface (such as skin or wall of eyeball), distribution The end of element stands away with surface, described distance in Figure 39 B by arrow mark.This distance can ensure that in injection journey Before sequence, distribution member end does not directly contact with any surface, and (such as skin divides from source to this prevent distribution member Secretion, discharge of eye or tears) unexpected germ contamination, and the eye that may cause entophthamia will be brought during intraocular injection program into The risk of interior infection medium is down to minimum.

In some variations, the end of distribution member is recessed relative to the most proximal end of apparatus casing, and with apparatus casing Most proximal end stands away, and described distance is from about 0.01mm to about 10mm, from about 0.1mm to about 5mm or from about 0.5mm Scope to about 2mm.

In another modification, the eye contact surface directly contacted with ocular of equipment end is annular, is wherein setting There is between inwall and the distribution member of standby housing the gap of about 360 degree, described gap in Figure 39 C by arrows.Here, Pollute if the eye interface of annular becomes infected pathogen and be placed in ocular, then distribution member can contact and pierce through Ocular with contaminated equipment end has separated gap area, this prevent the unexpected germ contamination of distribution member and will bring into The risk that may cause the intraocular infection of entophthamia is down to minimum.On the contrary, this gap around distribution member is lacked (such as Figure 39 D Shown in) equipment end can be allowed in the unexpected germ contamination of injection site.

In some variations, have between the inwall and distribution member of apparatus casing from about 0.1mm to about 5mm, from about 0.3mm to 3mm or from about 0.5mm to the gap of about 2mm scope.

In other modification, having solid film or separator (105), described solid film or separator make distribution member End (107) separates with external environment condition, and as shown in Figure 39 E, wherein film or separator can be fluid-tight and/or airtight 's.Film or separator can ensure that does not has air to flow in or out equipment, result in formation of aeroseal and maintains at device interior Certain constant air pressure.

Additionally, film or separator can ensure that before injection process distribution member end not with any unexpected germ contamination Source (such as tear or discharge of eye) contacts, and this prevent the unexpected germ contamination of distribution member and by injection process within the eye Period band membership causes the risk of the intraocular infection of entophthamia to be down to minimum.

The separate film of end or the separator of the end of distribution member Yu apparatus casing can be included selected from a certain set Material, described set include biocompatibility and can not Biodegradable material, described material includes but not limited to: metering system Acid methyl esters (MMA), polymethyl methacrylate (PMMA), polyethyl methacrylate (PEM) and the polymerization of other acrylic Thing；Polyolefin, such as polypropylene and polyethylene；Vinylacetate；Polyvinyl chloride；Polyurethane；Polyvinylpyrrolidone；2-pyrrole Pyrrolidone；Acrylonitrile butadiene；Merlon；Polyamide；Fluoropolymer, such as polytetrafluoroethylene (PTFE) is (such as Teflon^TMPolymerization Thing)；Or PEP (FEP)；Polystyrene；Styrene-acrylonitrile；Cellulose acetate;Acrylonitrile-butadiene-benzene second Alkene；Polymethylpentene；Polysulfones；Polyester；Polyimides；Natural rubber；Oppanol；Polymethylstyrene；Silicones；It Derivative and copolymer and mixture.

In some variations, film or separator (30) can recess at equipment terminus inner, thus when equipment end is arranged to When contacting with any surface (such as skin or ocular), described film or separator are separated a distance with described surface, described away from From by arrows, as shown in Figure 39 E.This distance can ensure that distribution member end (31) before injection process not with any Surface directly contacts, and this prevent the distribution member accident from source (such as skin secretion, discharge of eye or tears) Germ contamination, and band membership during injection process within the eye causes the risk of the intraocular infection of entophthamia be down to minimum.

Film or separator can relative to the end of apparatus casing at eye interface recessed, and exist with the end of apparatus casing Standing away at eye interface, described distance is from about 0.01mm to about 10mm, from about 0.1mm to about 5mm or from about The scope of 0.5mm to about 2mm.

In other modification, measuring parts (32) (discussed further below) can be relative to the end of apparatus casing (33) recessed at eye contact surface (Figure 39 F to Figure 39 H), thus (the figure when equipment end (34) contacts with ocular (35) 39I), measure parts (32) not contact with ocular (35).This configuration can be by covering the delicate tissues of ocular (such as Cornea and the non-cuticulated epithelium of conjunctiva) wound risk be down to minimum.Avoid between measuring cell and ocular directly contact can Be conducive to the risk by ocular wound (such as cornea or conjunctiva wear and tear) to be down to minimum, this prevent more serious complication (as Bacterium including ulcer of the cornea infects).In an alternative embodiment, the end (32) of measuring cell can be angled away from or towards Eyes (respectively Figure 39 G and Figure 39 H).Measure parts can a segment distance recessed relative to the end of apparatus casing, described distance From about 0.01mm to about 5mm, from about 0.1mm to about 3mm or from about 0.5mm to the scope of about 2mm.

In some variations, as shown in Fig. 2 A to Fig. 2 C, equipment end may also include eye contact surface and the measurement of annular Device, described measurement apparatus help relative to the correct position being perpendicular to a certain distance of corneoscleral junction and determining injection site Put.In a modification, measure parts (20) and be positioned at the side (22) of equipment end.In another modification, more than one measurement Parts are positioned at more than side of equipment end.The end measuring parts at this is flat (Fig. 2 C) and the most not at eye contact surface Protruding above.In other modification, the end of measurement parts is at eye contact surface (Fig. 2 A to Fig. 2 B) raised above, and this makes it Be prevented from eyelid to slip on the top measuring parts, be therefore prevented from eyelid and device end aseptic eye contact surface or point Join element to contact.This then accidental pollution and the risk of intraocular infection during injection process can be reduced.

In other modification, eye contact surface include flange (such as Fig. 3 A1 to Fig. 3 A3, Fig. 3 B1 to Fig. 3 B3, Fig. 4 A and Fig. 4 B1 to Fig. 4 B2).Flange can provide the contact surface of expansion between equipment end and ocular, is thus positioned at ocular when equipment Increase the stability of equipment time upper, and reduce the pressure of the per unit area of equipment-eyes interface.Minimizing equipment-eyes are handed over The pressure of the per unit area of junction then the conjunctiva caused by equipment end can be reduced when equipment end compresses wall of eyeball and damage The possibility of wound.It is desirable for avoiding this conjunctival damage, because conjunctiva is covered by fine non-cuticulated epithelium, and described non-angling Epithelium contains polyesthesia nerve endings and pain receptor.

In some variations, flange can have featheredge, and described featheredge contacts with ocular, and allows eyelid on flange top Move on portion, but prevent eyelid from contacting with the aseptic eye contact surface of equipment end.Eye contact surface can also is that annular Flange (such as Fig. 4 A and Fig. 4 B1 to Fig. 4 B2).This annular flange flange still prevents the aseptic eye of eyelid and equipment end and connects Contacting surface contacts.

More particularly, as it is shown on figure 3, flange can have featheredge (Fig. 3 A1), described featheredge allows eyelid to slip over described flange And contact with the axle of equipment end.In optional modification, described flange can be that thick (Fig. 3 B1) is to prevent eyelid sliding Cross flange and prevent eyelid from contacting with equipment axle, being therefore prevented from the accidental pollution of injection site.When the eye of equipment end connects When flange at contacting surface is thick, its edge (the such as edge at its ocular) can be rounding to prevent ocular tissue The accident of (being such as coated with the conjunctiva of fine non-cuticulated epithelium, described non-cuticulated epithelium is rich in nerve endings and pain receptor) Damage.In the optional modification of equipment end, eye contact interface can be flat (Fig. 3 A1 and Fig. 3 B1), convex (Fig. 3 A2 and Fig. 3 B2) or recessed (Fig. 3 A3 and Fig. 3 B3) to reduce the possibility of the accidental injury to ocular tissue (such as conjunctiva), simultaneously There is provided and apply a force on wall of eyeball and increase the device of intraocular pressure so that needle-penetration wall of eyeball, be also used at injection process Period partly fixes eyes by providing the attachment friction interface of eye contact surface.Fig. 4 A and Fig. 4 B to Fig. 4 B2 illustrates The stereogram of flanged contact surface and front view.

In also having other modification, eye contact surface may be configured to (such as Fig. 5 and Tu that be flat, convex, recessed or that tilt 7).In Fig. 5 A1 to Fig. 5 A2, equipment end has flat eye contact surface.In an alternate embodiment of the invention, equipment end has prominent That go out or convex eye contact surface (Fig. 5 B1 to Fig. 5 B2), this can compress when wall of eyeball causes wall of eyeball recessed contracting at equipment end and improve Contact between inside opening and the ocular of equipment end.In also having another modification, the eye contact surface of equipment end is indentation Or recessed, which reduce the risk of accidental injury to ocular tissue (such as conjunctiva).This of the eye contact surface of equipment end Plant configuration and can reduce the possibility of the accidental injury to ocular tissue (such as conjunctiva), provide simultaneously and apply pressure to wall of eyeball Go up and increase the device of intraocular pressure so that needle-penetration wall of eyeball, being also used for during injection process by offer equipment-eye Table adheres to friction interface and partly fixes eyes.

More particularly, as it is shown in fig. 7, eye contact surface can be flat and be perpendicular to major axis (Fig. 7 A1 extremely figure of described equipment 7A2), or flat and relative to described equipment major axis tilt (Fig. 7 B1 to Fig. 7 B2) (such as, take relative to the major axis of equipment Angle beyond for 90 degree, such as from about 45 degree to about 89 degree), or major axis that is convex and that be perpendicular to equipment (Fig. 7 C1), or It is convex and major axis relative to equipment tilts (Fig. 7 C2), or (Fig. 7 D) of circle or (Fig. 7 E) of ellipse.One In individual modification, eye interface is circular or (such as, being similar to the end of cotton swab) of ellipse.The thickness of eye contact surface is permissible It is from about 0.01mm to about 10mm, from about 0.05mm to about 5mm or from about 0.1mm to about 2mm.

Eye contact surface can include one or more feature contributing to and being stablized in ocular.Such as, a change In type, eye contact surface includes that multiple attachment friction element, such as protuberance, ridge are dashed forward etc., and described attachment friction element adds eye Contact surface surface attachment frictional force in ocular is without there being abrasive action.During this eye contact surface can provide or high attachment rubs Wipe interface to prevent equipment from moving stable for equipment in ocular and during medicine delivers within the eye.In another modification, eye Contact surface includes attaching interface, such as aspirating mechanism.The type changing the material for manufacturing a contact surface can also contribute to Prevent its sliding in ocular.

Can also contribute to prevent the abrasion to ocular, scraping or stimulate for manufacturing the material of a contact surface.Adoptable Exemplary non-lost material includes but not limited to: nylon fiber, cotton fiber, hydrogel, spongy material, polystyrene foam material Material, other foam-like material, silicones, plastics, PMMA, polypropylene, polyethylene, PEP (PEF) and polytetrafluoro Ethene (PTEE).These materials can be smooth hard, semi-rigid or soft, and can desirably prevent through sclera dispose Conjunctiva abrasion, subconjunctival hemorrhage or other accident trauma (Fig. 6) to ocular tissue during pin.May be used without typically using In the material manufacturing stealthy mirror.

In some variations, the edge of eye contact surface be also rounding to prevent from (being such as coated with fine to ocular tissue The conjunctiva of non-cuticulated epithelium, described non-cuticulated epithelium is rich in nerve endings and pain receptor) accidental injury.In this situation Under, as shown in Figure 6, eye contact surface can have contour, and described contour is corresponding to the contour (Fig. 6 A1 to Fig. 6 A2) of equipment end.? In other modification, outside the contour of the axle that the contour of eye contact surface can be projected into equipment end, (Fig. 6 B1 is extremely to be consequently formed flange Fig. 6 B2).Flange can increase the eye contact surface of equipment end, maintains the elongated profile of the axle of end simultaneously so that it is can easily insert Enter between the eyelid of eyes in crack.

Eye contact surface also can provide softness or deformable handing-over surface, and described handing-over surface medicine within the eye delivers Comply with described ocular when being placed against ocular during process.Directly connect with the described handing-over surface of disclosed equipment The ocular touched includes but not limited to: the ocular of orbiculus ciliaris overlying regions (described region be defined to after corneal limbus and The border circular areas between about 2mm to 7mm around) or between precontract 2mm and the most about 2mm of corneal limbus and around corneal limbus Corneoscleral junction region.The handing-over surface complying with ocular curvature can make it possible to form optimum contact friendship between equipment and eyes Junction, and can ensure that intraocular drug delivery process is aseptic and eyes fixing, this then the security of injection process can be improved.With Eye interface material in equipment is the material (deformable or soft) usually complying with ocular, particularly complies with angle and consolidates After film edge, the curvature of the eye outer surface in orbiculus ciliaris region, about 2 to 5mm place is so that intravitreal drug application, and Comply with corneoscleral junction region so that anterior chamber's medicine application.As it was earlier mentioned, the non-angling conjunctiva to ocular and cornea can be used Epithelium is without the material of abrasiveness.Especially, material and its configuration (such as, foam, braiding, knitting, intertexture, fibre bundle, etc.) In can including being formed or the material of high attachment friction surface and configuration (such as hydrogel or cotton), described in or high attachment rub Wiping surface makes eyeball can fix during injection process.

In some variations, the material of eye contact surface changes its characteristic when contacting fluid, such as, reduces its attachment friction Coefficient (such as in the example of cotton fiber), this can reduce the risk of conjunctiva abrasion when eye contact surface contacts with ocular.At it In its modification, composition eye contact surface material touch cover ocular fluid (such as tears) time do not change its physics and Chemical characteristic.

It is hemorrhage that eye contact surface as herein described can desirably prevent conjunctiva and/or episclera during intraocular pin is injected.Example As, can by include annular eye interface equipment compress wall of eyeball, this then apply pressure to conjunctivae and selerae outer blood vessel, Thus reduce the blood flow by there.Assuming that by the Oligemia of these blood vessels, then can reduce within the eye during injection process The risk of subconjunctival hemorrhage.After medicine application completes within the eye, pin is recalled, but ring-shaped end can still compress wall of eyeball, Thus apply lasting pressure to conjunctivae and selerae outer blood vessel and reduce hemorrhage wind further and/or extent of hemorrhage dropped To minimum.

In some variations, the eye contact surface that equipment includes plays the function of medicament reservoir.Can mix at this medicine or It is coated on the material of a contact surface.Medicine can spread from eye contact surface, adhere to ocular subsequently.For comprising the model of medicine Example material is hydrogel and its derivative.

Eye contact surface also can cover distribution member (conduit) (such as entry needle), and (such as, eye contact surface can be to cover completely The block of lid pin), this can make the syringe can be by end (far-end of such as block) is compressed wall of eyeball and executed by pressure Add on eyes.This then intraocular pressure can be increased with wall of eyeball before pin contacts, and thus can be easy to pin puncture, because of For compared to the wall of eyeball punctured by the pin in conventional syringe, wall of eyeball is more tightened.Typically, with the pin of conventional syringe Puncture more difficulty, because produced relatively low intraocular pressure makes the most yielding and easy movement of wall of eyeball.Additionally, cover The equipment end of distribution member (conduit), such as entry needle, it is possible to protect described distribution member not and connect with the accident of eyelid because of it Touch and be contaminated.

Intraocular pressure controlling organization (wall of eyeball tension control mechanism)

In delivery process (such as, intraocular injection or the intravitreal injection) period control to intraocular pressure (IOP) Can be favourable.Before the deployment of distribution member (conduit), apply limited intraocular pressure can reduce sclera pliability, this turn And any discomfort sense that can reduce in ocular during injection process and/or prevent equipment backlash.Typically, term " backlash " refers to Be conduit due to the pliability of sclera and elastic and cannot smoothly puncture wall of eyeball, this makes to thrust at conduit and pass through to consolidate Before film, sclera is retracted into certain point and reversely promotes conduit and equipment.Thus, equipment as herein described can include one or many Individual IOP controlling organization, referred to herein as wall of eyeball tension control mechanism.This is because wall of eyeball tension force ratio is relevant to, And it is partly dependent on intraocular pressure.The other factors that can affect wall tension force is scleral thickness and rigidity, and described factor can be because of Patient age, sex and individual variation and change.

IOP mechanism can be during the placement of equipment end target location in ocular and location and/or at medicine IOP is controlled during the intraocular of distribution member (conduit) or vitreum inner position during intraocular or intravitreal injection.Such as, IOP Mechanism can be before the intraocular of distribution member or vitreum inner position or period controls IOP, and described distribution member is for through sclera Or through keratonyxis.Once occurring to be punctured ocular by distribution member, typically, IOP will reduce.The minimizing of this IOP can by Distribution member occurs after puncturing ocular immediately.

In some variations, IOP controlling organization allow equipment (can) in equipment end target location in ocular The IOP between 15 to 120mm Hg is produced during the placement at place and location and/or during the intraocular location of distribution member.At it In its modification, IOP controlling organization allow equipment (can) in the placement of equipment end target location in ocular and fixed IOP between 20 to 90mm Hg is produced during Wei and/or during the intraocular location of distribution member.In also having other modification, IOP Controlling organization allow equipment (can) equipment end target location in ocular placement and location during and/or IOP between 25 to 60mm Hg is produced during the intraocular location of distribution member.

IOP controlling organization may also allow for equipment (can) will during any duration of injection process within the eye IOP maintains between 10 to 120mm Hg, or between 15 to 90mm Hg or between 20 to 60mm Hg.In some variations, if Intraocular pressure exceedes a certain predetermined value, such as 120mm Hg or 60mm Hg or 40mm Hg, then drug injection speed is by equipment Reduce or stop completely.This IOP controlling organization may be configured to detect during drug injection within the eye such as 90mm Hg or The IOP level of 60mm Hg or 40mm Hg.

IOP controlling organization can include spring or its can include machinery or electric control mechanism.It is said that in general, IOP controls machine Structure is configured to balance the stop pressure of the frictional force of injection piston and fluid injection and (pushes fluid through pin and enter pressurized eye fluid Required power).IOP controlling organization can be linked to apparatus casing and actuating mechanism by some way, and described mode allows automatically to adjust The power that the deployment of whole distribution member and plunger move ahead.It is to say, IOP controlling organization may be configured to realize the predetermined of distribution member The power of level and predetermined intraocular pressure level.Additionally, before the employing of IOP controlling organization can produce than distribution part deployment IOP high for tranquillization IOP, thus reduce that sclera is elastic and the possibility of equipment backlash, and be easy to be punctured sclera by distribution member.

In a modification, IOP controlling organization is pressure-reducing valve, once reaches maximum pressure, and described pressure-reducing valve makes injected current From by-passing around.In another modification, IOP mechanism is accumulator, and IOP is suppressed in the range of specific by described accumulator.IOP Some modification of controlling organization can include pressure sensor.In also having another modification, IOP controlling organization includes slidable cover Cap, described block covered distribution member before distribution member is disposed, but can slide along the surface of apparatus casing or retract with example As made distribution member expose when reaching predetermined IOP level, disposing or move ahead.The slip of block can be the most adjustable (such as utilizing dial) or the most adjustable, stepping or substantially be incremented by.Such as, as shown in figure 40, integrated note Jet device (500) the most also includes: block (502), retainer (504), trigger (506), spring (508), plunger (510), seal (512), medicament reservoir (514), pin (516) and syringe (518).In use, When block (502) is disposed against ocular and pressure is applied in ocular, along with syringe (518) and pin (516) are pushed into, (in the direction of arrow) to retainer (504) is the most proximally retracted in block (502).Subsequently can depression of trigger (506) (example Such as lever) to discharge spring (508), described spring-advance plunger (510) and seal (512) are with from medicament reservoir (514) Medicine is injected by pin (516).Once having injected medicine, block (502) slides back in pin (516) top.

It is also with lockable mechanism to prevent block, lid or eye contact surface from sliding or anti-before reaching predetermined IOP The only deployment of distribution member.Lockable mechanism can also be used for preventing block, lid or eye contact surface when the most predetermined IOP Slide.Such as, when IOP reaches predeterminated level (between such as 20mm Hg to 80mm Hg), can slide in as herein described including On the equipment of dynamic lid, block etc., included lockable mechanism can manually or automatically discharge.This lockable mechanism can wrap Include but be not limited to: high attachment friction surface, lock pin, interlocking ridge or any other type of lockable mechanism, described locking machine Structure prevents the end (block of such as equipment or lid) of equipment from sliding and thus exposing pin.

In also having other modification, IOP controlling organization is being positioned at the block on distribution member, lid or eye contact surface On include high attachment friction surface or ridge.This feature may be arranged on the inner surface of block, lid or eye contact surface and structure Cause so that when sliding in the proximal direction, height adheres to friction surface or ridge and apparatus casing or other suitable equipment portion Counter structure (such as fold, depression, protuberance, other ridge) on the surface of part coordinates to provide block, lid or eye to connect The contacting surface resistance (thus increasing wall of eyeball tension force and IOP) to wall of eyeball.In this case, IOP controlling organization includes dynamically Stop member, as further discussed below.As it was noted above, it is hand that block, lid or eye contact surface are configured so to slip Dynamic or the most adjustable, stepping or substantially incremental.When using ridge, any suitable quantity, and they can be used Can be any suitably sized, shape and geometric shape.Such as, ridge can circularly be arranged in block, lid or Within eye contact surface.In some cases, ridge is configured with the surface of Different Slope.Such as, distal surface may be configured to More precipitous than proximal end face.There is this design, incremental cunning can have been produced when block, lid or eye contact surface proximally slide The dynamic incremental increase with IOP, but also can complete block, lid or eye contact surface sliding back to above distribution member, because near-end Ridge dash forward surface slope reduce.

Dynamically stop member

Can include that by making injection device dynamic stop member completes and the pressure to ocular that becomes more meticulous further.Dynamically Stop member can include the slidable element being linked to housing.In some variations, slidable element includes dynamic sleeve pipe, described Dynamically sleeve pipe is configured to regulation and applies the amount of the pressure to ocular, as further discussed below.As it was earlier mentioned, wall of eyeball tension force Some modification of controlling organization plays the effect of dynamic stop member.

Dynamically stop member also may be configured to dynamic sleeve pipe.Being similar to previously described slidably block, dynamic sleeve pipe can It was configured to before pin is injected increase intraocular pressure and the tension force of wall of eyeball.But, dynamic sleeve pipe can be manually actuated with by The amount (and thus regulating the amount of wall of eyeball tension force) of the pressure that this regulation is applied in ocular.Have and manually regulate pressure applied Ability can allow injector (user) that injection site is placed and injection angles has the control of improvement, and also improve The ability that equipment was stably positioned in ocular before the deployment of pin by user.It is said that in general, dynamically sleeve design becomes to make The target site that equipment end can be positioned accurately in ocular of user equipment end is firmly compressed eye Ball wall is to increase wall tension force and intraocular pressure.Dynamically sleeve pipe can be used for sleeve movement start with the deployment of pin before by intraocular pressure Power rises to predeterminated level, as described above.Should be understood that term " dynamic sleeve pipe ", " sleeve pipe ", " dynamic sleeve pipe stop control machine Structure " and " sleeve pipe blocking mechanism " be interchangeably used in full.Dynamically sleeve pipe is generally configured such that when user is on sleeve pipe When applying pulling force (such as recalling), this motion can be easy to pin and exposes and reduce the amount (as little as 0 newton) of pressure (" N " refers to power Unit " newton "), described pressure is applied to wall of eyeball so that sleeve pipe slides back to and exposes the pressure needed for pin.Dynamically sleeve pipe also may be used It is configured so that, when user applies thrust (such as moving ahead) on sleeve pipe, this motion can offset and stop pin to expose, and this can Permission equipment end applies the pressure increased at the forward direction wall of eyeball that sleeve movement starts to expose with pin.

Dynamically some modification of sleeve pipe provides the variable force following U-shaped curve, such as institute further in example 1 and Figure 46 State.Highest resistance is run at dynamic sleeve pipe along the initial of housing motion and destination county at this, and initial at dynamic canula stroke And be the resistance reduced between terminal.In use, this is converted into and has the initial high-drag stage (when being initially placed at eyeball Time on wall) it is followed by pin proceeds to a chamber period drag reduction to sleeve movement.When pin is fully deployed, typical case Ground, dynamic sleeve pipe is by the terminal in its travel paths, and will again run into the resistance of increase.The increase of this resistance allows sleeve pipe Smooth, stop (rather than destination county is unexpected stiff stop) step by step the transmission of the power to inactive wall of eyeball to be damaged The risk of wound amount is down to minimum (this turns back and is down to minimum by the risk causing discomfort or injury eyes).At this exemplary dynamically Sleeve pipe may be configured to the most tapered.With reference to the sectional view in Figure 42, integrated injection device (42) includes housing (44), whole or in part around barrier strip (46) and the dynamic sleeve pipe (48) of housing, described dynamic sleeve pipe can be at housing (44) move ahead movably on and retract.Dynamically sleeve pipe (48) has tapered near-end (50) and far-end (not shown).Tapered End can be at dynamic sleeve pipe along initial and destination county (the i.e. initial and terminal of the deployment of pin of the travel paths of apparatus casing (44) Place) higher attachment friction is provided.At the section start of dynamic sleeve movement, when its contact barrier strip (46), in near-end (50) The tapered of place provides higher attachment friction and resistance.The thickness of barrier strip (46) can be hindering so that regulation is required of change The amount of power.When arriving wider interstitial segment (52), encounter relatively low attachment friction and the motion of lower drag, be followed by The destination county of the deployment of pin, when arrive at dynamic boot proximal end tapered time higher attachment friction and higher resistance.With Dynamically sleeve pipe and become the most tapered at far-end, apparatus casing is created more attachment friction until it is the most complete Stop.In addition to two ends are the most tapered, in some variations dynamically sleeve pipe can be one of proximally and distally tapered.

Also can be provided variable attached by parts (the such as circular embossed belt on the outer surface of equipment end or ridge prominent) Frictional force.When close to and against the circular embossed belt of another on the inner surface of removable dynamic sleeve pipe or ridge prominent (internal band or Ridge is dashed forward) time, these parts can provide and reversely adhere to friction.Before starting to move at dynamic sleeve pipe, outwardly and inwardly band or ridge are dashed forward When contacting with each other, they produce high attachment friction and the high-drag to dynamic sleeve movement.Once dynamically sleeve pipe starts mobile, Embossed belt on the outside of apparatus casing is moved through the embossed belt on the inside of dynamic interlocking state sleeve pipe, and this may result in dynamically The rapid minimizing of the resistance of sleeve movement, and thus reduced by equipment end pressure on wall of eyeball.The mutual lock strap of relief or ridge Prominent shape generally defines the shape of drag reduction.Such as, the minimizing of resistance can follow the curve of sinusoidal shape.

In another modification, dynamic sleeve pipe can produce and persistently reduce the power to its minimum point from its peak, described the highest Point is before the deployment of pin (when dynamic sleeve pipe is completely covered pin), and described minimum point is to start to move with dew at dynamic sleeve pipe The when of going out needle point.Hold relatively low here, try hard to keep until dynamic canula stroke terminates and completes the deployment of pin.This style of resistance Minimizing can follow the curve of sinusoidal shape.

Dynamically slidably moving ahead of sleeve pipe can produce from 0N to the power of about 2N scope between himself and housing.At some In the case of, slidably moving ahead of dynamic sleeve pipe produces from about 0.1N to the power of about 1N scope between himself and housing.

Measure parts

Equipment as herein described can include measuring parts, and described measurement parts can help to determine intraocular injection in ocular The position at position.Integrated equipment generally includes measurement parts.Measure parts can be attached regularly or be removably attached to eye Contact surface.Can be raised above so that it prevents the aseptic of eyelid and equipment end in ocular as it was earlier mentioned, measure parts Eye contact surface carries out contacting (such as Fig. 2 A to Fig. 2 B and Fig. 8).The particular configuration measuring parts can also contribute to aseptic The risk of the accidental pollution of medicine distribution member (conduit) (such as entry needle) is down to minimum.This pollution can arise from multiple Reason, the most aseptic pin carries out unexpected contact with eyelid or other non-sterile surface.Also parts will can be measured by some way Colour to provide the color contrast to ocular (including conjunctiva, sclera and iris).

It is said that in general, measure parts, intraocular injection position can be had a common boundary away from corneal-scleral by being arranged in more accurately Place specific range and locate before it or afterwards, described corneal-scleral intersection is referred to as " corneal limbus ".In some modification In, measure parts can be used for being arranged in intraocular injection position after corneal limbus from about 1mm to about 5mm, from about 2mm to about 4.5mm or at about 3mm to about 4mm.In another modification, measure parts and can be used for intraocular injection position is arranged in cornea After edge at about 2mm to about 5mm, or after corneal limbus at about 3.5mm.In other modification, measure parts can be used for by Intraocular injection position is arranged within corneal limbus about 3mm or about 2mm and locates before it, or away from corneal limbus about 0.1mm extremely Between about 2mm and locate before it.In a modification, measure parts for intraocular injection position is arranged in corneal limbus it Precontract 1mm is between about 6mm after corneal limbus.In another modification, measure parts for intraocular injection position is arranged in angle After film edge between about 3mm to about 4mm.

Measure parts and can have any suitable configuration.Such as, measure parts and can be located at the side of a contact surface, or be positioned at More than side (such as Fig. 9, Figure 10 and Figure 11) of eye contact surface.Here, consolidate when the end measuring parts is arranged in next-door neighbour angle During film edge, the position of intraocular pin injection is arranged in away from corneal limbus specified distance, such as about 3mm to about 4mm after corneal limbus Between.

In optional modification, measure parts and include one or more element (such as Fig. 9, Figure 10 and Figure 11).These Element can be from the radial stretching, extension of eye contact surface.Formed measurement parts by more than one element to it is advantageously ensured that and be perpendicular to corneal limbus And non-tangentially measure the distance between corneal limbus and injection site, because when measurement apparatus includes discrete component likely It it is this tangential situation.When the end of all elements that composition measures parts aligns along corneoscleral junction, the injection of intraocular pin Position is arranged in away from the specific distance of corneal limbus, such as after corneal limbus between about 3mm to about 4mm.

More particularly, as shown in Figure 8, the equipment end with a contact surface includes measuring parts (80), described measurement portion Part makes it possible to determine injection site at a certain distance from relative to corneoscleral junction.As it was earlier mentioned, in a modification, measure Parts are positioned at the side of equipment end.In another modification, more than one is measured parts and is positioned at more than side of equipment end.? Also have in other modification, measure the end of parts can be protruding, bending, etc., this prevent eyelid and slip over measurement portion Part also carries out unexpected contact with the distribution member of equipment (conduit).The most in fig. 8, distribution member (conduit) is shown as the most hidden Within equipment end.

Fig. 9 provides other details about another modification measuring parts.Include that at this equipment end the eye of annular connects Contacting surface (90) and measurement parts (91), described measurement parts make it possible to determine injection at a certain distance from relative to corneoscleral junction Position.The periphery carrying out contacting with ocular of equipment end has the eye interface of such as annular, and distribution member (is such as injected Pin) equipment terminus inner can be hidden in and protected by it.In fig .9, measure parts (91) and be positioned at side (Fig. 9 A of equipment end To Fig. 9 B) or more than side (Fig. 9 C) of equipment end.Thus, when the end next-door neighbour's corneoscleral junction measuring parts is arranged, eye The position of interior pin injection is arranged in away from corneal limbus specified distance, such as after corneal limbus between about 3mm to about 4mm.Any Appropriate number of measurement parts may be provided on equipment end, such as, be attached to a contact surface.When using multiple measurement parts, They can use any suitable pattern to be arranged in around a contact surface.Such as, they can be arranged in a circular formation around eye contact surface Or the side at eye contact surface.They can around the contour of ocular equal or different spaced apart.In other modification, measure parts Can be symmetrically spaced open or the most spaced apart around the contour of eye contact surface.These configurations can advantageously allow syringe along long Axle slewing.

Figure 10 A provides other view measuring parts to figure C, and described measurement parts are similar to shown in Fig. 9 A to Fig. 9 C Measure parts.In Fig. 10, the eye contact surface (93) of annular is shown as has measurement parts (93), and described measurement parts make it possible to Relative to corneoscleral junction (94) certain distance and be perpendicular to corneoscleral junction (94) place and determine injection site.Measure parts to be shown as The side of equipment end, or in more than side of equipment end in another modification.Again, measure parts can include one or Multiple elements.Formed measurement parts by more than one element to it is advantageously ensured that and be perpendicular to corneal limbus and non-tangentially measure angle Distance between film edge and injection site, because being likely to be this tangential situation when measuring parts and including discrete component. When the end of all elements that composition measures parts aligns along corneoscleral junction, the position of intraocular pin injection is arranged in away from corneal limbus Specific distance, such as after corneal limbus between about 3mm to about 4mm.

In Figure 11 A to Figure 11 D, it is also shown for more than one measures parts.Measure parts (95) to be shown as from eye contact at this Same attachment point (96) on face is stretched out.When forming the end of all elements of described measurement parts and aliging along corneoscleral junction, The position of intraocular pin injection is arranged in away from the specific distance of corneal limbus, such as after corneal limbus between about 3mm to about 4mm.

Alternatively, measure parts and may be configured to one or more flexible measuring bar.Can be used for manufacturing the flexible material measuring bar Material includes flexible polymer, such as silicones.As shown in Figure 44 A, measuring bar (800) can be from equipment end (802), generally from eye The side of contact surface (804) stretches out, thus the distance measuring between corneal limbus and injection site while corneal limbus can be perpendicular to.Can adopt With register guide parts (806) to guarantee correctly to use measurement bar (800).Such as, as shown in Figure 44 B, when location instruction When device parts are fully tightened, it may be determined that measure bar (800) and be properly positioned and (thus measuring shape between bar and apparatus casing (808) Become an angle of 90 degrees).On the contrary, lax register guide parts (as shown in Figure 44 C) show incorrect location.Register guide Parts can be rope.In a modification, integrated equipment includes that at least three measures bar.In another modification, integrated Equipment includes that at least four measures bar.When using multiple measurement bar, they may be configured in any suitable manner around collection The end of forming apparatus (it is equally spaced around the contour of a contact surface, symmetrically or asymmetrically contour around eye contact surface to arrange, etc. Deng).Such as, as shown in Figure 44 D, measurement bar may be configured to cross over required an angle of 90 degrees and (is 45 degree between farthest bar and adds 45 Degree) so that permission controls 90 degree of rotations of bar, the hand without user replaces.

In some variations, measure parts to may be configured to mark end component (97).As shown in figure 12, at its far-end The mark end component (97) of (closer eyes) joins with ocular and leaves visible mark when compressing conjunctival surface thereon Note (98) (such as Figure 13).The region relative to corneoscleral junction (99) safety that mark end makes it possible to by eyes realizes eye Interior injection, such as after corneal limbus between about 3mm to about 4mm, on the region, capsulociliary par of eyes.Mark end Diameter (such as can scheme to the scope of about 2.4mm from about 1mm to about 8mm or from about 2mm to about 5mm or from about 2.3mm 12).

Conduit

Intraocular drug delivery equipment as herein described can include any suitable conduit (or distribution member) to arrive eye Bioactive agent delivery is also delivered to wherein by interior space.Conduit can have any suitable configuration, but be generally of near-end, far-end and The inner chamber extended by it.When the first, not disposing (before deployment) state, within conduit is usually located at housing.The second, Deployable state, i.e. after actuating mechanism activates, typically, conduit or one part will stretch out from housing." near-end " means The hand near user and the end at the end opposite near eyes when equipment is located against ocular.

The far-end of conduit is normally constructed to sharp-pointed, that splay or otherwise can pierce through ocular (such as sclera). The conduit used can be any suitable specification (gauge), such as, and about 25 specifications, about 26 specifications, about 27 rule Lattice, about 28 specifications, about 29 specifications, about 30 specifications, about 31 specifications, about 32 specifications, about 33 specifications, about 34 rule Lattice, about 35 specifications, about 36 specifications, about 37 specifications, about 38 specifications or about 39 specifications.The wall of conduit also can have Any suitable thickness.Such as, in addition to conventional wall thickness (RW), the wall thickness of conduit may be designed to thin-walled (TW), spy/ultra-thin-wall Or special special thin-walled (XXTW) (XTW/UTW).Known to these entitled those skilled in the relevant art.Such as, conduit can be Intubating or pin of thin specification.In some variations, conduit can have the specification between about 25 to about 39.In other modification, lead Pipe can have the specification between about 27 to about 35.In also having other modification, conduit can have the specification between about 30 to about 33.

Conduit can have end (Figure 14 B to Figure 14 C and Figure 15 A1 to Figure 15 A2) sharp-pointed, band tip rather than picture Circular distal (Figure 14 A) in conventional pin.Syringe needle with tip is formed by lateral side surfaces, and described lateral side surfaces is at it Be straight to the assembling of end, and at assembling, define ramp angles (inclined-plane and axle by pin are formed), described tiltedly Angle of slope can be between about 5 degree to about 45 degree (Figure 14 B), between about 5 degree to about 30 degree, between about 13 degree to about 20 degree or about The scope of (Figure 14 C) between 10 degree to about 23 degree.

Sharply, the pin end of band tip needle-penetration scleral tissue fibrous, fibrous can be made to be improved, described Gong Membrane tissue is the primary structural covering of eyes and comprises strong collagenous fiber network.Therefore, this needle point can pierce through eyeball at it Form less resistance during wall and thus reduce the impulsive force being transferred to intraocular structure (such as retina and crystalline lens), then The less damage to intraocular structure (pin compared to conventional) is caused within the eye during injection process.

Additionally, this narrow ramp angles can make pin can pierce through wall of eyeball at it, (outer layer of described wall of eyeball is complete Entirely being arranged by Sensory nerve fibre tip, described Sensory nerve fibre tip is positioned in conjunctiva and cornea the most thick and fast) time draw Play less sensation, compared to other less sensitive position, when relating to intraocular injection, described in the sensation that causes can be to ask Topic.

Narrow ramp angles also allows for longer chamfer length and bigger inclined-plane opening and thus at entry needle The bigger opening of far-end.When having this configuration, the power in infusion of medicine eye chamber can reduce, and thus reduces eye inner tissue By the possibility of strong injected material mass flow damage, this when with conventional short inclined-plane pin it may happen that.

In some configuration, conduit is to have one or more flat table planes and one or more sides cut surface Entry needle, as shown in Figure 16 and Figure 17.This example includes: have the needle shaft of the multiple table planes separated of being dashed forward by sharp ridge (Figure 16 A to Figure 16 C), and there is the needle point of sharp side cut surface, described side cut surface be positioned at the inclined-plane of pin either side, At about 90 degree of inclined-plane (Figure 17).Conduit can also be bibeveled, i.e. has two inclined-planes, about 180 degree of said two inclined-plane Ground is facing with each other and is positioned at the both sides of conduit.Conduit can also be cated (such as scribble silicones, PTFE, etc.) so that Wall of eyeball is pierced through in it.

In other modification, conduit may be configured to the most flattened, as along Figure 18 A Line A-A intercept Figure 18 C sectional view shown in.Such as, conduit can be the most flattened (i.e. lateral from the inclined-plane of pin Its offside).In a modification, the outer surface of pin and inner surface is the most flattened and be rendered as on section ellipse.Separately In one modification, the inner surface of pin is circle and is rendered as ring on section, and the outer surface of pin flattened allow it to lighter Loose ground pierces through fibrous sclera or the cornea tissue of wall of eyeball.In another modification, the more than one outer surfaces of pin is opened up Put down and allow it to more easily control pierce through fibrous wall of eyeball, and the inside opening of described pin can be any shape, bag Include circle or ellipse.

As it was earlier mentioned, stretch out housing at deployable state the second, conduit or pin.The part stretching out housing of pin can It is referred to as the pin section exposed.When mechanism is actuated at actuating, pin from the first, non-deployable state (state before Bu Shuing) (described Under state, it is completely in the housing of equipment) become its outside housing second, dispose configuration, under described configuration it dew Go out certain length.This length exposed can from about 1mm to about 25mm, from about 2mm to about 15mm or from about 3.5mm to about The scope of 10mm.The pin section that these expose can make to realize intraocular completely and puncture, and is entered by sclera, choroid and ciliary body In vitreous chamber, the risk of intraocular damage is down to minimum simultaneously.In some variations, the pin Duan Cong about 1mm exposed is to about 5mm or from about 1mm to about 4mm or from about 1mm to the scope of about 3mm.The pin section exposed at this can make to realize eye completely Interior puncture, is entered in anterior chamber by cornea, is down to minimum by the risk of intraocular damage simultaneously.

In some variations, equipment can include for distribution member (11) (conduit) expose controlling organization (9) (Figure 19 and Figure 20).Expose controlling organization (9) generally to allow users to be set in the maximum that during distribution member is disposed, distribution member exposes Length.In a modification, expose controlling organization by providing retrogressing stop to work for pin protection element (13).At another In modification, exposing controlling organization (9) can be with the revolution ring that can dial scale.Can be come by a part for millimeter or millimeter Exposing of metering needle, such as 1mm, 1.5mm, 2mm, 2.5mm, 3mm, etc..Retraction mechanism, described contracting is may be provided with at this equipment Return mechanism controls pin to be retracted in pin protection element.This needle retraction mechanisms can be spring-actuated (Figure 20).

Equipment may also include detachable far-end (towards the eyes) element (protecgulum in such as Figure 21 covering and protecting conduit (15)).In a modification, equipment may also include detachable near-end (away from eyes) element (such as, the bonnet in Figure 21 (19)), described proximal members covers and protects the proximal part of equipment, and such as, described equipment includes loading docking mechanism (17).

Reservoir

Reservoir is typically housed in enclosure interior and can construct in any suitable manner, as long as it can utilize institute herein Bioactive agent delivery is delivered in intraocular space by the actuating mechanism stated.Reservoir can accommodate any for intraocular space, such as vitreum The suitable medicine in interior space or formula or medicine or the combination of formula.Should be understood that term " medicine " and " agent " are in the most in full Use convertibly.In a modification, medicament reservoir without silicone oil (not one of silicate-containing oil or derivatives thereof) and Do not covered or lubrication by silicone oil, its derivative or its improvement thing in inside, which ensure that silicone oil will not enter in eye and cause flying Mosquito disease or intraocular pressure raise.In another modification, medicament reservoir without any lubricant or sealant and in inside not by Any lubrication or sealing material lubrication, which ensure that described lubrication or sealing material will not enter in eye and cause muscae volitantes or eye Interior pressure raises.

In some variations, reservoir is made up of a kind of material, and described material includes that cyclenes system resin, cyclenes-ethene are common Polymers (includes that commercially available prod is such asCyclic olefin polymer (ZEON company, Tokyo, Japan) or CrystalOlefin polymer (great Xie Jinggong Co., Ltd, Tokyo, Japan) and APEL^TMCyclic olefine copolymer (COC) (three Well KCC, Tokyo, Japan)), cyclenes-ethylene copolymer, PET series resin, polyphenyl second Olefine resin, polybutylene terephthalate (PBT) resin and combinations thereof.In a modification, use cyclenes system resin and Cyclenes-ethylene copolymer is favourable, described cyclenes system resin and cyclenes-ethylene copolymer have the high grade of transparency, high-fire resistance, And with pharmacology product (such as protein, protein fragments, polypeptide or include antibody, acceptor or protein-bonded chimeric point Son) minimum or even there is no chemical reaction.

Exemplary medicament is selected from such as following class: antiphlogistic (such as steroid and non-steroid), anti-infective Medicine (such as antibiotic, antifungal agent, antiparasitic, antiviral drugs and disinfectant), cholinergic antagonist and excitement Agent, adrenaline antagonist and activator, antiglaucoma agent, neuroprotective agent, for cataract prevention and the medicament for the treatment of, anti- Oxidant, antihistaminic, anti-platelet agents, anticoagulant, antithrombotic agents, anti-scar agent, antiproliferative, anticancer, complement press down Preparation (such as, anti-C5 agent, including anti-C5a and anti-C5b agent), vitamin (such as, Cobastab and its derivative, vitamin A, Depaxapenthenol and retinoic acid), growth factor, the medicament for the Developing restraint factor, gene therapy vector, chemotherapy Medicament, kinases inhibitor, TYR inhibitors of kinases, PEGF(PE growth factor), small molecules interference RNA, its Analog, derivative, complex and its improvement thing and combinations thereof.

Can include individually or as non-limiting, the concrete example of the medicine that a part for composition of medicine therapy uses Lucentis^TM(Lucentis), Avastin^TM(bevacizumab), Macugen^TM(Pei Jianibu), steroids, such as, ground plug rice Pine, dexamethasone sodium phosphate, fluoxyprednisolone, Triamcinolone acetonide and FA, taxanes medicine, integration or anti-integrated agent, blood Endothelial tube growth factor (VEGF) inhibitor (VEGF Trap), anecortave acetate (Retaane) and do not take charge of compounds of group. The non-limiting example of the member not taking charge of compounds of group includes sirolimus (rapamycin) and its water-soluble analogues SDZ- RAD, tacrolimus, everolimus, Elidel and Zuo Tamosi and their analog, derivative, complex, salt Class and improvement thing and combinations thereof.

Reservoir may also comprise local anesthetic.Such as, lidocaine, proparacaine, procaine, Ding Ka can be used Cause, betacaine, benzocainum,(eutectic mixture of local anesthetic) and they Combination.

Reservoir as herein described and equipment are suitable to the eye of very small amount of solution, suspension, gel or semi-solid material Interior administration.Such as, can deliver between about 1 μ l to about 200 μ l or between about 10 μ l to about 150 μ l or about 20 μ l to about 100 μ l Between amount.To this end, equipment is generally of the least " dead angle ", described dead angle makes to realize very small amount of eye drops.

Equipment reservoir can during manufacture process prefilled or within the eye injection before manually load, as further Described.

Medicine filler

When medicine or formula were packed into before injecting within the eye the reservoir of equipment, filling element can be used.Dress Fill out element and can be removably attached to the far-end of housing.Such as, filling element may act as loading interfacing part, and described filling is docked Part quantitatively controls the volume of the liquid in equipment to be filled to, semiliquid, gel or liquid suspension pharmaceutical.Such as, filling unit Part can include drive disc mechanism (21) (Figure 21 and Figure 22), and described drive disc mechanism allows operator to preset equipment to be filled to In the volume of medicine.Can be loaded by the precision from about 0.01 μ l to about 100 μ l or from about 0.1 μ l to about 10 μ l scope. This filling element can allow with specific volume for equipment reservoir filling liquid, semiliquid, gel or liquid suspension pharmaceutical, institute Stating specific volume and store volume of a container equal to or less than medicine, this allows to be filled in equipment by medicine without air ground.This Being favourable, because the air injected in eye can cause patient to feel to see " floating thing ", this is driving or other is similar to especially Patient can be made not accommodate time movable to divert one's attention.

As shown in figure 22, medicine filling mechanism (23) includes roomy base component (25), and described base component is used for storing The storage (27) the upright filling by its remote (further away from eyes) end (29).It is illustrated that exemplary protecgulum (31) and bonnet equally (33), and for setting load and/or the controlling organization dialled (21) of volume injected.In other modification, equipment includes all As loaded the filling mechanism of interfacing part (35A), wherein (such as those skilled in the art are known for interfacing part (35A) and medicine storage container Bottle) handing-over (Figure 25 A to Figure 25 B) pierce through bottle stopper and with the medicine that touches vial contents and receive thus medicine can be packed into Equipment reservoir.In Figure 25 A to Figure 25 B, docking mechanism is positioned at hanging position, so that medicine bottle (37) is positioned directly in docking Above part, so that medicine moves down from bottle on gravity direction.

In a modification, docking mechanism includes that pin or sharp-pointed intubating, described pin or sharp-pointed intubating have at its base portion There are opening or fenestra (39).Load interfacing part simultaneously puncture to time in medicine bottle when being in desired loading position, described opening Or fenestra is located immediately adjacent the inside face of bottle stopper, this then achieve and without air, medicine be filled in equipment and by medicine Remove completely from storing container.Airfree medicine filling can be favourable, because it can prevent patient from seeing little intraocular gas Bubble or " suspension ".In view of typically using little dose and expensive medicine, fully remove medicine and be also advantageous.

In other modification, such as, when equipment, there is flat side surface (Figure 24 A to Figure 24 D) or flat front or rear surface (Figure 22), time, filling mechanism includes loading interfacing part, and described filling interfacing part is positioned at this 180 degree flat of surface.This causes Filling interfacing part directs at upwards so that it is can puncture to the medicament reservoir being in hanging position, this then make to achieve without empty Deliver the medicament in equipment gas, and by medicine from store container remove completely and be packed into described equipment without Drug carry and loss is had in storing container.

In other modification, as shown in Figure 33 A to Figure 33 B, can arrange at the far-end of needle assemblies (125) and be passed through mouth (144) being passed through mouth described in, allows the medicine from storing container (146) to be packed in reservoir (122).It is passed through mouth (144) May be arranged at any correct position on needle assemblies (125) or housing (102).Such as, if necessary, it is passed through mouth can arrange Housing antetheca or even in eye contact surface (not shown) so that medicine filling is carried out from the front portion of equipment.It is passed through mouth (144) can be made up of this material: described material allows sealably to be punctured by sharp-pointed conduit, such as silicones.Also can example As arrange in eye contact surface (108) one or more film (148) with seal up housing inner compartment stop air leakage and/ Or outside germ contamination.One or more little hole (150) is may also comprise to contribute to controlling sky in the wall (102) of housing Gas flows out from housing (102).The quantity of hole (150) and diameter can be disposing controlling (needle assemblies and) pin of changing Speed.

In some variations, such as, when using pneumatic actuating mechanism, medicine filling can be controlled by medicine filling piston. Such as, as shown in figure 38, equipment (400) can include that medicine filling piston (402), described medicine filling piston have near-end And far-end (406) (404).Far-end (406) is suitable to include threaded section (408).Thus, pass through from container (410) at medicine Adapter (412) and be passed through mouth (414) filling during, rotatable and retraction medicine filling piston (402) is with at reservoir (416) negative pressure is formed in.This negative pressure is transferred to draw medicine and by pin (418) and is entered reservoir (416).Equipment far-end also Receiver (420) can be set to accommodate the medicine of initially filling before transferring reservoir.

Actuating mechanism

Equipment as herein described is typically included in the actuating mechanism in housing, and described actuating mechanism disposes leading from housing Manage and make to realize being delivered to intraocular space medicine from equipment.In other modification, conduit is by being contained in single socket In actuating mechanism dispose, described single socket can such as utilize and be clasped or other interlocking member is removably attached to Apparatus casing.Actuating mechanism can have any suitable configuration, if its can accurately, hurtless measure and controllably by medicine It is delivered in intraocular space.Such as, medicine or formula can be delivered in eye by actuating mechanism via intraocular injection, and described intraocular is noted The speed penetrated is from about 1 μ l/ second to about 1ml/ second, from the about 5 μ l/ seconds to about 200 μ l/ seconds or from the about 10 μ l/ seconds to about 100 μ l/ The scope of second.Actuating mechanism generally can provide the power that pin is disposed, and described power is sufficiently strong includes conjunctiva, sclera and ciliary to puncture The wall of eyeball in region, body par, but less than causing the power of damage intraocular structure due to high speed impact.This power depends on some Individual physical factor, includes but not limited to: the pin at the specification of the pin used, the contact point between needle point and wall of eyeball is disposed Speed/rate, described speed/rate then determine impulsive force.The exemplary scope of the power that can be produced by actuating mechanism is about 0.1N(newton) to about 1.0N(newton).The speed that pin is disposed also can scope between about 0.05 second to about 5 second.

In some example, actuating mechanism is single spring mechanism.In other modification, actuating mechanism is dual spring mechanism. In other modification, actuating mechanism is pneumatic, the mechanism driven for example with negative pressure (such as vacuum) or malleation.At other In modification, actuating mechanism is magnetic or electrically driven (operated), such as, driven by piezoelectricity or track mechanism.The actuating mechanism of these types can structure Cause allow the independent speed controlling drug injection and power (such as being controlled by the first spring element in dual spring modification) and The speed of distribution member deployment and power (such as being controlled by the second spring element in dual spring modification).Exemplary dual spring mechanism It is shown in Figure 26 and Figure 27.

Figure 28 also show the exemplary integrated intraocular drug delivery equipment with dual spring actuation mechanism.In Figure 28, Equipment (100) includes the housing (102) with near-end (104) and far-end (106).Eye contact surface (108) is attached to far-end (106).Measure parts (110) and be attached to the side of a contact surface (108).As further discussed below, it is operatively coupled to The trigger (112) of housing (102) is cooperated with first spring (114) of actuating mechanism and the second spring (116) to dispose pin (118) by the opening (120) in housing (102), thus to deliver medicine from reservoir (122).Figure 29 preferably shows The first spring (114), the second spring (116), pin (118), opening (120) and reservoir (122) are gone out.Same at Figure 29 In, conduit (such as pin (124)) is shown as and is in its first non-deployable state in the housing.Pin (124) is configured to assembly (125) A part, so that the motion of assembly causes the corresponding motion of pin (124).Retainer (115) is arranged on the near-end of assembly (125) (127), described retainer is connected to far-end and the near-end of the second spring (116) of the first spring (114).Spring and equipment Other parts can via medical grade adhesive, rub or be clasped and connect.

In fig. 30, the second spring (116) is operable by the frictional fit in the compartment (134) of plunger (132) Be connected to plunger (132).State before actuating, as shown in figure 29, plunger (132) and the second spring (116) are protected by pin (118) Hold in position.Pin (118) at plunger recess (138) place movably with plunger (132) combine, and via with plunger recess And plunger (132) is locked in appropriate location by the frictional fit of housing (102) (138).

Being activated by first spring (114) of actuating mechanism by actuating trigger makes pin (124) be deployed to intraocular space In, say, that pin (124) is moved to its second deployable state (Figure 30) from its first non-deployable state (Figure 29) by it.Ginseng Examine Figure 30 and Figure 31 A to Figure 31 C, by being there is the first spring by such as one or two finger depression of trigger (112) (114) actuating, described finger also press push button (126).As shown in Figure 31 A and Figure 31 B, button (126) is configured with button slot (128), described button slot allows button (126) to align with the passage (130) in housing (102).Once right with passage (130) Together, button (126) can be slidably advanced along passage (130).Can by user's Non-follow control, automatically controlled by spring tension or two Person controls the speed along passage (130) movement in combination.This motion of button (126) allows the first spring (114) expansion to support Live retainer (115), thus needle assemblies (125) and pin (124) can be disposed.Passage in housing can have any suitable structure Type.Such as, as shown in Figure 31 C, passage (130) can be that the helical cuts in housing is to allow the pin rotation when moving ahead or spiral shell Rotation type moves, and this can be easy to needle-penetration wall of eyeball.

Typically, the actuating of the first spring (114) can cause the actuating of the second spring (116) so that medicine is delivered out equipment And enter in intraocular space.Such as, as shown in figure 30, the first spring (114) props up retainer (115) (described retainer also connects Be connected to the near-end of the second spring (116)) tension force play expansion the second spring (116) effect so that assembly (125) is at shell Body moves ahead in (102).As shown in Figure 32 A to Figure 32 C, when the pin (118) combined with plunger (132) movably arrives opening (120), time, they are deployed away by opening (120).Pin (118) is discharged from equipment, is then allowed for the second spring (116) and support Live plunger (132) free wxpansion, thus will be located in the medicine release equipment of reservoir (122).Opening (120) can be by film or close Envelope (140) covers, described film or seal and can pierce through to provide by pin (118) visual cues delivering medicine.

May be used without the dual spring actuation mechanism as shown in Figure 41 A to Figure 41 B.With reference to Figure 41 A, integrated equipment (600) wraps Including actuating mechanism, described actuating mechanism includes the first spring (602) and the second spring (604).In use, depression of trigger is worked as (606) (such as lever), the first spring (602) is released with impeller-hub in the direction of the arrow (608), and this transfers pin (610) The end of release equipment (600).Persistently moving ahead of axle (608) has promoted injection cannula (612) and top to seal (614), thus Pin (610) can be passed through and deliver the medicine in reservoir (616).With reference to Figure 41 B, the most having injected medicine, short teat (618) can move Combining shell nozzle (620) thus to discharge the second spring (604), axle (608) is moved rearwards by pin of retracting by subsequently dynamicly (610) (not shown).

In some variations, have employed single spring-actuated mechanism, as shown in Figure 36 and Figure 37.When using single spring, In addition to eliminating the second spring, actuating mechanism is configured to be very similar to dual spring mechanism mentioned above.Therefore, at it Before activating under state, as shown in figure 36, the equipment (300) with single spring (302) can be by by such as one or two hand Refer to that depression of trigger (304) activates single spring (302), described finger also press push button (306).Button 306 is configured with to be pressed Button groove (308), described button slot allows button (306) to align with the passage (not shown) in housing (310).Once with passage pair Together, button (306) can slide along passage and move ahead.It is swollen that this motion of button (306) allows spring (302) to prop up plunger (312) Swollen, thus needle assemblies (314) and pin (316) can be disposed.When the pin (318) combining plunger (312) movably arrives housing (310), during opening (320) in, they are deployed away by opening (320).Pin (318) is discharged from equipment, is then allowed for bullet Spring (302) props up plunger (312) and expands further, thus will be located in the medicine release equipment of reservoir (322).Although at this Not shown, but opening (320) can be covered by film or sealing, and described film or sealing can be pierced through to be given by pin (318) and deliver medicine The visual cues of thing.

May be used without pneumatic actuating mechanism.In a modification, as shown in Figure 34 and Figure 35 A and Figure 35 B, pneumatically actuated machine Structure is to include plunger, pin and shell nozzle to the same way described in single spring and dual spring mechanism.But, make use of work Fill in the needle assemblies slided in propelling housing rather than utilize spring to dispose needle assemblies and plunger.Such as, in Figure 34, band The equipment having pneumatic actuating mechanism (200) includes piston (202) and trigger (204).Piston (202) is used for compressing air to In the housing (206) of equipment (202).If necessary, piston can be controlled beaten by dial or other mechanism's (not shown) Enter the compressed-air actuated amount in equipment.The near-end of housing also may be configured to such as have flange, fold or other plugging structure, Described plugging structure allows piston (202) to enter housing but can not be from housing linear motion out.When depression of trigger (208) Time, the compressed air that a pair lock pin (210) is also depressed thus to allow to be formed by piston (202) promotes forward needle assemblies (212).Pin (214) is deployed to from equipment out (Figure 35 B) by this moving ahead of needle assemblies (212).As it was earlier mentioned, be also provided with Pin (216), described pin is similar to above be locked in by plunger (218) pin of appropriate location.When they are due to needle assemblies (212) travel forward and time opening (220) from housing (206) is discharged equipment, compressed air moves further along Plunger (218) is thus to promote the medicine being positioned in reservoir (222) from equipment out.May also include rotating dog (224), described Rotating dog allows needle assemblies (212) to rotate relative to housing (206) when by needle assemblies (212) release slided.

As it was noted above, trigger can be linked to housing and be configured to activate actuating mechanism.In a modification, trigger Device is positioned at the side of apparatus casing, equipment end (the such as distance between trigger and equipment end at eye interface Can scope between 5mm to 50mm, between 10mm to 25mm or between 15mm to 20mm) so that trigger can be by finger tip Activate and simultaneously equipment be positioned desired ocular position by the finger on the same hand.In another modification, trigger is positioned at The side becoming 90 degree with measurement parts of apparatus casing, thus when eye contact surface is placed on ocular with being perpendicular to corneal limbus, can Actuating trigger is carried out by the second of the same hand being positioned in ocular by equipment or the finger tip of the 3rd finger.

Some modification of equipment can include controlling bar to initiate plunger motion.In these cases, control bar and can use machine Tool mode actuating plunger, such as by spring-actuated, similarly as described above.In other modification, mechanical and manual spy can be passed through Levy the combination of part there is the actuating of plunger.Such as, initiation plunger motion can be assisted by the manual force applied to controlling on bar, Also use the spring-actuated mechanism for producing mechanical force so that plunger moves forward with injection drug in equipment barrel simultaneously Thing.In the case of control bar is connected to plunger, beginning and the drug injection of plunger motion are controlled by manual components, and flow The speed of body injection is controlled by mechanical force.Due to manual force and mechanical force combination in the same direction, can apply to subtract to plunger at this Little manual force, is thus easy to be positioned at stablizing of the equipment at accurate injection position in ocular.

Control bar may be arranged at away from equipment and locate, or away from equipment end between the end 10mm to 50mm of ocular handing-over Locate between 20mm to 40mm.Be arranged in such a way control bar can make it possible to a hand hurtless measure and accurately operate set Standby.

As shown in Figure 43 A to 43D, exemplary integrated equipment (700) include housing (702), can slide on dynamic Sleeve pipe (704), eye contact surface (706), plunger (708) and for manual actuation plunger (708) with by pin (712) inject The control bar (710) of medicine.Figure 43 B shows the eye contact surface (706) shown in Figure 43 A, dynamic sleeve pipe (704), plunger And the enlarged drawing of pin (712) (708).In use, after eye contact surface (706) is placed on eyes, applied Pressure can make dynamic sleeve pipe (704) slide back to (in the direction of the arrow) to expose pin and to allow needle-penetration wall of eyeball automatically.Subsequently may be used To manually advance control bar (710) (in the direction of arrow shown in Figure 43 C) slidably to advance plunger (708).When passing through Pin (712) injection medicine completes, and can manually advance dynamic sleeve pipe (704) slidably to cover pin, as shown in Figure 43 D.

Before can manually being made dynamic sleeve pipe slidably by fine moving control mechanism (also referred to as moving control mechanism) Row or retraction.In these cases, dynamic sleeve pipe can include high attachment friction surface, and described surface is positioned at the outer surface of sleeve pipe On, and the motion of available finger tip auxiliary sleeve pipe.In a modification, high attachment friction surface can be impressed or comprise tool There is the mark of saw tooth pattern.In other modification, as shown in Figure 45 A, platform or mat (such as finger tip pad) (900) can be attached to The outer surface of sleeve pipe (902) is to help to manually advance or retract sleeve pipe.Platform or mat may also comprise high attachment friction surface (904), the stereogram on described surface, side view and top view are shown in Figure 45 B, Figure 45 C and Figure 45 D.Typically, Platform or mat (900) include base portion (912) to be attached to sleeve pipe (902).Base portion (912) can be any suitable structure Type.Such as, the base portion of platform or mat may be configured to cylinder (Figure 45 H) or has constriction (part that diameter is less), Such as dumbbell or apple core shaped (Figure 45 I).

Some modification of equipment described herein includes having retraction slit or the grasping member of passage, described retraction slit or logical Road and dynamic stop member act on jointly with by drug injection to eye.With reference to Figure 45 A, grasping member (906) can be at sleeve pipe (902) parts of near-end (912) place link (the most affixed) to apparatus casing (908).Grasping member (906) may be configured at it Wall includes the slit (910) that bounces back.In use, when sleeve pipe (902) is retracted, as in Figure 45 J by shown in the direction of arrow, mat Or the base portion (912) of platform moves into slit (910).Retraction slit (910) may be configured to the consistent passage of width (Figure 45 F) or tool The passage of keyhole type configuration, such as near-end or far-end at slit is had to have constriction (Figure 45 G) or amplifier section (figure 45E).Retraction slit such as can provide sense feedback when arriving the terminal of retraction.The configuration of the base portion of platform or mat is optional It is selected to make its frictional fit provided with slit.Such as, when slit has constriction, base portion can have narrowed portion equally Point.

When using grasping member, equipment may also include lockable mechanism.In a modification, when arriving sleeve pipe retraction and pin dew During the terminal going out/disposing, in opening in the wide portion of sleeve pipe slit and the wide portion of grasping member slit and housing and plunger axis Register, this allow flat base insert plunger axis with by it relative to platform locking, described platform becomes for manually The actuator lever of injection medicine.The narrow portion of base portion enters the narrow portion of sleeve pipe slit, and this makes platform unlock relative to sleeve pipe, it is allowed to it moves To equipment end.In another modification, when flat base arrives the terminal of retraction slit, it can be pressed into opening in plunger axis Mouth also becomes lock pin with connecting platform and plunger.When it is depressed, its narrow portion enters the keyhole slit in sleeve pipe, and becomes Obtain and can move and shift to cannula end (flat base and sleeve pipe being unlocked) in slit.

When user wishes that the amount of pressure controlling to be applied in ocular by equipment end is disposed during puncturing at its intraocular During pin, moving control mechanism is favourable.There are moving control mechanism, user to may utilize finger tip and regulation set has been decreased or increased Pipe motion and the reaction force exposed of pin.

Such as, if user (the high of sleeve pipe will will adhere to friction in pulling force applying to the most described high attachment friction surface Surface is pulled away from equipment end), this motion can be easy to pin expose and reduce applying to wall of eyeball so that sleeve pipe slides back to and exposes pin The amount (as little as 0 newton) of required pressure.In another modification, if user applies thrust and (the high of sleeve pipe will adhere to friction Equipment end is pushed on surface to), this motion can hinder and stop pin to expose, and this can allow equipment end to reveal in sleeve movement and pin Before the beginning gone out, the pressure increased is applied to wall of eyeball.

In use, available second or the 3rd finger sliding platform or mat.Again, this allows injector manually to adjust The a whole set of resistance of pipe and moving along equipment end.Such as, by promoting forward mat with finger tip and thus promoting sleeve pipe, injection Person provide (when equipment end is positioned in ocular) when the beginning of process some resistance (and pin need keep quilt completely Cover).Injector will unclamp his/her finger tip to realize the deployment of pin and it is through sclerotic puncture from casing cushion subsequently.Equipment At the destination county in sleeve pipe path, some modification also can include that step or annular ridge are dashed forward, thus sleeve pipe pulled back through this step it After, it will trigger spring-actuated plunger motion automatically.Finger tip pad can be used for retracting sleeve pipe through described at the end of pin is disposed Step is to activate plunger motion and drug injection.

When using platform or mat, can make to start to move equipment before exposing pin at sleeve pipe and be applied to epibulbar pressure The amount of power reduces, and thus allows to customize the amount of pressure applied according to different patients.

On the other hand, dynamic sleeve pipe can provide step-type pin to expose so that pin is at ocular when needle-penetration wall of eyeball 1mm or less is exposed when running into maximum resistance.Remainder at this pin is positioned at inside pipe casing, and at least its farthest not exposing Point or longer section are screened and are exited in aperture or duct at narrow.This sleeve design long exposes the normal of pin compared to having The risk that pin bends can be down to minimum by rule syringe.This design can make it possible to the pin utilizing relatively small dimension without increasing It is the risk of bending when puncturing wall of eyeball.Less gauge can make its more comfortable and less wound during its intraocular punctures Wound.

II. method

The method that utilize integrated intraocular drug delivery equipment has been also described herein.It is said that in general, method includes following step Rapid: the eye contact surface of equipment is positioned in ocular, utilize eye contact surface to apply pressure to ocular at targeted injection position, And by actuating mechanism is activated, activating agent is delivered to eye from the reservoir of equipment.Typically, position, exert a force and The step delivered is to be completed by a hand.

Utilizing eye contact surface to apply pressure to ocular to can also be used for producing intraocular pressure, described pressure is at 15mm Hg extremely Scope between 120mm Hg, between 20mm Hg to 90mm Hg or between 25mm Hg to 60mm Hg.As it was earlier mentioned, Before the deployment of distribution member (conduit) produce intraocular pressure can reduce sclera pliability, this then conduit can be easy to and pierce through Gong Film, reduces any uncomfortable sensation in ocular during injection process, and/or prevents the backlash of equipment.Available decompression Valve, pressure sensor, accumulator, pressure sensor or parts manually or automatically produce or maintain intraocular pressure control, institute State the parts slidably block with lockable mechanism the most as discussed previously and/or ridge is dashed forward.

Utilize equipment can reduce each layer of needle-penetration wall of eyeball (such as rich in the knot of pain nerve ending according to described method Film) adjoint pain.Can pass through before pin is injected and/or period applies machinery pressure on the injection site of conjunctiva and wall of eyeball Power and provide the anaesthetic effect at injection site during injection process within the eye.Applying mechanical pressure to wall of eyeball also can be temporary transient Increase intraocular pressure and increase the consolidation (and it is elastic to increase it) of wall of eyeball, being thus easy to needle-penetration sclera.Additionally, to eyeball Wall applies the ocular fluids of the displaceable inside ofeye of mechanical pressure and injects medicine to form potential space for by equipment.

Equipment can be used for treating any suitable eye conditions.Exemplary eye conditions includes but not limited to: any type Retina or macular edema and the disease relevant to retina or macular edema, such as, AMD, sugar Urine characteristic of disease macular edema, cystoid macular edema and postoperative macular edema；In retinal vascular occlusive disease, such as CRVO( Centre retinal vein obstruction), BRVO(branch retinal vein block), CRAO(central retinal artery occlusion), BRAO(branch Retinal arterial obstruction) and ROP(retinopathy of prematurity), neovascular glaucoma；Uveitis, center slurries Property chorioretinopathy；And BDR.

When using dexamethasone sodium phosphate solution to treat eye conditions, eye can be administered to by each single injection device In the dosage of dexamethasone sodium phosphate can between about 0.05mg to about 5.0mg, between about 0.1mg to about 2.0mg or about Scope between 0.4mg to about 1.2mg.

In some variations, before equipment is placed on eye, local anesthetic is applied in ocular.Can use and appoint What suitable local anesthetic.Exemplary local anesthetic includes but not limited to: lidocaine, proparacaine, procaine, fourth Cacaine, betacaine, benzocainum, Bupivacaine, (the eutectic mixing of local anesthetic Thing) and combinations thereof.In a modification, local anesthetic includes lidocaine.When using lidocaine, can be There is provided in such concentration range: from about 1% to about 10%, from about 1.5% to about 7% or from about 2% to about 5%.In another modification In, local anesthetic mixes with another medicament of phyenlephrinium or the anaesthetic effect of reinforcement and/or prolongation pharmaceutical formulation.Can be by Any suitable form provides local anesthetic.Such as, it can provide as solution, gel, ointment etc..

Also before equipment is placed on eyes, disinfectant can be applied in ocular.The suitably example bag of disinfectant Include but be not limited to: the tincture of iodine, PVP-IChlorhexidine, saponin, antibiotic, salt and its derivative and Combinations thereof.Disinfectant may or may not combine application with local anesthetic.When disinfectant includes PVP-ITime, the concentration of PVP-I can from about 1% to about 10%, from about 2.5% to about 7.5% or from about 4% to The scope of about 6%.

During delivery process, equipment as herein described is configured so to entry needle and (consolidates to be perpendicular to wall of eyeball Film) right angle enter eyes.In other cases, equipment is configured so to entry needle and passes through cornea with being parallel to iris plane Enter the anterior chamber of eyes.

III. system and kit utility

There is also described herein system and the kit utility including intraocular drug delivery equipment.Kit utility can include one or Multiple integrated drug delivery devices.This equipment can be prefilled active dose.When including multiple prefilled equipment, they Can pack and accommodate identical activating agent or different activating agents respectively, and accommodate the activity of same dose or various dose Agent.

System and kit utility may also include one or more equipment treating manually to load packed respectively.If equipment is to treat Manually load before use, then the active groups that one or more parts is packed respectively can be bonded in kit utility.It is similar to pre- The activating agent packed respectively in the device systems of filling or kit utility, system herein and kit utility can be identical Or different, and by each activating agent packed respectively provide dosage can be identical or different.

Certainly, system and kit utility can include prefilled equipment, for the equipment of manually filling and appointing of activating agent What combination.Should also be understood that the operation instruction of the equipment of may also include.In some variations, one or more measurements packed respectively Parts may be disposed in system and kit utility for being removably attached to equipment.May also include local anesthetic and/or disappear Toxic agent.

IV. example

Following example is for the method being described more fully below using intraocular injection equipment mentioned above.Should be understood that this model Example is used for limiting the scope of the present invention never in any form, but proposes for purposes of illustration.

Example 1: the resistance produced by dynamic sleeve pipe

The intraocular injection equipment including the pin of 30 specifications is fixed to Imada tension test bed and with 10mm/ minute Speed is mobile against Imada 10N dynamometer, and by dynamic sleeve pipe, (every one end of two-way tapered design, i.e. sleeve pipe is described pin Tapered) covering.While analog casing motion in practice makes sleeve pipe be pushed back to expose pin, measure resistance.This Create the power of " u "-shaped and the curve of sleeve pipe displacement, as shown in figure 46.At the initial of sleeve pipe mobile route and the resistance of destination county Resistance between being more than in the paths.In figures 4-6 can, the diagram scope of produced resistance can between zero newton to about 2 newton or Between about 0.1 newton to about 1.0 newton.

In one case, the resistance of the section start in sleeve pipe path punctures mankind's sclera equal to the pin of 30 or 31 specifications Required power (between such as 0.2 newton to 0.5 newton).When using the sleeve pipe of higher drag, at the section start in sleeve pipe path Resistance puncture the power (being greater than 1 newton) needed for mankind's sclera more than the pin of 30 or 31 specifications.But, power of a sufficiently low with Make patient comfort and avoid the potential injury to eyes (such as to avoid increasing intraocular pressure more than 60mm Hg).Transport at sleeve pipe The centre in dynamic path, resistance is close to zero newton.

Claims (58)

1., for an integrated equipment for intraocular drug delivery, described integrated equipment includes:

Housing, the size and dimension of described housing determines into be easy to operate with a hand, and housing has proximally and distally；

Measure parts；

Conduit in housing at least in part, described conduit has near-end, far-end and extends through the interior of described conduit Chamber；

Actuating mechanism, described actuating mechanism is contained in housing and may be operably coupled to described conduit and for accommodating work The reservoir of property agent；

Trigger, described trigger is linked to described housing and is configured to trigger described actuating mechanism；

Dynamically sleeve pipe, described dynamic sleeve pipe can move between the first configuration and the second configuration, under described first configuration, institute State conduit to be fully collapsed in dynamic sleeve pipe, under described second configuration, along with described dynamic sleeve pipe is proximally retracted, described Conduit extends distally beyond the far-end of dynamic sleeve pipe；And

Eye contact surface, described eye contact surface is positioned at dynamic boot proximal end, and described eye contact surface is configured to do not wear and tear conjunctiva and cornea Surface；

Wherein, described housing, described conduit and described dynamic sleeve pipe are combined in single integrated equipment.

Integrated equipment the most according to claim 1, wherein said dynamic sleeve pipe includes near-end, far-end and inner surface.

Integrated equipment the most according to claim 2, wherein dynamic sleeve pipe is proximally and distally tapered.

Integrated equipment the most according to claim 3, the most tapered dynamic sleeve pipe and housing produce between 0N to 2N Power.

Integrated equipment the most according to claim 3, the most tapered dynamic sleeve pipe and housing produce between 0.1N to 1N Power.

Integrated equipment the most according to claim 2, wherein dynamically the inner surface of sleeve pipe includes that one or more high attachment rubs Wipe surface.

Integrated equipment the most according to claim 6, its middle shell includes one or more high attachment friction surface.

Integrated equipment the most according to claim 7, wherein dynamically sleeve pipe and the one or more high of housing adhere to friction table Face produces the power between 0N to 2N.

Integrated equipment the most according to claim 7, wherein dynamically sleeve pipe and the one or more high of housing adhere to friction table Face produces the power between 0.1N to 1.0N.

Integrated equipment the most according to claim 2, wherein dynamically sleeve pipe also includes fine sleeve pipe mobile control unit.

11. integrated equipments according to claim 1, wherein eye contact surface includes ring, flange or combinations thereof.

12. integrated equipments according to claim 11, wherein eye contact surface includes ring.

13. integrated equipments according to claim 12, wherein ring has the diameter between 0.3mm to 8mm.

14. integrated equipments according to claim 1, wherein eye contact surface is flat, convex or recessed.

15. integrated equipments according to claim 1, wherein eye contact surface includes one or more attached component.

16. integrated equipments according to claim 1, wherein eye contact surface includes attaching member.

17. integrated equipments according to claim 16, wherein attaching member includes aspirating mechanism.

18. integrated equipments according to claim 1, wherein eye contact surface includes the material selected from a set, described set Including nylon fiber, cotton fiber, hydrogel, spongy material, foamed material, silicones, plastics and combinations thereof.

19. integrated equipments according to claim 1, wherein actuating mechanism includes manual actuation mechanism.

20. integrated equipments according to claim 19, wherein manual actuation mechanism includes controlling bar so that the sliding of plunger Move and move ahead.

21. integrated equipments according to claim 1, wherein actuating mechanism includes automatic actuating mechanism.

22. integrated equipments according to claim 21, wherein actuating mechanism includes spring-loaded actuating mechanism automatically.

23. integrated equipments according to claim 22, the most spring-loaded actuating mechanism be configured to from 1 μ l/ second to Bioactive agent delivery is delivered in intraocular space by the speed of 1ml/ second scope.

24. integrated equipment according to claim 23, the most spring-loaded actuating mechanism is with from the 10 μ l/ seconds to 100 μ l/ Bioactive agent delivery is delivered in intraocular space by the second speed of scope.

25. integrated equipments according to claim 22, the most spring-loaded actuating mechanism produces the power of 0.1N to 1.0N.

26. integrated equipments according to claim 22, the most spring-loaded actuating mechanism includes the first spring and second Spring.

27. integrated equipments according to claim 26, wherein the second spring is configured to dispose plunger and control activating agent Delivery rate.

28. integrated equipments according to claim 26, wherein the first spring is configured to conduit from the first non-deployable state Move to the second deployable state control the speed of deployment and the power of conduit.

29. integrated equipments according to claim 1, wherein actuating mechanism is part actuating mechanism automatically.

30. integrated equipments according to claim 29, wherein part automatically actuating mechanism includes controlling bar so that plunger Slidably move ahead.

31. integrated equipments according to claim 29, wherein part actuating mechanism automatically includes spring-loaded actuating Mechanism.

32. integrated equipments according to claim 31, the most spring-loaded actuating mechanism be configured to from 1 μ l/ second to Bioactive agent delivery is delivered in intraocular space by the speed of 1ml/ second scope.

33. integrated equipments according to claim 31, the most spring-loaded actuating mechanism is with from the 10 μ l/ seconds to 100 μ l/ Bioactive agent delivery is delivered in intraocular space by the second speed of scope.

34. integrated equipments according to claim 31, the most spring-loaded actuating mechanism produces the power of 0.1N to 1.0N.

35. integrated equipments according to claim 31, the most spring-loaded actuating mechanism includes the first spring and second Spring.

36. integrated equipments according to claim 35, wherein the second spring is configured to dispose plunger and control activating agent Delivery rate.

37. integrated equipments according to claim 35, wherein the first spring is configured to conduit from the first non-deployable state Move to the second deployable state control the speed of deployment and the power of conduit.

38. integrated equipments according to claim 1, wherein actuating mechanism is pneumatic actuating mechanism.

39. integrated equipments according to claim 1, wherein activating agent is selected from the set including following material: steroid Antiphlogistic, NSAI drugs, anti-infectious agent, antiallergic, cholinergic antagonist and activator, adrenaline antagonist With activator, antiglaucoma agent, neuroprotective agent, for cataract prevention and treatment medicament, antiproliferative, anticancer, benefit Body inhibitor, vitamin, growth factor, the medicament for the Developing restraint factor, gene therapy vector, chemotherapeutic agents, albumen swash Enzyme inhibitor, small molecules interference RNA, their analog, derivative and improvement thing and combinations thereof.

40. integrated equipments according to claim 1, wherein activating agent is selected from the set including following material: Lucentis, Bevacizumab, Pei Jianibu, dexamethasone, dexamethasone sodium phosphate, fluoxyprednisolone, Triamcinolone acetonide, FA, taxanes medicine Thing, VEGF Trap, anecortave acetate and do not take charge of compounds of group.

41. integrated equipments according to claim 40, the most department's compounds of group is not selected from the set including following material: west Luo Mosi, SDZ-RAD, tacrolimus, everolimus, Elidel, Zuo Tamosi, CCI-779, AP23841 and ABT-578, Their analog, derivative, complex, salt and improvement thing and combinations thereof.

42. integrated equipments according to claim 1, wherein reservoir is made up of cyclenes system resin.

43. according to the integrated equipment described in claim 39, wherein reservoir not silicate-containing oil or the derivative of silicone oil.

44. integrated equipments according to claim 1, wherein measure parts and are attached to a contact surface.

45. integrated equipments according to claim 1, wherein measure parts and include one or more element radially extended.

46. integrated equipments according to claim 45, wherein one or more elements radially extended include the remote of projection End.

47. integrated equipments according to claim 45, wherein one or more elements radially extended are flexible.

48. integrated equipments according to claim 47, wherein measure parts and include register guide parts.

49. integrated equipments according to claim 1, wherein prefilled active dose of reservoir.

50. integrated equipments according to claim 2, wherein dynamically sleeve pipe be one of proximally and distally tapered.

51. integrated equipments according to claim 1, also include lockable mechanism.

52. integrated equipments according to claim 51, wherein lockable mechanism is manually operated mechanism.

53. integrated equipments according to claim 51, wherein lockable mechanism is the mechanism being automatically brought into operation.

54. integrated equipments according to claim 51, wherein lockable mechanism includes lock pin.

55. integrated equipments according to claim 51, the most slidably block includes one or more high attachment friction table Face.

56. integrated equipments according to claim 55, wherein one or more high attachment friction surfaces are included in slidably Ridge on the inner surface of block is dashed forward.

57. integrated equipments according to claim 1, also include pressure sensor.

58. integrated equipments according to claim 1, also include accumulator.