EP1924309A1 - Ophthalmic syringe - Google Patents

Abstract

The present invention provides a device for use in ophthalmology. In particular, the present invention provides a device for use in intravitreous administration of ocular agents. The present invention also provides methods of delivering one or more drugs to a human eye and methods for treating an ophthalmic disease, disorder, or condition.

Description

OPHTHALMIC SYRINGE

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Serial Number 60/717,865 filed September 16, 2005, Attorney Docket No. EYE-036P, which is hereby incorporated in its entirety by reference.

FIELD OF THE INVENTION

The present invention relates to methods of administering ophthalmic medicines and devices related thereto. In particular, the invention relates to intravitreous injection using an ophthalmic syringe and needle.

BACKGROUND OF THE INVENTION

Intravitreous (FVT) injection has been used in the treatment of human ocular disease for nearly a century beginning in 1911 as means to introduce air for retinal tamponade and repair of detachment (J. Ohm, Albrecht von Graefes Arch Ophthalmol 1911; 79:442-450). Over the past two decades, the use of intravitreous injection has gained increasing acceptance in the therapeutic management of many intraocular diseases, particularly disorders affecting the posterior segment of the eye (Jager et ah, Retina 24:676-698, 2004). IVT injection is increasingly being incorporated into management of ocular diseases and the number of approved products for IVT injection is anticipated to grow on the basis of promising results from ongoing clinical studies. Currently formivirsen sodium (Vitravene®, Novartis AG, Basel, Switzerland), ranibizumab injection (Lucentis™, Genentech, Inc., South San Francisco, CA) and pegaptanib sodium (Macugen®, (OSI) Eyetech, Inc. NY, NY) are three medicines approved by the Food and Drug Administration as IVT injections.

Advantages of IVT injection of medicines and diagnostics include the achievement of maximum vitreous concentrations while minimizing toxicity attributed to systemic administration. While these advantages are becoming widely appreciated, the ophthalmology community turns its focus to various complications potentially associated with IVT injection. Risks of rVT injection, some vision threatening, include endophthalmitis, retinal detachment, iritis/uveitis, inflammation, intraocular hemorrhage, ocular hypertension, hypotony, pneumatic retinopexy, and cataract (R.D. Jager et al., Retina 24:676-698, 2004 and CN. Ta, Retina, 24:699-705, 2004).

Endophthalmitis is a condition in which the tissues inside the eyeball become inflamed and is generally caused by bacterial infection. The most common sources of bacteria causing postoperative endophthalmitis are believed to be the patient's conjunctiva or eyelids. Unless treated effectively, endophthalmitis can rapidly lead to severe vision loss or blindness. The relative risks of developing postoperative endophthalmitis depend on a number of factors, including the presence of eyelid or conjunctival diseases, the patient's general health, the use of immunosuppressant medications, the type of intraocular surgery, and intraoperative complications. Of these factors, intraoperative complications, particularly breaks in the posterior capsule with vitreous loss, carry the greatest risk for the development of endophthalmitis.

Although intravitreous injection is a simple procedure with a small wound, it has been demonstrated that bacteria potentially introduced by the procedure are sufficient to induce endophthalmitis, which is likely due to the inability of the vitreous to clear the infectious microorganisms. Other equally plausible explanations for the apparent high risk of endophthalmitis after intravitreous injections may be the very limited sample size as well as publication bias. It is important, nevertheless, to minimize the risk of developing endophthalmitis by reducing or eliminating bacteria from the ocular surface at the time of the injection and to strictly adhere to aseptic technique. The use of topical antibiotics has been shown to reduce conjunctival and eyelid bacterial flora, which may in turn also decrease the risk of endophthalmitis.

Because transient increases in intra-ocular pressure (IOP) may cause mild discomfort and can be associated in rare instances with irreversible damage to retinal ganglion cells and/or retinal vascular occlusion, many investigators reported using prophylactic and/or therapeutic measures to prevent increases in IOP after IVT injection. These have included the use of aqueous paracentesis, preoperative treatment with pressure-lowering agents and digital massage or the use of a Honan IOP reducer.

Particulate contaminants present in a drug, in a syringe, or in or on materials used at the time of injection also may have the potential to induce detrimental effects when injected into the vitreous. This has been demonstrated in the case of glove lubricants, which are highly inflammatory when injected into the posterior ocular chamber (H. S. Park, Korean J. Ophthalmol. 1991; 11:51-59).

Other serious complications rarely occurred after IVT injection, making it difficult, in most instances, to determine whether these were truly injection-related or simply sporadic, unrelated comorbidities.

Serious adverse events are for the most part transient and/or treatable, and the risks of serious adverse events reported after IVT injection is low. Even so, there is a need for improved devices and methods for IVT injection. The risks and benefits of IVT injection will likely carry increased weight in patient and clinician treatment as more treatment options become available.

Guidelines for IVT injection are continuing to evolve (L.P. Aiello et al, Retina, 24:S3-S19, 2004). For example, povidone iodine and an antibiotic are administered prior to IVT injection. Also, IVT injections are generally performed with a sterile surgical drape and lid speculum in place and a 27 or 30 gauge needle is typically used with an injection site 3.5-4.0 mm posterior to the limbus.

As new treatment modalities for macular diseases become available, the number of intravitreous injections administered is expected to increase dramatically. For example, intravitreous injection of the vascular endothelial growth factor (VEGF) inhibitor, Macugen®, has become available for the treatment of age-related macular degeneration. Also, intravitreous injections of triamcinolone acetonide are now commonly used for the treatment of macular edema.

The prevalence of endophthalmitis after intravitreous injection of anti-VEGF agents is unknown. Due to the very limited data regarding the rate of endophthalmitis after intravitreous injections, it is difficult to speculate about the true prevalence of endophthalmitis after these types of procedures. The increased use of intravitreous injections for the delivery of these agents to the retina will provide data regarding the prevalence and risk factors for post-injection endophthalmitis and in the future define a more accurate rate of endophthalmitis.

Drug delivery into the eye is challenging because the anatomy, physiology and biochemistry of the eye includes several defensive barriers that render ocular tissues impervious to foreign substances. Techniques used for administering active agents into the eye include systemic routes, intraocular injections, injections around the eye, intraocular implants, and topical applications. Patient acceptance and safety are key issues that play a key role as to which treatments are used.

Ocular bioavailability of drugs applied topically in formulations such as eye drops is very poor. The absorption of drugs in the eye is severely limited by some protective mechanisms that ensure the proper functioning of the eye, and by other concomitant factors, for example: drainage of the instilled solutions; lacrhymation, tear evaporation; nonproductive absorption/adsorption such as conjunctival absorption, poor corneal permeability, binding by the lachrymal proteins, and metabolism.

Alternative approaches to delivery include in situ activated gel- forming systems, mucoadhesive formulations, ocular penetration enhancers and ophthalmic inserts. In situ activated gel-forming systems are liquid vehicles that undergo a viscosity increase upon instillation in the eye, thus favoring pre-corneal retention. Such a change in viscosity can be triggered by a change in temperature, pH or electrolyte composition. Mucoadhesive formulations are vehicles containing polymers that adhere via non-covalent bonds to conjunctival mucin, thus ensuring contact of the medication with the pre-corneal tissues until mucin turnover causes elimination of the polymer. Ocular penetration enhancers are mainly surface active agents that are applied to the cornea to enhance the permeability of superficial cells by destroying the cell membranes and causing cell lysis in a dose-dependent manner. Ophthalmic inserts are solid devices intended to be placed in the conjunctival sac and to deliver the drug at a comparatively slow rate. One such device is Ocusert®, by Alza Corporation, which is a diffusion unit consisting of a drug reservoir enclosed by two release- controlling membranes made of a copolymer. M.F. Saettone provides a review of continued endeavors devoted to ocular delivery. ("Progress and Problems in Ophthalmic Drug Delivery", Business Briefing: Pharmatech, Future Drug Delivery, 2002, 167-171).

Many types of ophthalmic surgeries such as cataract surgery require use of various fluids which are both delivered and removed from the eye over the course of the surgery. The simultaneous delivery of two or more therapeutics typically requires multiple separate needle penetrations. In areas where bacterial infection and/or structural damage are a concern, the risks associated with multiple injections may become unacceptable. Multiple injections may be circumvented by using a multi-compartment syringe or a double-barrel syringe. Administration of multiple viscoelastic solutions with a multi-compartment syringe is described in US Patent Application Publication No. 2004/0167480. A double-barrel syringe for ophthalmic surgeries is described in US Patent Application Publication No. 2004/0064102.

Such invasive intraocular administrations may not be favorable because they cause patient discomfort and sometimes fear, while risking permanent tissue damage. A device which allows the simultaneous or sequential delivery of a therapeutic while requiring a single needle penetration would significantly reduce any needle associated complications.

SUMMARY OF THE INVENTION

The present invention provides a device for use in ophthalmology. In particular, the present invention provides a device for use in intravitreous administration of ocular agents. The present invention also provides methods of delivering one or more drags to a human eye.

In one aspect, the invention relates to ophthalmic drug delivery devices and features a device for delivery of a therapeutic agent to the eye of a mammal.

The invention features a drag delivery device for delivering a therapeutic compound to the eye and drag delivery methods related thereto. The invention also features a syringe for intravitreal delivery and methods of using the syringe to treat an ophthalmic disease, disorder, or condition.

Other features and advantages of the invention will be apparent from the following description, the drawings, and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a schematic representation of a needle assembly comprising a luer hub, a cannula and a needle tip having a standard bevel.

Figure 2 is a schematic representation of a needle assembly comprising a luer hub, a cannula and a needle tip shield.

Figure 3 is a schematic representation of a syringe and needle assembly comprising a low dead space hub assembly.

Figure 4 shows drawings of a first embodiment of a double barrel syringe.

Figure 5 shows drawings of a first embodiment of a double barrel syringe.

Figure 6 is a schematic representation of a fluid exchange device.

Figure 7 is a schematic representation of a tandem syringe.

Figure 8 is a graph showing penetration force required by various needles.

DETAILED DESCRIPTION OF THE INVENTION

One aspect provides a syringe useful in ophthalmic applications for delivery of a material into the eye.

Needle

Any suitable needle may be used. Suitable needles provide facile penetration of the sclera with minimal injury. A needle typically includes an elongated tube with an outside surface, a proximal end, a distal end and an open bore therethrough. As seen in Figure 1, the needle assembly 20 may have a hub 23 attached to the proximal end of the needle 22 that is used to attach the needle to a syringe. In one embodiment the hub is a Luer hub.

The needle may be attached to the syringe permanently (e.g., staked) or may be attached to the syringe by a Luer fitting. The Luer fitting may be a standard Luer fitting, Luer slip fitting or a Luer lock fitting. The Luer fitting has either a tip (male) or hub (female) component, and provides the ability to insure leak-proof and mechanically secure connections to any other device having a mating Luer fitting. Luer connectors can comprise round and tapered male and matching female mating surfaces. Luer connectors can form a locking configuration by adding a threaded locking collar to the male luer connector, which mates with ears on the female luer connector, thereby providing a positive "locked" connection. Luer fittings have several advantages. Luer fittings provide compatibility among various medical devices, offering the clinician the benefits of choosing a preferred needle. In addition, Luer-lock connections insure against possibility of needle coming off of the syringe during the injection procedure. Standards for Luer fittings are described in American National Standard ANSI/HIMA MD 70.1-1983 and the International Standard ISO-594-1 and ISO-7886-1.

A non-standard Luer fitting may be used. Examples of non-standard Luer fittings include, but are not limited to, the Tru-Lok™ fluid transfer adaptor by Becton Dickinson. Other non-standard fittings include Tyco Health Care, Kendall Monoject® low dead space (LDS) needles featuring tri bevel, anti-coring, stainless steel needles. Examples of low waste space fittings are found in US Patent Nos. 6,840,291, 5,902,277 5,902,271, 5,902,270 5,902,269 5,782,803, the contents of each are hereby incorporated by reference in its entirety.

The needle may also be attached to the syringe via a ceramic coated tip (CCT) interface, i.e. 'press fit'.

In one embodiment, the needle is beveled and coated with a suitable silicone. In one embodiment, the needle is a PrecisionGlide® needle available from Becton-Dickenson. Suitable PrecisionGlide® needles include but are not limited to a Vi inch 30 gauge needle and a ¹A inch 27 gauge needle. In one embodiment, the needle is a PrecisionGlide® shown in Figure 3. Referring to the figure, the needle comprises a polypropylene Luer hub 33 and a stainless steel cannula 34, lubricated with silicone, having a three-bevel point, attached to the hub via an epoxy joint.

The needle tip may have a standard bevel. In one embodiment, the needle may have more than one bevel. In one embodiment, the needle has three bevels. In one embodiment, the needle has five bevels. Examples of a five-bevel needle are described in US Patent No. 6,629,963, and 6,009,933, US patent Application publication Nos. 2044/0111066, 2004/0030303 and PCT Application No. 2005/016420 In one embodiment, the needle is a coated needle. In one embodiment, the needle is a lubricated needle. The needle optionally includes a lubricious coating applied to and adherent to the outside surface of the tube, as described in US Patent No. 5,911,711.

In one embodiment, the coating is a silicone coating. Any suitable silicone coating may be used. Examples of suitable coatings include, but are not limited to, those available from SurModics, Eden Prairie, MN (see US Patent Nos. 6,706,408, 6,669,994, 6,254,634 and 6,121,027).

In one embodiment the coating is a medicated coating.

Preferably the needle is a 27 gauge needle or smaller. In one embodiment the needle is a 30 gauge needle.

In one embodiment, the needle has a length of less than 1 inch. In another embodiment, the needle has a length of about 0.5 inches.

Needle tip shield

As seen in Figure 2, the needle assembly 20 may comprises a needle tip shield 21 enclosing needle 22. Needle 22 is attached to luer hub 23 via epoxy joint 24. In one embodiment, the tip shield 21 is rigid. Examples of suitable rigid shields include but are not limited to those disclosed in US Patent No. 4,986,818. As depicted in Figure 2, the tip shield is not in contact with the needle tip. Needle tip shields in contact with the needle potentially dull the needle and wipe away any lubrication on the needle. In another embodiment, the tip shield comprises one or more apertures or is permeable to sterilizing gases. The apertures may facilitate sterilization by allowing sterilizing gasses or steam to access the interior of the needle shield. In a particular embodiment, the tip shield is synthetic isoprene, ethylene oxide (EtO) or hydrogen peroxide (H₂O₂) permeable. In another embodiment, the syringe barrels, stoppers and plunger rod components and assemblies can also be gamma irradiated. In one embodiment, the needle tip shield comprises a polypropylene. In another embodiment, the needle tip shield comprises a styrene block thermoplastic elastomer.

Penetration Force

The needles of the present invention are used for penetration of the scleral tissue for administration of the syringe contents into the vitreous. Preferably the needles require a low penetration force. Preferably the needles require a low penetration force with low variability. In one embodiment, the needles require a penetration force of less than 500 grams (g). In another embodiment, the needles require a penetration force of less than 100 grams (g). In another embodiment, the needles require a penetration force of less than 50 grams (g).

In one embodiment, the needles require a penetration force with a variability range of

+/- 20 %. In one embodiment, the needles require a penetration force with a variability range of +/- 50 g. In another embodiment, the needles require a penetration force with a variability range of +/- 20 g

In one embodiment, the penetration force is reduced by reducing the needles coefficient of friction. In one embodiment the penetration force is reduced by using a lubricious coating on the needle.

Syringe

The syringe barrel is typically made of glass or a thermoplastic material. In one embodiment the syringe is a 1 mL Type I glass barrel syringe sealed with a bromobutyl rubber stopper. Examples of pre-filled syringes are found in US Patent No. 4,252,118. In one embodiment the syringe is a BD Hypak SCF® syringe. In a particular embodiment, the syringe is a single dose, pre-filled syringe. In one embodiment, the syringe barrel has a volume of 1 mL or less. In a particular embodiment, the syringe barrel has a microliter volume. The syringe barrels of the present invention may further be provided with graduations to assist in precision filling of the barrel.

In one embodiment, the syringe is a plastic syringe. In another embodiment, the syringe comprises a cyclic olefin copolymer (COC). In another embodiment the cyclic olefin copolymer is TopPac® (Schott).

In another embodiment, the final Luer formation is made using a platinum wire. In a particular embodiment, the syringe is substantially free of tungsten. Staked needle production requires a small hole and seat for gluing in the needle. The small hole requires a high temperature tungsten pin. Some of the tungsten pin material may shed into the glass during processing. Luer lock syringes are alternatively formed using a platinum pin material. The platinum may not leave a significant residue in the glass as compared to tungsten. Optimal particulate matter concentrations maybe achieved primarily through strict control of the environment and material cleanliness.

Volume

The ophthalmic injection solutions of the present invention are useful as microliter (μL)-volume injections. Microliter (μL)-volume injections may also be referred to as "ultra- low volume injections". In one embodiment, the ophthalmic injection solution to be delivered has a volume of about 1.0 mL (1000 μL) or less. In another embodiment the ophthalmic injection solution to be delivered has a volume of about 200 μL or less. In another embodiment the ophthalmic injection solution to be delivered has a volume of about 100 μL or less. In another embodiment the ophthalmic injection solution to be delivered has a volume of about 90 μL. In another embodiment the ophthalmic injection solution to be delivered has a volume of about 50 μL.

Sub-Visible Particulate Matter

The ophthalmic injection solutions of the present invention, including solutions constituted from sterile solids intended for parenteral use, as used herein are substantially free from particles that can be observed on visual inspection. There are also strict controls on sub-visible particulate matter for ophthalmic injections. The ophthalmic injection solutions of the present invention can be tested by a light obscuration procedure or may be tested by a microscopic procedure as described in USP Chapter <788>. United States Pharmacopoeia (USP) Chapters <788> Particulate Matter in Injections and <789> Particulate Matter in Ophthalmic Solutions describe physical tests for the purpose of enumerating extraneous particles within specific size ranges. The United States Pharmacopoeia, 28^th revision and the National Formulary, 23^rd edition (USP28-NF23), The United States Pharmacopeial Convention, Inc (2005), is hereby incorporated by reference in its entirety.

In one embodiment, the ophthalmic solution contained within the syringe of the present invention has a 10μm~size or larger sub-visible particulate count of less than or equal to about 60 particles per mL, a 25μm-size or larger sub-visible particulate count of less than or equal to about 10 particles per mL, or a 50μm-size or larger sub-visible particulate count of less than or equal to about 5 particles per mL. In one particular embodiment, the concentration of sub- visible particulate matter is less than or equal to about 150 ppb. In one embodiment the ophthalmic solution contained within the syringe of the present invention is subject to the particulate matter limits set forth in USP <789> wherein the average number of particles present in the units tested does not exceed the values listed in Table 1.

Table 1.

In one embodiment, the ophthalmic solution contained within the syringe of the present invention has a lOμm-size or larger sub-visible particulate count of less than or equal to about 20 particles per mL, a 25μm-size or larger sub-visible particulate count of less than or equal to about 5 particles per mL, or a 50μm-size or larger sub-visible particulate count of less than or equal to about 2 particles per mL. In one particular embodiment, the concentration of sub-visible particulate matter contained within the syringe of the present invention is less than or equal to about 150 ppb.

Waste volume

As represented in Figure 3, the syringe assembly has a low waste space, which is defined as the volume located in the syringe tip 31 of syringe barrel 32, needle hub 33 and needle cannula 34. The International Standard ISO-7886-1 identifies the maximum waste space for a 3ml syringe tip to be 0.07 mL.

In a particular embodiment, the needle/syringe combination of the present invention has a low waste space. Examples of low waste space fittings are found in US Patent Nos. 6,840,291, 5,902,277 5,902,271, 5,902,270 5,902,269 5,782,803, the contents of each is hereby incorporated by reference in its entirety. An example of a needle/syringe combination having a low waste space includes Tru-lok™ fluid transfer adaptors by Becton Dickinson (US Patent No. 6,840,291) and Monoject® low dead space (LDS) needles Tyco Health Care, Kendall (catalog Nos. 1188005058 and 1188001112) featuring tri bevel, anti-coring, stainless steel needles.

The needle/syringe combination of the present invention has a waste space of less than 0.1 mL. In one embodiment, the waste space is less than 0.05 mL. In another embodiment, the waste space is approx. 50-60 μL. In one embodiment, the waste space for the 1 mL Hypak Luer tip syringe is from about 0.040 to about 0.050 mL. In another embodiment, the waste space is less than 0.001 mL.

Syringe tip cap

The syringe assembly may comprise a syringe tip cap. The syringe tip cap is used to seal the barrel of a prefilled syringe. In one embodiment, the syringe tip cap is a plastic rigid tip cap. Examples of suitable syringe tip caps include, but are not limited to, those found in US Patent Nos. 6,190,364; 6,196,998; 6,520,935 and 5,833,653; US patent Application Publication No. 2004/0215148 and US design patent Nos. 457954S1 and 493526S1. In one embodiment, the rigid tip cap is an elastomeric formulation comprising an elastomer, reinforcement and a curing system. In another embodiment, the elastomer is a synthetic isoprene blend, the reinforcement is an inert material, and the curing system is a resin. In another embodiment, the syringe tip cap comprises a chloro/bromobutyl rubber stopper.

Multiple barrel syringe

Another aspect of the invention provides a syringe comprising more than one barrel.

The multiple barrel syringe may permit simultaneous, selective or sequential delivery of one or more different materials.

In one embodiment the syringe comprises a first and second barrel positioned in side- by-side relationship including a first and second plunger for telescoping movement within their respective chambers (see US Patent Application Publication No. 2004/0064102, which is herby incorporated by reference in its entirety). The plungers are optionally connected to a common handle allowing for the dispensing of the materials from the two chambers simultaneously at the same rate, as disclosed, for example, in US Patent No. 5,792,103. In another embodiment, the plungers are detachably connected to the plunger stopper. Figures 4 and 5 show examples of dual barrel syringes for the simultaneous or sequential delivery of two or more therapeutic agents. The syringe includes a first barrel, a second barrel, and one or more needles. Each barrel contains a therapeutic agent dissolved or suspended in a liquid formulation. Referring now to the drawings, there is seen in Figures 4 and 5 first and second embodiments of the double barrel syringe which differ in the respect that the first embodiment (Figure 4) is configured for direct filling of the first and second materials inside their respective barrels while the second embodiment (Figures 5) is configured for insertion of pre-filled first and second carpules into the first and second barrels, respectively.

Referring to the first embodiment shown in Figure 4, the syringe comprises first and second barrels 41, 42 each having an internal chamber 43, 44 for holding a quantity of first and second, liquefied materials therein, respectively. The first and second barrels 41, 42 are arranged in side-by-side relationship with each other. First and second plungers 45, 46 are positioned for sliding within the first and second barrels 41, 42 for telescoping movement therein, respectively. The syringe tip 47 is located adjacent the distal ends of the first and second barrels 41, 42 and is in common, fluid communication therewith via exit orifices 48 and 49. The exit orifices 48 and 49 provide the pathway for the first and second materials, respectively, to tip 47 and thereby allowing passage of the first and second therethrough. Tip 47 may be in the form of a needle directly attached to the syringe body, or may be in the form of a cannula which is attached to the syringe body via a Luer lock.

Referring to the second embodiment shown in Figure 5, the syringe comprises first and second carpules 51, 52 removably insertable within said first and second barrels 53, 54, respectively. First and second syringe needles 55, 56 located in the first and second barrels 53, 54 adjacent the distal ends thereof. As such, upon fully inserting the first and second carpules 51, 52 in the first and second barrels 53, 54, the first and second syringe needles 55, 56 pierce the carpule plug provided at the respective carpule distal end. The first and second needles 55, 56 extend into the tip 57.

A single needle with two or more hollow bores may perform both injections or multiple needles may be used. When one needle is employed, two cannulas, one affixed to one of each barrel, may lead to the one needle. Alternatively, when one needle is employed, the hollow bores may be arranged in a concentric pattern. In such a concentric pattern, one bore is for introduction of a first fluid into the vitreous, and one bore is for introduction of second fluid into the vitreous. When two needles are employed, a second needle may be attached to the exterior of a first needle. Needles may be manufactured from standard materials, e.g., stainless steel, by methods known in the art.

PCT Publication No. WO 2004/073765 describes, in part, a Fluid Exchange System (FES) which is designed to remove a specific volume from a closed system and sequentially deliver a measured volume. By replacing the vacuum chamber with a housing that can accept a pre-filled syringe and removing the air vents (manifolds) an addition therapeutic may be delivered utilizing the original needle penetration. Additional syringe housings could also be added to allow for multiple sequential administrations. Figure 6 illustrates an apparatus comprising a first and second housing 61, 62 capable of accepting a first and second prefilled syringe 63, 64.

In one aspect, multiple medicaments can be administered using a tandem syringe. A tandem syringe typically comprises two or more compartments within one external barrel. Examples of tandem syringes include but are not limited to those found in US Patent Nos. 4,313,440; 4,715,854; 5,102,388; 5,298,024; 6,132,400; and US Patent Application Publication No. 2004/0167480, each of which is herby incorporated by reference in its entirety.

In one embodiment, the tandem syringe comprises an outer first compartment including a first sealing member and an inner second compartment in which the first sealing member functions as the plunger for the outer first compartment (see Figure 7). Referring to Figure 7, the outer first compartment 71 is filled with a first injection solution. The inner second compartment 72 is filled with a second injection solution. The inner second compartment comprises a first sealing member 73 and functions as the piston for the first compartment. When the first injection solution in completely administered, the first sealing member 73 is pierced using a piercing device 74 at the distal end of the outer first chamber. Once the first sealing member 73 is pierced, the second injection solution is administered by pushing stopper 75 with plunger 77 thereby forcing the second injection solution past stopper 73 and out through the needle 76.

Each compartment may be pre-filled with its injection solution separately providing for storage of the injection solutions without mixing or contact with each other. In one embodiment compartment 71 (inner compartment) contains the final solution to be injected. Compartment 71 is first loaded separately, then assembled with the main housing forming compartment 72. Compartment 72 in then loaded with the first solution to be injected.

Advantages

The syringes of the present invention have several advantages. Advantages include the benefits of ease of use, flexibility, cost effectiveness, patient comfort and safety. An advantage of using a non-fixed needle/syringe combination, such as one using a Luer fitting, as described herein is the allowance for a choice of application needle. For example, a practitioner may select either a 27 or 30 gauge disposable needle. A non-fixed needle is typically sharper than a fixed needle because the non-fixed needle will not be susceptible to dulling as a result of contact with the sheath needed for a fixed needle pre-filled syringe. Sharper needles reduce patient discomfort and reduce the risk of infection.

Definitions

The grammatically correct and preferred term "intravitreous" is used herein and in the art. The term "intravitreal" is used colloquially as an alternative to the term "intravitreous" for injections into the eye's vitreous humor between the lens and the retina.

"Particulate matter" includes mobile, randomly sourced, extraneous substances, other than gas bubbles, that cannot be quantitated by chemical analysis because of the small amount of material they represent or because of their heterogeneous composition.

The portion of the device that is toward the practitioner is termed "proximal" and the portion of the device that is toward the patient is termed "distal."

"Penetration force" is the measure of force applied to the needle prior to the needle cutting the tissue. Penetration force is typically measured throughout the art in grams (g).

"Drag force" is a measure of force applied to the needle required to continue the penetration into the tissue. An "Injection" is a preparation intended for parenteral administration. Injections include, but are not limited to, liquid preparations that are drag substances or solutions/suspensions thereof.

By "substantially constant pressure" is meant pressure that is constant with minor, temporary variations due to filling, emptying, or a change in osmotic pressure of the surrounding liquid.

"Parenteral" articles are preparations intended for injection through the skin or other external boundary tissue, rather than through the alimentary canal, so that the active substances they contain are administered, using gravity or force, directly into a blood vessel, organ, tissue, or lesion. Parenteral articles are prepared by methods designed to ensure that they meet Pharmacopeial requirements for sterility, pyrogens, particulate matter, and other contaminants (USP Chapter 1).

The designation "Small- Volume Injection" applies to an injection that is packaged in containers labeled as containing 100 mL or less.

The designation "Microliter-volume Injection" or "Ultra-Low- Volume Injection" applies to an Injection that is packaged in containers labeled as containing 1.0 mL (1000 μL) or less.

As used herein, the term "dead space" or "Waste space" is the volume of injection solution within the syringe/needle assembly containing any residual injection solution present following an injection that does not get evacuated from the syringe during the injection.

By "therapeutic agent" is meant any compound or mixture of compounds that provide a therapeutic effect for one or more diseases, disorders, or conditions. Such compounds include, without limitation, small organic or inorganic molecules, proteins (e.g., antibodies), peptides, lipids (e.g., steroids) and nucleic acids (e.g., aptamers). Therapeutic agents are, for example, antibiotics, analgesics, anti-inflammatory compounds, or any other compound for the treatment of a disease, disorder, or condition.

By "treating" is meant the medical management of a patient with the intent that a cure, amelioration, or prevention of a disease, pathological condition, or disorder will result. This term includes active treatment, that is, treatment directed specifically toward improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventive treatment, that is, treatment directed to prevention of the disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the disease, pathological condition, or disorder. The term "treating" also includes symptomatic treatment, that is, treatment directed toward constitutional symptoms of the disease, pathological condition, or disorder.

Ophthalmic solutions are sterile solutions, essentially free from foreign particles, suitably compounded and packaged for instillation or injection into the eye. Preparation of an ophthalmic solution requires careful consideration of such factors as the inherent toxicity of the drug itself, isotonicity value, the need for buffering agents, the need for a preservative (and, if needed, its selection), sterilization, and proper packaging.

While specific reference has been made to the use of the devices of the present invention to administer therapeutic agents to the eye, it is to be understood that the present invention can be used to deliver a therapeutic agent to any desired site, including, but not limited to, intraorbital, intraocular, intraaural, intratympanic, intrathecal, intracavitary, peritumoral, intratumoral, intraspinal, epidural, intracranial, and intracardial.

A device of the invention may be used in the treatment of any eye disease. A device of the invention may also be used to direct a therapeutic agent to a particular eye tissue, e.g., the retina or the choroid. The therapeutic agent or combination of agents will be chosen based on the disease, disorder, or condition being treated. In addition to a therapeutic agent for a particular condition, other compounds may be included for secondary effects, for example, an antibiotic to prevent microbial growth. The amount and frequency of the dosage will depend on the disease, disorder, or condition being treated and the therapeutic agent employed. One skilled in the art can make this determination.

Therapeutic agents that maybe employed in the device of the invention include, without limitation, small molecules, hormones, proteins, peptides, aptamers, antibodies, lipids, glycolipids, DNA, RNA, PNA, enzymes, sugars, saccharides, glycoproteins, polymers, metalloproteases, transition metals, or chelators. In addition, nucleic acid vectors can also be delivered wherein the nucleic acid may be expressed to produce a protein that may have a variety of pharmacological, physiological or immunological activities. Macromolecules with a molecular weight of about 5 kDa to about 500 kDa may also be used in accordance with the invention.

For ophthalmic drag delivery applications, exemplary disease states include macular degeneration, diabetic retinopathy, glaucoma, optic disc neovascularization, iris neovascularization, retinal neovascularization, choroidal neovascularization, pannus, pterygium, macular edema, vascular retinopathy, retinal vein occlusion, histoplasmosis, ischemic retinal disease, retinal degeneration, uveitis, inflammatory diseases of the retina, keratitis, cytomegalovirus retinitis, an infection, conjunctivitis, cystoid macular edema, cancer, and proliferative vitreoretinopathy.

Classes of therapeutic agents include anti-infectives including, without limitation, antibiotics, antivirals, and antifungals; analgesics; antiallergenic agents; mast cell stabilizers; steroidal and non-steroidal anti-inflammatory agents; decongestants; anti-glaucoma agents including, without limitation, adrenergics, beta-adrenergic blocking agents, alpha-adrenergic blocking agonists, parasympathomimetic agents, cholinesterase inhibitors, carbonic anhydrase inhibitors, and protaglandins; antioxidants; nutritional supplements; angiogenesis inhibitors; antimetabolites; fibrinolytics; wound modulating agents; neuroprotective drags; angiostatic steroids; mydriatics; cyclopegic mydriatics; miotics; vasoconstrictors; vasodilators; anticlotting agents; anticancer agents; immunomodulatory agents; VEGF antagonists; immunosuppresant agents; and combinations and prodrugs thereof.

Specific therapeutic agents include MACUGEN® (pegaptanib sodium injection) as described in U.S. Patent No. 6,051,698, herein incorporated in its entirety by reference. Pegaptanib sodium is also referred to as EYEOOl or NXl 838.

Pegaptanib sodium is a covalent conjugate of an oligonucleotide of twenty-eight nucleotides in length that terminates in a pentylamino linker, to which two 20-kilodalton (kDa) monomethoxypolyethylene glycol (PEG) units are covalently attached via the two amino groups on a lysine residue. The molecular formula for pegaptanib sodium is C₂^H₃₄₂F₁₃N₁O₇Na₂₈O₁₈₈P_2S(C₂H₄O)_n (where n is approximately 900) and the molecular weight is approximately 50 kDa. The chemical name for pegaptanib sodium is as follows: RNA, ((2'-deoxy-2⁽- fluoro)C-G_m-G_m-AA-(2^!-deoxy-2'-fluoro)U-(2^l-deoxy-2^t-fluoro)C-A_m-G_m-(2'-deoxy-2^/ - fluoro)U-G_m-A_m-A_m-(2'-deoxy-2^!-fiuoro)U-G_m-(2'-deoxy-2¹-fluoro)C-(2'-deoxy-2'-fluoro)U- (2'-deoxy-2'-fluoro)U-A_m-(2^l-deoxy-2'-fluoro)U-A_in-(2'-deoxy-2'-fluoro)C-A_m-(2'-deoxy-2^l- fluoro)U-(2'-deoxy-2'-fluoro)C-(2'-deoxy-2'-fluoro)C-G_m-(3^3')-dT), 5'-ester with α, α '- [4, 12-dioxo-6-[[[5-(phosphoonoxy)pentyl]amino]carbonyl]-3 , 13-dioxa-5, 11 -diaza-1 ,15- pentadecanediyl]bis[ω-methoxypoly(oxy-l ,2-ethanediyl)], sodium salt.

MACUGEN® (pegaptanib sodium injection) is a sterile, aqueous solution containing pegaptanib sodium for intravitreous injection. Macugen is supplied in a single-dose, pre- filled syringe and is formulated as a 3.47 mg/mL solution, measured as the free acid form of the oligonucleotide. The active ingredient is 0.3 mg of the free acid form of the oligonucleotide without polyethylene glycol, in a nominal volume of 90 μL. This dose is equivalent to 1.6 mg of pegaptanib sodium (PEGylated oligonucleotide) or 0.32 mg when expressed as the sodium salt form of the oligonucleotide moiety. The product is a sterile, clear, preservative-free solution containing sodium chloride, monobasic sodium phosphate monohydrate, dibasic sodium phosphate heptahydrate, hydrochloric acid, and/or sodium hydroxide to adjust the pH and water for injection. Macugen is formulated to have an osmolality of 280-360 mOsm/Kg, and a pH of 6-7.

Dosage levels of pegaptanib sodium on the order of about 1 μg/kg to 100 mg/kg of body weight per administration are useful in the treatment of neo vascular disorders.

Examples of formulations are found in WO 03/039404, which is hereby incorporated by reference in its entirety. In some embodiments, pegaptanib sodium is administered at a dosage of about 0.1 mg to about 1.0 mg locally into the eye, wherein the treatment is effective to treat occult, minimally classic, and predominantly classic forms of wet macular degeneration. When administered directly to the eye, the dosage range is about 0.3 mg to about 3 mg per eye, in some embodiments the dosage range is about 0.1 mg to about 1.0 mg per eye. In one embodiment, pegaptanib sodium is administered in a therapeutically effective amount of about 0.003 - 3.0 mg, 0.1 - 1.0 mg, or about 0.3 mg. In one embodiment, pegaptanib sodium is present in an ophthalmic injection solution formulation at a concentration ranging from 0.003 to 3.0 mg/mL. According to one embodiment, the carrier comprises sodium phosphate and sodium chloride. According to one specific embodiment the carrier comprises 10 mM sodium phosphate and 0.9% sodium chloride. According to one embodiment, the dose is effective to achieve a vitreous concentration of the anti-VEGF aptamer of about 10-30 ng/mL. According to another embodiment, the dose is effective to maintain a vitreous concentration of the anti-VEGF aptamer of about 10-30 ng/mL throughout a 6 week dosing interval.

In alternative embodiments, the anti-VEGF agent is an anti-VEGF aptamer and is administered at a dosage of less than 0.3 mg to about 0.003 mg locally into the eye. In some embodiments, the anti-VEGF aptamer is administered at a dosage less than about 0.30 mg. Examples of such formulations are found in US Patent Application Serial No. 60/692,727; which is hereby incorporated by reference in its entirety.

Specific therapeutic agents also include the anti-PDGF aptamer ARC- 127 (Archemix

Corp., Cambridge, MA), a PEGylated, anti-PDGF aptamer having the sequence CAGGCUACGN CGTAGAGCAU CANTGATCCU GT (SEQ ID NO: 10 from U.S. Patent No. 6,582,918, incorporated herein by reference in its entirety) having 2'-fluoro-2'- deoxyuridine at positions 6, 20 and 30, 2'-fluoiO-2'-deoxycytidine at positions 8, 21, 28, and 29, 2'-O-Methyl-2'-deoxyguanosine at positions 9, 15, 17, and 31 , 2'-O-Methyl-2'- deoxyadenosine at position 22, hexaethylene-glycol phosphoramidite at "N" in positions 10 and 23, and an inverted orientation T (i.e., 3'-3'-linked) at position 32.

A combination therapy for the treatment of ocular neovascular disorders using a VEGF antagonist and a PDGF antagonist is described in PCT Application No. WO 2005/020972, which is incorporated herein by reference in its entirety. An example of such a therapy comprises the administration of a combination of Macugen® and ARC127.

According to another embodiment, the present invention features a method for treating a patient suffering from an ocular disease, which method includes the following steps: (a) administering to the patient an effective amount of an anti- VEGF aptamer; and (b) providing the patient with phototherapy, such as photodynamic therapy or thermal laser photocoagulation as further described in PCT WO 03/039404, incorporated in its entirety by reference.

In one embodiment of the invention, the photodynamic therapy (PDT) includes the steps of: (i) delivering a photosensitizer to the eye tissue of a patient; and (ii) exposing the photosensitizer to light having a wavelength absorbed by the photosensitizer for a time and at an intensity sufficient to inhibit neovascularization in the patient's eye tissue. A variety of photosensitizers may be used, including but not limited to, benzoporphyrin derivatives (BPD), monoaspartyl chlorine, zinc phthalocyanine, tin etiopurpurin, tetrahydroxy tetraphenylporphyrin, and porfimer sodium (PHOTOFRIN), and green porphyrins.

Other therapeutic agents include 4,9(1 l)-pregnadien-17α,21-diol-3,20-dione, 4,9(11)- pregnadien-17α,21-diol-3,20-dione-21-acetate, combretastatin, timolol, betaxolol, atenolol, brimonidine, acetazolamide, methazolamide, dichlorphenamide, diamox, nimodipine, eliprodil, colchicine, vincristine, cytochalasin B, tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamycin, erythromycin, sulfonamides, sulfacetamide, sulfamethizole, sulfisoxazole, fluconazole, nitrofurazone, amphotericin B, ketoconazole, trifluorothymidine, acyclovir, ganciclovir, didanosine, AZT, foscamet, vidarabine, idoxuridine, ribavirin, protease inhibitors, anti- cytomegalovirus agents, methapyrilme; chlorpheniramine, pyrilamine pheniramine, hydrocortisone, dexamethasone, fiuocinolone, prednisone, prednisolone, methylprednisolone, fluorometholone, betamethasone, triamcinolone, phenylephrine, naphazoline, tetraliydrozoline, pilocarpine, carbachol, diisopropylfluorophosphate, echothiophate iodide, demecarium bromide, atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, epinephrine, heparin, antifibrinogen, fibrinolysin, anti clotting activase, acetohexamide, chlorpropamide, glipizide, glyburide, tolazamide, tolbutamide, insulin, aldose reductase inhibitors, thalidomide, folic acid, 5-fluorouracil, adriamycin, asparaginase, azacytidine, azathioprine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin, estramustine, etoposide, etretinate, filgrastim, fioxuridine, fludarabine, fluoxymesterone, flutamide, goserelin, hydroxyurea, ifosfamide, leuprolide, levamisole, lomustine, nitrogen mustard, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, pentostatin, pipobroman, plicamycin, procarbazine, sargramostim, streptozocin, tamoxifen, taxol, teniposide, thioguanine, uracil mustard, vinblastine, vindesine, pituitary hormones, , insulin-related growth factor, thyroid hormones, growth hormones, heat shock proteins, immunological response modifiers such as muramyl dipeptide, interferons (including α, β, and γ interferons), interleukin-2, cytokines^ FK506, tumor necrosis factor, thymopentin, transforming factor beta2, erythropoietin; antineogenesis proteins, monoclonal antibodies, brain nerve growth factor (BNGF), celiary nerve growth factor (CNGF), vascular endothelial growth factor (VEGF), monoclonal antibodies or aptamers directed against growth factors, and combinations and prodrugs thereof. A therapeutic agent may be present in any suitable formulation for delivery to the eye. Methods well known in the art for making formulations are found, for example, in Remington: The Science and Practice of Pharmacy (20th ed., A.R. Gennaro ed., Lippincott: Philadelphia, 2000). Therapeutic agents may be administered to humans, domestic pets, livestock, or other animals with a pharmaceutically acceptable diluent, carrier, or excipient.

Therapeutic formulations may be liquid solutions, suspensions, or other formulations deliverable via a needle. Formulations may, for example, contain excipients, sterile water, saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.

The therapeutic agent may be admixed with a pharmaceutically acceptable carrier adapted to provide sustained release of the therapeutic agent. Sustained release carriers include emulsions, suspensions, polymeric matrices, microspheres, microcapsules, microparticles, liposomes, multivesicular liposomes, lipospheres, hydrogels, salts, and polymers with the therapeutic agent reversibly bound electrostatically, chemically or by entrapment. Suitable sustained release formulations which may be used are known in the art and are disclosed in, for example, U.S. Patent Nos. 4,865,846, 4,115,544, 5,185,152, 4,078,052, 4,241,046, 4,853,224, 4,865,846, 6,309,669, 5,326,761, 6,071,534, 6,132,766 and 6,277,413 and PCTs WO 01/74400, WO 03/24420, WO 03/028765, WO 02/15888, WO 03/092665 and WO 03/070219, all of which are hereby incorporated in their entirety by reference.

Formulations of the drag may also include a transscleral diffusion promoting agent, such as dimethylsulfoxide, ethanol, dimethylformamide, propylene glycol, N- methylpyrolidone, oleic acid, isopropyl myristate, polar aprotic solvents, polar protic solvents, steroids, sugars, polymers, small molecules, charged small molecules, lipids, peptides, proteins, and surfactants.

A therapeutic agent may be optionally administered as a pharmaceutically acceptable salt, such as a non-toxic acid addition salts or metal complexes that are commonly used in the pharmaceutical industry. Examples of acid addition salts include organic acids such as acetic, lactic, pamoic, maleic, citric, malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic, tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic acids or the like; polymeric acids such as tannic acid, carboxymethyl cellulose, or the like; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, or the like. Metal complexes include cations, such as divalent cations including calcium and magnesium, zinc, iron, and the like. In addition, a therapeutic agent may be optionally administered as a pharmaceutically acceptable prodrug, e.g., an ester or amide.

The chemical compounds for use in such therapies may be produced and isolated as described herein or by any standard technique known to those in the field of medicinal chemistry. Conventional pharmaceutical practice may be employed to provide suitable formulations or compositions to administer the identified compound to patients suffering from a disease, disorder, or condition of the eye. Administration may begin before, during, or after the patient is symptomatic.

Although the above process was described using the syringe of the invention, alternative methods of injection can be employed. Other variations on these configurations will be apparent to one skilled in the art.

EXAMPLES

The following examples serve to illustrate certain useful embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof. Alternative materials and methods can be utilized to obtain similar results.

Example 1

Macugen® Formulation

Macugen® ((OSI) Eyetech, Inc., NY, NY) is formulated at 0.3mg/90μL having a tungsten particulate count of less than 150 ppb. The solution is presented in USP Type I glass barrel syringes fitted with a Luer lock hub and sealed with a bromobutyl rubber plunger stopper. The syringe is fitted with a Luer lock 27-gauge, multi-beveled, silicone coated needle with a rigid plastic outer shield. The needle requires a penetration force of less than 100 g. Example 2

Macugen® Formulation

Macugen® (Eyetech Pharmaceuticals, NY, NY) is formulated at 0.3mg/90μL, 0.03mg/90μL or 0.003mg/90μL and presented in USP Type I glass barrel syringes sealed with a bromobutyl rubber plunger stopper. The syringe is fitted with a Luer lock 27-gauge needle with a rigid plastic outer shield. The stoppered syringe is packaged in a foil pouch. A plastic plunger rod and flange adapter are also supplied for administration purposes. These components are provided in a separate foil pouch. Use of the flange is optional and is not required to administer the injection. The drug product is preservative-free and intended for single use by intravitreous injection only. The product should not be used if cloudy or if particles are present.

Active Ingredient: Pegaptanib Sodium Injection formulated as:

• 0.0347mg/mL solution to deliver a dose of 0.003mg pegaptanib sodium injection

• 0.347mg/mL solution to deliver a dose of 0.03mg pegaptanib sodium injection

• 3.47mg/mL solution to deliver a dose of 0.3mg pegaptanib sodium injection

Excipients: Sodium Chloride, USP

Sodium Phosphate Monobasic, Monohydrate, USP

Sodium Phosphate Dibasic, Heptahydrate, USP

Sodium Hydroxide, USP (as needed)

Hydrochloric acid, USP (as needed)

Water for injection, USP

Preparation

The drug product pegaptanib sodium is a ready-to-use sterile solution provided in a single-use glass syringe. Administration of the syringe contents involves attaching the threaded plastic plunger rod to the rubber stopper inside the barrel of the syringe. The rubber end cap is then removed to allow administration of the product. An optional flange is provided for administrative purposes.

Example 3

Intravitreous Injection

1% Mydriacyl and 2.5% Phenylephrine are applied topically to the study eye to achieve adequate pupillary dilation. Two to three drops of 50% saline diluted 10% povidone- iodine (betadine) solution are instilled into the eye. In the event of allergy to iodine, a drop of topical antibiotic is placed on the conjunctiva in place of iodine. A subconjunctival injection of 0.5 ml 2% xylocaine without epinephrine is administered in the inferotemporal quadrant in all patients - 3.0 to 3.5 mm from the limbus in aphakic/pseudophakic patients, and 3.5 to 4.0 mm in phakic patients. Investigators are instructed to select one of two pre-injection procedures (Options A and B, below). For patients with iodine allergy, investigators are required follow Option A, instilling one additional drop of antibiotic instead of povidone- iodine.

A. Administer topical ofloxacin, levofloxacin, or an antibiotic drop with comparable antimicrobial coverage for three days prior to the treatment followed by three consecutive drops of antibiotic and several drops of 5% povidone-iodine immediately before the treatment

B. Administer three consecutive drops of antibiotic and a 5% povidone-iodine flush of the fornices and caruncle with at least 10 cc of solution just prior to treatment.

Prior to treatment, topical antibiotic drops are administered 3 times separated by at least 5 minutes within one hour prior to treatment.

For patients who are prepared under Option A, following the last dose of antibiotic, the investigator instills two or three drops of 5% povidone-iodine into the eye. Using sterile gloves and cotton-tip applicators soaked in 5% povidone iodine, the investigator scrubs the eyelids, the upper and lower eyelid margins, and the caruncle 3 times. In the event of allergy to iodine, one additional drop of antibiotic is instilled instead of povidone-iodine. For patients who are prepared under Option B, the investigator waits at least 5 minutes after the last dose of antibiotic to perform a 5% povidone-iodine flush, irrigating the fornices and the caruncle with at least 10 cc of 5% povidone-iodine using a forced stream from a syringe connected to an angio-catheter to effect mechanical debridement.

After changing gloves, the investigator isolates the ocular field with a drape, pinning the eyelashes to the eyelids, and places one or two drops of 5% povidone-iodine on the ocular surface at the intended treatment site. An eyelid speculum is used for all injections.

Example 4

Needle Penetration of Porcine Sclera

Data was recorded on a Universal Material Testing Machine (Instron Corporation, Norwood, MA) to mimic insertion of the needle into the eye 6 mm below the sclera. The data was then transferred to a MINIT AB® statistical software (Minitab, Inc, State College, PA) for analysis.

The samples (n=l 5) were tested as follows:

Control: Becton Dickenson (BD) Ice TB syringe paired with a 27Ga Vz inch PrecisionGlide™ needle.

Group 1 : HYPAK 1 mL long syringe 27Ga five-bevel Vz inch needle Group 2: HYPAK 1 mL long syringe 29Ga five-bevel ¹A inch needle Group 3: BD ImL TB syringe paired with a 30Ga ¹A inch precision glide needle

A porcine eye is fixed in test stand and pressurized to standard conditions for blade tests to simulate live conditions. The syringe is placed in the test position on the Instron device. The crosshead speed is set to 150 millimeters per minute. The needle is penetrated about Vz the way into the sclera. The penetration location is about 6 mm below the center of the eye pointing toward the center axis of the eye. A new eye is used for each test (60 eyes total). The penetration force resulting from various needles are shown in Table 2 and Figure Table 2.

Incorporation by Reference

The patent and scientific literature referred to herein establishes knowledge that is available to those of skill in the art. AU patents, patent applications, and published references cited herein are hereby incorporated by reference in their entirety.

Equivalents

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMSWe claim:

1. An apparatus for intravitreal injection comprising:

a syringe comprising a barrel having a proximal and a distal end and a volume of 1 mL or less, said barrel adapted to contain an injection solution wherein said solution contains a sub-visible particulate count of less than 50 particles per mL when contained in the barrel;

a Luer lock tip attached to the distal end of the barrel;

a needle having a gauge of 27 or narrower, said needle comprising a cannula attached to a Luer lock hub for attachment to the Luer lock tip, wherein the needle requires a penetration force of less than 100 g to penetrate scleral tissue;

a syringe tip cap attached to the Luer lock tip for sealing a solution contained in the barrel; and

a needle tip shield adapted to attach to the Luer lock hub and enclose the needle.

2. The apparatus of claim 1 , wherein the needle has a gauge of 29 or narrower.

3. The apparatus of claim 1, wherein the needle is a 30 gauge cannula.

4. The apparatus of claim 1, wherein the needle comprises a multi-bevel tip.

5. The apparatus of claim 1, wherein the needle comprises a 3-bevel tip.

6. The apparatus of claim 1, wherein the needle comprises a 5-bevel tip.

7. The apparatus of claim 1 , wherein the needle comprises a silicon coating.

8. The apparatus of claim 1 , wherein the needle requires a penetration force of less than 70 g to penetrate scleral tissue.

9. The apparatus of claim 1 , wherein the needle requires a penetration force of less than 50 g to penetrate scleral tissue.

10. The apparatus of claim 8, wherein the needle requires a penetration force having a variability of +/- 50 %.

11. The apparatus of claim 8, wherein the needle requires a penetration force having a variability of +/- 30 %.

12. The apparatus of claim 8, wherein the needle requires a penetration force having a variability of +/- 10 %.

13. The apparatus of claim 1 , wherein the injection solution contained in the barrel comprises a lOμm-size or larger sub-visible particulate count of less than or equal to

60 particles per mL.

14. The apparatus of claim 1, wherein the injection solution contained in the barrel comprises a 25μm-size or larger sub-visible particulate count of less than or equal to 10 particles per mL.

15. The apparatus of claim 1 , wherein the injection solution contained in the barrel comprises a 50μm-size or larger sub-visible particulate count of less than or equal to 5 particles per mL.

16. The apparatus of claim 1, wherein the injection solution contained in the barrel comprises a lOμm-size or larger sub-visible particulate count of less than or equal to 20 particles per mL.

17. The apparatus of claim 1 , wherein the injection solution contained in the barrel comprises a 25μm-size or larger sub-visible particulate count of less than or equal to 5 particles per mL

18. The apparatus of claim 1, wherein the injection solution contained in the barrel comprises a 50μm-size or larger sub-visible particulate count of less than or equal to

2 particles per mL.

19. The apparatus of claim 1 , wherein the injection solution contained in the barrel comprises a 50μm-size or larger sub-visible particulate concentration of less than 150 ppb.

20. The apparatus of claim 1, wherein the injection solution contained in the barrel comprises a 25μm-size or larger sub-visible particulate concentration of less than

150 ppb.

21. The apparatus of claim 1, wherein the injection solution contained in the barrel comprises a lOμm-size or larger sub-visible particulate concentration of less than 150 ppb.

22. The apparatus of claim 1 , wherein the injection solution contained in the barrel has a volume of about 200 μL.

23. The apparatus of claim 1, wherein the injection solution contained in the barrel has a volume of about 100 μL.

24. The apparatus of claim 1 , wherein the injection solution contained in the barrel has a volume of about 90 μL.

25. The apparatus of claim 1, wherein the injection solution contained in the barrel has a volume of about 50 μL.

26. The apparatus of claim 1, wherein the apparatus comprises a waste space of less than 60 μL.

27. The apparatus of claim 1, wherein the apparatus comprises a waste space of less than 0.1 μL.

28. The apparatus of claim 1, wherein the apparatus comprises a waste space of less than 0.05 μL.

29. The apparatus of claim 1 , wherein the apparatus comprises a waste space of less than 0.001 μL.

30. The apparatus of claim 1, wherein the syringe tip cap is plastic.

31. The apparatus of claim 1 , wherein the syringe tip cap comprises an elastomeric formulation.

32. The apparatus of claim 1, wherein the syringe tip cap comprises an isoprene blend.

33. The apparatus of claim 1, wherein the syringe tip cap comprises a chlorobutyl or a bromobutyl rubber stopper.

34. The apparatus of claim 1, wherein the needle tip shield is rigid.

35. The apparatus of claim 1 , wherein the needle tip shield does not contact the cannula.

36. The apparatus of claim 1, wherein the needle tip shield comprises one or more apertures.

37. The apparatus of claim 1 , wherein the needle tip shield is permeable to a sterilizing gas or vapor, or plasma.

38. The apparatus of claim 37, wherein the sterilizing gas or vapor is H₂O₂ or EtO or plasma generated from H₂O₂.

39. The apparatus of claim 1 , wherein the needle tip shield comprises polypropylene or a ■ styrene block thermoplastic elastomer.

40. The apparatus of claim 1 , wherein injection solution contained in the barrel comprises a therapeutic agent.

41. The apparatus of claim 1 , wherein the therapeutic agent is an anti-VEGF aptamer.

42. The apparatus of claim 1 , wherein the therapeutic agent is pegaptanib sodium.

43. The apparatus of claim 1, wherein injection solution comprises about 0.003 mg to about 3.0 mg of pegaptanib sodium.

44. The apparatus of claim 1, wherein injection solution comprises about 0.3 mg of pegaptanib sodium.

45. The apparatus of claim 1, wherein the syringe comprises more than one barrel.

46. The apparatus of claim 45, wherein the syringe comprises a first barrel having a proximal and a distal end and a second barrel having a proximal and a distal end, each of the first barrel and the second barrel independently comprises a first injection solution and a second injection solution respectively.

47. The apparatus of claim 46, wherein the first barrel and second barrel are set in a tandem arrangement.

48. The apparatus of claim 46, wherein the first barrel and second barrel are set in a side- by-side arrangement.

49. The apparatus of claim 46, wherein the first injection solution comprises pegaptanib sodium and the second injection solution comprises an anti-PDGF aptamer.

50. The apparatus of claim 45, wherein the syringe comprises:

an outer first compartment having a proximal and distal end and a first sealing member;

an inner second compartment, said inner second compartment is filled with a second injection solution, wherein the inner second compartment functions as the plunger for the outer first compartment;

a piercing device at the distal end of the outer first compartment for piercing the first sealing member;

a first injection solution contained in the outer first compartment; and

a second injection solution contained in the inner second compartment.