WO2013040310A1 - Dispositif et procédé pour l'administration contrôlée d'une solution ophtalmique dans le stroma de l'œil - Google Patents

Dispositif et procédé pour l'administration contrôlée d'une solution ophtalmique dans le stroma de l'œil Download PDF

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Publication number
WO2013040310A1
WO2013040310A1 PCT/US2012/055339 US2012055339W WO2013040310A1 WO 2013040310 A1 WO2013040310 A1 WO 2013040310A1 US 2012055339 W US2012055339 W US 2012055339W WO 2013040310 A1 WO2013040310 A1 WO 2013040310A1
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WIPO (PCT)
Prior art keywords
plunger
syringe body
syringe
needle
tube insert
Prior art date
Application number
PCT/US2012/055339
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English (en)
Inventor
Bruce H. Dewoolfson
Mike Luttrell
Original Assignee
Dewoolfson Bruce H
Mike Luttrell
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Filing date
Publication date
Application filed by Dewoolfson Bruce H, Mike Luttrell filed Critical Dewoolfson Bruce H
Publication of WO2013040310A1 publication Critical patent/WO2013040310A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M2005/3125—Details specific display means, e.g. to indicate dose setting
    • A61M2005/3126—Specific display means related to dosing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
    • A61M5/31511—Piston or piston-rod constructions, e.g. connection of piston with piston-rod
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M5/315—Pistons; Piston-rods; Guiding, blocking or restricting the movement of the rod or piston; Appliances on the rod for facilitating dosing ; Dosing mechanisms
    • A61M5/31533—Dosing mechanisms, i.e. setting a dose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/46—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests having means for controlling depth of insertion

Definitions

  • the present disclosure is directed to an ophthalmic solution delivery device and method, and, more particularly, to a syringe device configured to deliver an ophthalmic solution to the stroma and method of delivering an ophthalmic solution to the stoma via the syringe device.
  • the cornea is the first and most powerful refracting surface of the optical system of the eye,
  • the human cornea is a highly specialized tissue combining optical transparency with mechanical strength. It is made up of five layers, the outermost of which is the epithelium. The epithelium is only four to five cells thick, and renews itself continuously. Underneath the epithelium, the second layer is the acellular Bowman's membrane. It is composed of collagen fibrils and is normally transparent. Below Bowman's membrane, the third layer, and largest part of the cornea, is the stroma. The stroma makes up approximately 90% of the cornea's thickness, and is about 500 microns ( ⁇ ) thick.
  • the stroma comprises a well organized matrix architecture composed of
  • SLRPs Small leucine-rich repeat proteoglycans
  • decorin small leucine-rich repeat proteoglycans
  • the stroma is mostly water (-78%) and collagen (-16%), although other proteoglycans and glycoproteins are also present.
  • RK radial keratotomy
  • Photorefractive keratectomy is another vision correction technique. It uses an excimer laser to sculpt the surface of the cornea. In this procedure, the epithelial basement membrane is removed, and Bowman's membrane and the anterior stroma are photoablated.
  • corneal haze can also occur following PRK, and the greater the correction attempted, the greater the incidence and severity of the haze.
  • LASIK Laser in situ keratomileusis
  • an epithelial-stromal flap is cut with a microkeratome or a laser.
  • the flap is flipped back on its hinge, and the underlying stroma is ablated with a laser.
  • the flap is then reseated.
  • the CRS-USA LASIK Study noted that overall, 5.8% of LASIK patients experienced complications at the three-month follow up period that did not occur during the procedure itself.
  • corneal edema 66%
  • corneal scarring 0.1%)
  • persistent epithelial defect 0.5%)
  • significant glare 0.2%)
  • persistent discomfort or pain 0.5%)
  • interface epithelium 66%
  • cap thinning 0.1%)
  • interface debris 3.2%).
  • LASIK can result in haze as well, although less frequently than with PRK, presumably because LASIK preserves the central corneal epithelium.
  • the chance of having regression following LASIK is related to the initial amount of refractive error. Patients with higher degrees of myopia (-8.00 to -14.00) are more likely to experience regression. For example, a -10.00 myope may initially be 20/20 after LASIK at the 2 week follow-up visit.
  • the refractive error may shift (regress) from -0.25 to -1.50, or even more. This could reduce the patient's visual acuity without glasses to less than 20/40, a point at which the patient would consider having an additional surgical procedure to correct the regression.
  • keratoconus is a condition in which the rigidity of the cornea is decreased. Its frequency is estimated at 4-230 per 100,000. Clinically, one of the earliest signs of keratoconus is an increase in the corneal curvature, which presents as irregular astigmatism. The increase in curvature is thought to be due to stretching of the stromal layers. In advanced stages of keratoconus, a visible cone-shaped protrusion forms which is measurably thinner than surrounding areas of the cornea.
  • Keratoconus may involve a general weakening of the strength of the cornea, which eventually results in lesions in those areas of the cornea that are inherently less able to withstand the shear forces present within the cornea.
  • Smolek et al. Invest. Ophthalmol. Vis. Sci. Vol. 38, pp. 1289-90 (1997).
  • Andreassen et al. Exp. Eye Res., Vol. 31, pp. 435-41 (1980)
  • compared the biomechanical properties of keratoconus and normal corneas found a 50% decrease in the stress necessary for a defined strain in the keratoconus corneas.
  • This may be related to abnormal insertion into Bowman's structure or to abnormalities in interactions between collagen fibrils and a number of stabilizing molecules such as type VI collagen or decorin.
  • stabilizing molecules such as type VI collagen or decorin.
  • Many of the clinical features of keratoconus can be explained by loss of biomechanical properties potentially resulting from interlamellar and interfibrillar slippage of collagen within the stroma and increased proteolytic degradation of collagen fibrils, or entire lamellae.
  • both keratoconus and postoperative keratectasia involve reduced corneal rigidity
  • relief from each condition could be provided by methods of increasing the rigidity of the cornea.
  • methods that increase the rigidity of the cornea can be used to treat postoperative keratectasia.
  • the treatment can be administered to a patient who plans to undergo a refractive surgical procedure as a prophylactic therapy. In other cases, the treatment can be administered during the surgical procedure itself. In still other situations, the treatment may not be initiated until after the refractive surgical procedure.
  • various combinations of treatment before, during, and after the surgery are also possible.
  • Some of these treatments suffer from drawbacks that include development of corneal haze and scarring, as well as the risk of endothelial cell damage. While some of these drawbacks are associated with the particular agents used, some of these drawbacks are associated with the techniques used to administer the agents. In addition, other such treatments, while practiced with some degree of success, could benefit from enhanced delivery of the agents to the cornea. The need exists, therefore, for system that provides improved delivery of agents to the cornea.
  • Riboflavin has been shown to reduce the progression of keratectasia in patients with keratoconus.
  • Aldehydes have also been used to crosslink collagen fibers and, thereby improve the structural integrity of the cornea.
  • U.S. Patent No. 6,537,545 describes the application of various aldehydes to a cornea in combination with a reshaping contact lens.
  • the contact lens is used to induce the desired shape following either enzyme orthokeratology or refractive surgery, and the aldehyde is used to crosslink collagens and proteoglycans in the cornea.
  • application of such agents can be problematic.
  • SLRPs small leucine-rich repeat proteoglycans
  • FACITs fibril- associated collagens with interrupted triple helices
  • transglutaminase can be used to retard relaxation of corneal tissue back to the original curvature when used as an adjunct to an orthokerotological procedure.
  • SLRPs small leucine-rich repeat proteoglycans
  • FACITs fibril- associated collagens with interrupted triple helices
  • transglutaminase can be used to retard relaxation of corneal tissue back to the original curvature when used as an adjunct to an orthokerotological procedure.
  • orthokeratology and surgical techniques such as LASIK seek to improve visual acuity using radically different approaches, the success of both orthokeratology and surgical techniques may be improved by increasing structural integrity of the cornea.
  • methods of stabilizing collagen fibrils using proteins that crosslink the collagen fibrils, such as decorin or the enzyme transglutaminase have been shown to improve the outcome following a surgical procedure to improve visual acuity.
  • Those results also provide a basis for treating diseases of the cornea, such as keratectasia from other causes, such as keratoconus.
  • ophthalmic solutions such as antibiotics and/or other agents
  • agents that enhance penetration such as agents that dissociate epithelial cell junctures.
  • satisfactory penetration of agents to the desired depth of the cornea may not always be achievable.
  • the present disclosure is directed to improvements in delivery of ophthalmic solutions to the cornea.
  • a syringe device may comprise a syringe body including a needle disposed therein and a plunger configured to be removably connected to the syringe body.
  • the plunger may comprise a plunger flange connected to both an insertion portion and a plunger stem, and a tube insert disposed within the syringe body.
  • the tube insert may be configured to receive ophthalmic solution to be delivered to a portion of an eye.
  • the plunger insertion portion may be configured to be inserted within the tube insert to deliver the ophthalmic solution.
  • a syringe device may comprise a syringe body including a syringe body flange at an upper portion of the syringe body, a hollow barrel connected to the syringe body flange, and a needle holding portion connected to the barrel and disposed at a lower portion of the syringe body.
  • the needle holding portion may include a needle disposed therein.
  • the syringe device may also include a plunger configured to be removably connected to the syringe body, wherein the plunger further comprises a plunger flange connected to both an insertion portion and a plunger stem, and a tube insert disposed within the barrel of the syringe body.
  • the tube insert may be fluidly connected to the needle and configured to receive ophthalmic solution to be injected through the needle into a portion of an eye.
  • a syringe device may comprise a syringe body including a syringe body flange at an upper portion of the syringe body, a hollow barrel connected to the syringe body flange, and a needle holding portion connected to the barrel and disposed at a lower portion of the syringe body.
  • the needle holding portion may include a needle disposed therein.
  • the syringe device may also include a plunger configured to be removably connected to the syringe body, wherein the plunger further comprises a plunger flange connected to both an insertion portion and a plunger stem, and a tube insert disposed within the barrel of the syringe body.
  • the tube insert may be fluidly connected to the needle and configured to receive ophthalmic solution to be injected through the needle into a portion of an eye, and the plunger insertion portion may be configured to be inserted within the tube insert to deliver the ophthalmic solution.
  • the method may include providing a syringe device having a syringe body with a needle disposed therein, a plunger configured to be inserted into the syringe body, and a tube insert disposed within the syringe body.
  • the method may further comprise filling the tube insert of the syringe body with an ophthalmic solution, inserting the plunger into the tube insert, inserting the needle into the portion of the eye, and injecting into the portion of the eye a specific amount of the ophthalmic solution.
  • FIG. 1 illustrates an exemplary embodiment of the disclosed syringe device with the plunger in a retracted position
  • FIG. 2 illustrates an exemplary embodiment of the disclosed syringe device with the plunger in a depressed position
  • FIG. 3 illustrates another view of an exemplary embodiment of the disclosed syringe device
  • Fig. 4A illustrates a cross-sectional view of an embodiment of the disclosed syringe device
  • Fig. 4B illustrates a detailed view of Fig. 4A of a needle holding portion of a syringe body with the plunger in a depressed position
  • Fig. 5A illustrates another cross-sectional view of an embodiment of the disclosed syringe device
  • Fig. 5B illustrates a detailed view of Fig. 5A of a needle holding portion of a syringe body
  • FIG. 6A illustrates a side view of an embodiment of a syringe body of the syringe device
  • Fig. 6B illustrates a detailed view of a needle protruding from the syringe body of Fig. 6A;
  • Fig. 7 shows the effects of decorin drops on corneal historesis for an individual patient;
  • Fig. 8 shows the effects of decorin drops on corneal historesis for multiple patients.
  • Fig. 9 shows the effects of decorin injections on corneal historesis for multiple patients.
  • a "refractive surgical procedure” includes, but is not limited to, Radial Keratotomy (RK), Photorefractive Keratoplasty (PRK), LASIK (Laser-Assisted In Situ Keratomileusis), Epi- LASIK, IntraLASIK, Laser Thermal Keratoplasty (LTK), and Conductive Keratoplasty.
  • RK Radial Keratotomy
  • PRK Photorefractive Keratoplasty
  • LASIK Laser-Assisted In Situ Keratomileusis
  • Epi- LASIK Epi- LASIK
  • IntraLASIK IntraLASIK
  • Conductive Keratoplasty includes, but is not limited to, Radial Keratotomy (RK), Photorefractive Keratoplasty (PRK), LASIK (Laser-Assisted In Situ Keratomileusis), Epi- LASIK, IntraLASIK, Laser Thermal Keratoplasty (LTK), and Conductive Keratoplasty.
  • Stabilizing includes increasing the rigidity, as measured by the Corneal Response Analyzer manufactured by Reichert Ophthalmic Institute. This instrument gives a quantitative measure of corneal rigidity called the Corneal Resistance Factor (CFR) and also a quantitative measure of corneal historesis (CH). “Stabilizing” can also mean decreasing the ability of one collagen fibril to move relative to another collagen fibril by virtue of increased intermolecular interactions.
  • CFR Corneal Resistance Factor
  • CH corneal historesis
  • Crosslinks includes the formation of both direct and indirect bonds between two or more collagen fibrils.
  • Direct bonds include covalent bond formation between an amino acid in one collagen fibril and an amino acid in another fibril.
  • the transglutaminase family of enzymes catalyze the formation of a covalent bond between a free amine group (e.g., on a lysine) and the gamma-carboxamide group of glutamine. Transglutaminase thus is not itself part of the bond.
  • Indirect bonds include those in which one or more proteins serve as an intermediary link between or among the collagen fibrils.
  • decorin is a horse-shoe shaped proteoglycan that binds to collagen fibrils in human cornea forming a bidentate ligand attached to two neighboring collagen molecules in the fibril or in adjacent fibrils, helping to stabilize fibrils and orient fibrillogenesis.
  • a "protein that crosslinks collagen fibrils” includes proteins that form direct or indirect crosslinks between two or more collagen fibrils. Examples include decorin and transglutaminase.
  • a protein that crosslinks collagen fibers is not a hydroxylase, such as lysyl oxidase or prolyl oxidase.
  • Transglutaminase includes any of the individual transferase enzymes having the enzyme commission (EC) number EC 2.3.2.13.
  • Examples of human transglutaminase proteins include those identified by the following REFSEQ numbers: NP_000350; NP_004604;
  • transglutaminase prepared from non-human sources is included within the practice of the exemplary embodiments disclosed herein.
  • non-human sources include, but are not limited to, primates, cows, pigs, sheep, guinea pigs, mice, and rats.
  • the transglutaminase is a transglutaminase solution prepared from an animal source (e.g., Sigma Catalogue No. T-5398, guinea pig liver).
  • the transglutaminase is from a recombinant source, and can be, for example, a human transglutaminase (e.g., the transglutaminase available from Axxora, 6181 Cornerstone Court East, Suite 103, San Diego, CA 92121 or from Research Diagnostics, Inc., a Division of Fitzgerald Industries Intl, 34 Junction Square Drive, Concord MA 01742-3049 USA).
  • a human transglutaminase e.g., the transglutaminase available from Axxora, 6181 Cornerstone Court East, Suite 103, San Diego, CA 92121 or from Research Diagnostics, Inc., a Division of Fitzgerald Industries Intl, 34 Junction Square Drive, Concord MA 01742-3049 USA.
  • Decorin includes any of the proteins known to the skilled artisan by that name, so long as the decorin functions as a bidentate ligand attached to two neighboring collagen molecules in a fibril or in adjacent fibrils.
  • decorin includes the core decorin protein.
  • decorin proteins include those proteins encoded by any of the various alternatively spliced transcripts of the human decorin gene described by REFSEQ number NM_001920.3.
  • the human decorin protein is 359 amino acids in size, and its amino acid sequence is set forth in REFSEQ number NP_00191 1.
  • Various mutations and their effect on the interaction of decorin with collagen have been described, for example by Nareyeck et al., Eur. J.
  • Decorin for use in the disclosed methods, may be from various animal sources, and it may be produced recombinantly or by purification from tissue. Thus, not only human decorin, but decorin from other species, including, but not limited to, primates, cows, pigs, sheep, guinea pigs, mice, and rats, may also be used in the disclosed methods.
  • An example of human decorin that can be used in the disclosed methods is the recombinant human decorin that is available commercially from Gala Biotech (now Catalant). Glycosylated or unglycosylated forms of decorin can be used.
  • treatment refers to efforts to obtain a desired pharmacologic and/or physiologic effect.
  • a treatment can administer a composition or product to a patient already known to have a condition.
  • a treatment can also administer a composition or product to a patient as part of a prophylactic strategy to inhibit the development of a disease or condition known to be associated with a primary treatment.
  • prophylactic treatment is any treatment administered to a patient scheduled to undergo a surgical procedure for the purpose of improving the outcome of that surgical procedure or otherwise reducing undesirable secondary effects associated with the surgical procedure.
  • An example of a prophylactic treatment is the administration of an
  • immunosuppressive agent to a patient prior to the transplantation of an organ or tissue.
  • Treatment covers any treatment of a condition or disease in a mammal, particularly in a human, and includes: (a) inhibiting the condition or disease, such as, arresting its development; and (b) relieving, alleviating or ameliorating the condition or disease, such as, for example, causing regression of the condition or disease.
  • the terms "individual,” “subject,” “host,” and “patient,” used interchangeably herein, refer to a mammal, including, but not limited to, murines, simians, humans, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian farm animals, mammalian sport animals, and mammalian pets.
  • the present disclosure is directed to a device for delivering an ophthalmic solution to the stroma of an eye.
  • the device 1 which may be referred to as an injector device, a syringe device, or the like, may include a syringe body 2, a plunger 3, and a needle 4.
  • Figs. 1 and 2 show one exemplary embodiment in which the syringe body 2 may include a syringe body flange 5, a barrel 6, and a needle holding portion 7.
  • the syringe body flange 5 may be integral to the barrel 6 and disposed atop the barrel 6.
  • the syringe body flange 5 allows a practitioner to grip and hold the syringe body 2 for steady and accurate placement of the syringe device 1 around the eye and accurate injection of ophthalmic fluid into the stroma of the eye.
  • the syringe body flange 5 may further include an opening 8 (Fig. 5A) for insertion of the plunger 3.
  • the opening 8 may taper, shown by the tapered portion 22 (Fig.
  • the angle at which the opening 8 tapers is about 30°.
  • This opening 8 may be advantageous for allowing a practitioner to more easily fill the syringe body 2 with ophthalmic fluid, and/or to allow a practitioner to more easily insert the plunger 3 into the syringe body 2 for delivery of the ophthalmic fluid during treatment.
  • the syringe body flange 5 may also include a notch 9 to receive a plunger stem 10 and to allow the plunger stem 10 to slide through the notch 9 during a treatment, as described in more detail below.
  • the syringe body flange 5 may have a length of about 1 inch and a width of less than about 0.5 inches.
  • the barrel 6 of the syringe body 2 may be made integrally with the syringe body flange 5.
  • the barrel 6 may be arranged in a substantially cylindrical shape, and the barrel 6 may include a hollow interior portion 1 1 (Fig. 5A), or reservoir, which allows ophthalmic solution to be stored therein.
  • the hollow interior portion 1 1 may be in fluid communication with the tapered portion 22 extending from the opening 8 through the syringe body flange 5 and a portion of the barrel 6 (Fig. 5A).
  • the hollow interior portion 1 1 may also be in fluid communication with the needle 4.
  • the hollow interior portion 11 of the barrel 6 also allows for insertion of the plunger 3 into the barrel 6 to deliver ophthalmic solution to the stroma of the eye.
  • the barrel 6 may have an outer diameter of about 0.25 inches, and an inner diameter of less than about 0.1 inches, although a barrel having various diameters could be used. Due to the manufacturing process of forming the barrel 6, to be described in more detail below, the barrel 6 may further include two holes 12a, 12b (Figs. 4B, 5A), near the needle holding portion 7 of the syringe body 2.
  • the two holes 12a, 12b can be formed due to stabilizing pins provided during the molding procedure in order to stabilize a tube insert 13 to ensure that the tube insert 13 is centered along a core of the barrel 6.
  • the two holes 12a, 12b may remain in the barrel 6 near the needle holding portion 7.
  • the two holes 12a, 12b remain in the barrel 6 when the syringe device 1 is in its finished form, i.e., the two holes 12a, 12b may not be filled with material before using the syringe device 1 during a procedure,
  • the syringe body 2 may also include the needle holding portion 7.
  • the needle holding portion 7 may be formed integrally with the barrel 6 of the syringe body 2, and like the barrel 6, the needle holding portion 7 may be arranged in a substantially cylindrical shape.
  • the needle holding portion 7 includes a space for the needle 4 to be disposed therein. The space may be arranged along a central axis of the needle holding portion 7. As shown in Figs. 1-6A, the needle holding portion 7 may have a smaller diameter than the diameter of the barrel 6.
  • the syringe device 1 may further include a plunger 3, which may include an insertion portion 14 to be inserted into the hollow interior portion 1 1 of the barrel 6, and a plunger stem 10 to be disposed on an exterior of the barrel 6.
  • the plunger 3 may also include a flange 15 connected to both the insertion portion 14 and the plunger stem 10 to guide the insertion portion 14 and the plunger stem 10.
  • the plunger flange 15 may further include ridges 16 formed on a flat portion of the plunger flange 15 where a practitioner could place a thumb when injecting ophthalmic solution into a portion of the eye.
  • the ridges 16 may help to ensure that the practitioner's thumb does not slip from the plunger flange 15 so that the ophthalmic solution can be delivered accurately and reliably to the stroma of the eye.
  • the plunger flange 15 may have a circular configuration, although other configurations are possible.
  • the insertion portion 14 of the plunger 3 may be configured to have a cylindrical shape to correspond to the hollow interior portion 1 1 of the barrel 6 of the tube insert 13 disposed within the syringe body 2, as described in more detail below.
  • the diameter of the insertion portion 14 may be smaller than the inner diameter of the tube insert 13 so that the insertion portion 14 may be slidably disposed within the tube insert 13.
  • the insertion portion 14 of the plunger 3 may include a circumferential notch 17 at a distal end of the insertion portion 14, as shown in Fig. 4B.
  • This notch 17 may be provided with a sealing mechanism 18, for example an o-ring, which may be a miniature o-ring, to provide a reliable seal between the plunger insertion portion 14 and the tube insert 13 containing ophthalmic solution.
  • the plunger stem 10 may be included as an indication to a practitioner of the amount of ophthalmic solution delivered during a treatment.
  • the plunger stem 10 extends from the plunger flange 15.
  • the plunger stem 10 extends from the plunger flange 15 in a tapered manner.
  • the plunger insertion portion 14 extends further from the plunger flange 15 than the plunger stem 10.
  • the plunger stem 10 terminates at a distal end of the plunger stem 10, which includes a flat portion 19 to reliably indicate the amount of ophthalmic solution delivered during a treatment.
  • the plunger stem 10 may be configured to include a flat side 20 to face the barrel 6 of the syringe body 2 when the plunger 3 is disposed within the hollow interior portion 11 of the syringe body 2.
  • the syringe may further include at least one needle 4.
  • the needle 4 may be fixedly molded in the needle holding portion 7, as shown at least in Figs. 4A and 4B.
  • the needle 4 may be in fluid communication with the hollow interior portion 11 of the barrel 6 to allow the ophthalmic solution to be delivered from the syringe device 1 into a portion of an eye, wherein the portion of the eye may be the stroma.
  • the needle 4 extends the length of the needle holding portion 7, and protrudes from the end of the needle holding portion 7 by a predetermined length.
  • the length at which the needle 4 protrudes from the needle holding portion 7 may be precise and sufficient so as to allow the needle 4 to puncture at least to the stroma of an eye of a patient receiving treatment, and to prevent the needle 4 from puncturing past the stroma.
  • the needle 4 protrudes by a length of between about 200 and 300 ⁇ .
  • the needle 4 may protrude from the needle holding portion 7 by a length of less than about 250 ⁇ , e.g., about 225 ⁇ . Providing a needle in this manner may promote accurate delivery of ophthalmic solution during treatment, allowing a practitioner to inject the solution at an appropriate depth in the eye tissue.
  • the needle 4 may include an aperture 26 at the tip of the needle 4 in fluid communication with the ophthalmic solution via a needle passage 24 extending through an interior of the needle 4 (Figs. 6A and 6B).
  • the ophthalmic solution may exit through the aperture 26 to be injected into a portion of the eye.
  • the aperture 26 may be provided on a side of the needle 4 rather than at the tip, which may allow delivery of the ophthalmic solution to the eye tissue while maintaining sharpness of the needle tip to facilitate puncturing a portion of the eye during treatment.
  • the plunger stem 10 may be provided to indicate to a practitioner the amount of ophthalmic solution delivered during treatment.
  • the barrel 6 of the syringe body 2 may be provided with markings 21 during or after the syringe body is formed.
  • the markings 21, which may be provided on an outside of the barrel 6, may be dashed lines with numbers corresponding to the amount of ophthalmic solution contained within the tube insert 13, which may be made from a metal such as stainless steel, molded within the barrel 6.
  • the markings 21 may indicate the amount of ophthalmic solution in microliters, although other units may be indicated on the barrel 6 of the syringe body 2.
  • the plunger stem 10 when the insertion portion 14 of the plunger 3 is inserted within hollow interior portion 11 of the barrel 6, the plunger stem 10 is disposed over the markings 21 provided on the exterior of the barrel 6.
  • a practitioner can easily identify the amount of ophthalmic solution delivered during a treatment without having to rely on visually inspecting the amount of ophthalmic solution contained within a syringe body based on the position of a plunger portion disposed within the syringe body.
  • the plunger stem 10 and markings 21 provide a means for a practitioner to easily identify the amount of ophthalmic solution delivered to a portion of an eye, for example the stroma, during a treatment.
  • the barrel 6 of the syringe body 2 may further include the tube insert 13 provided in the hollow interior portion 1 1 to define a hollow space into which the ophthalmic solution may be stored before, during, and/or after a treatment, as illustrated in Figs. 4A and 4B.
  • the tube insert 13 may be a made from a metal, such as stainless steel.
  • the tube insert 13 may be provided at the core of the barrel 6, and the plunger insertion portion 14 is configured to be slidably disposed within the tube insert 13 during injection of the ophthalmic solution.
  • the interior of the tube insert 13 may be in fluid communication with the needle 4.
  • the tube insert 13 has an outer diameter of less than about 0.1 inches, a inner diameter of less than about 0.08 inches, and a wall thickness of less than about
  • the tube insert 13 may have a length of less than about 1.2 inches, which may be less than the length of the barrel 6 of the syringe body 2. Also, in some embodiments, the tube insert 13 may be constructed of hypodermic needle tubing, for example, ETW 13 304 stainless steel.
  • Providing a stainless steel tube as the tube insert 13 may advantageously allow for a tube having a smaller diameter that that of a plastic molded tube, in which to hold ophthalmic solution to be injected during a treatment. It may be problematic to mold a plastic tube having such a small diameter while having a length sufficient to extend within a portion of the barrel in order to hold ophthalmic solution. Forming the tube insert 13 of stainless steel and providing the tube insert 13 along the core of the barrel 6 may solve this problem. Additionally, because a tube insert 13 provided as a stainless steel tube may be opaque, a practitioner would not likely be able to visually inspect the amount of ophthalmic fluid delivered or remaining in the stainless steel tube.
  • the plunger 3 having the plunger stem 10 and the barrel 6 having markings 21 as described above may provide a reliable external indication means for a practitioner to accurately determine the amount of ophthalmic solution injected and/or remaining in the syringe body 2 without having to see the fluid within the tube insert 13 when the tube insert 13 is constructed from an opaque material, such as stainless steel.
  • the syringe body 2 may be made from a number of plastic materials.
  • the syringe body 2 may be made from transparent polycarbonate radiation stabilized, medical grade, Bayer Makrolon® 2558, or an engineering approved equivalent.
  • typical plastic syringes may be incapable of having an inner diameter for holding ophthalmic fluid molded to a diameter small enough to allow a practitioner to accurately deliver small doses of the fluid to a portion of a patient's eye.
  • typical syringes may rely on the practitioner to visually inspect the position of a plunger within a barrel of the syringe or the level of the fluid held within the syringe to determine the amount of fluid injected and/or remaining in the syringe.
  • the tube insert 13 of the instant syringe device may be capable of having a substantially small inner diameter to store precise amounts of ophthalmic fluid, to be delivered to a portion of a patient's eye during a treatment.
  • the plunger 3 having a plunger stem 10 disposed on an exterior of the barrel 6 of the syringe body 2, along with markings 21, may reliably indicate to a practitioner the amount of ophthalmic fluid injected and/or remaining in the tube insert 13 of the syringe body 2.
  • the syringe device 1 may either be provided to a practitioner pre-filled with ophthalmic fluid, or the syringe device 1 may be provided to a practitioner in an empty state to be filled by the practitioner prior to treatment. If the syringe device 1 is provided in an empty state, the practitioner may remove the plunger 3 from the syringe body 2, and fill the syringe body 2 with ophthalmic fluid from a separate sealed package. The syringe body 2 may be filled through the opening 8 in the syringe body flange 5. It should be noted that filling the syringe body 2 with ophthalmic fluid involves filling the tube insert 13 with the ophthalmic fluid.
  • a practitioner may insert a syringe device into a fluid, then draw the plunger back in order to fill a barrel of the syringe with treatment fluid. While a practitioner may fill the instant syringe device 1 in this manner, because of the small diameter of the tube insert 13, which, as discussed herein, may be provided as a stainless steel tube, into which the ophthalmic fluid is received, either providing the syringe device 1 prefilled or filling the device 1 from the back end may be advantageous.
  • a practitioner may begin to administer dosages of the ophthalmic fluid freehand to a portion of the eye.
  • the practitioner may be capable of administering dosages directly where the treatment is needed, for example directly at a diseased location on a portion of the eye.
  • the practitioner may manually insert the needle 4, which, as illustrated in Fig. 5B, protrudes from the needle holding portion 7 of the syringe body 2, into the portion of the eye to be treated to a predetermined depth.
  • the insertion of the needle 4 may be assisted by providing a needle 4 having a sharp tip, as described above.
  • the depth of needle insertion may be limited by the length of the needle 4 and the location where the needle 4 contacts the needle holding portion 7, as illustrated, e.g., in Fig. 5B.
  • the length of the needle 4 may be predetermined to inject ophthalmic fluid into a portion of the eye to be treated, for example the stroma. Once the practitioner inserts the needle 4, she or he may begin to depress the plunger 3 to inject fluid contained within the tube insert 13 of the barrel 2 into the portion of the eye to be treated.
  • the practitioner may monitor the location of the plunger stem 10 relative to the markings 21 provided on the side of the barrel 2 in order to determine the amount of ophthalmic solution injected into the portion of the eye. Because of the plunger stem 10 and the markings 21 included on the barrel 2, the practitioner may need not rely on visualizing the fluid actually contained within the tube insert 13 to ascertain the amount of fluid remaining therein. Once the practitioner has administered the appropriate dosage of ophthalmic fluid for a particular treatment, she or he may withdraw the needle 4 and syringe device 1 from the portion of the treated portion of the eye.
  • the syringe device 1 may be disposable so that a practitioner can dispose of the entire device 1 after treatment of a patient.
  • the syringe device 1 may be provided as a single-use device, which may be used to inject ophthalmic fluid into a plurality of injection sites of a portion of a patient's eye or eyes during a single treatment.
  • the methods of strengthening the cornea in association with a surgical procedure may be initiated at any of a variety of points in time after the patient has been informed that surgery is needed, or informed that surgery is an option for that patient.
  • a patient considering LASIK may receive the strengthening treatment at the time of his or her LASIK prescree ing examination.
  • the strengthening treatment may be administered at a time between the prescreening exam and the surgery.
  • the strengthening treatment will take place within the month preceding the surgery, although, in some cases the time period may be more than a month before the surgery.
  • the strengthening treatment could be administered 5, 6, 7, 8, or even more weeks before.
  • the strengthening treatment could be administered 5, 6, 7, 8, or even more weeks before.
  • the strengthening treatment could be administered 5, 6, 7, 8, or even more weeks before.
  • the strengthening treatment could be administered 5, 6, 7, 8, or even more weeks before.
  • the strengthening treatment could be administered 5, 6, 7, 8, or even more weeks before.
  • the strengthening treatment could be administered 5, 6, 7, 8, or even more weeks before.
  • the strengthening treatment could be
  • strengthening treatment will be administered about one to two weeks before the corneal surgery. Often, when it is administered before surgery, the strengthening treatment will be administered about 10 days before the surgery, although it may be administered about 9, about 8, about 7, about 6, about 5, about 4, about 3, about 2, or about 1 days before the corneal surgery. It is also possible to treat the cornea on the same day as the corneal surgery.
  • the strengthening treatment takes place during the surgical procedure. These embodiments do not exclude treatments at other times, such as before and/or after the surgical procedure. Varying the amount of ophthalmic solution used when the strengthening treatment takes place during the surgical procedure is within the scope of the disclosed embodiments.
  • the amount of solution administered may depend at least in part upon the concentration of the agent in the solution used, as well as the potency of the particular agent, and the severity of the condition being treated. The amount administered may also depend on whether multiple injections will be given, either over time, or at different locations of the cornea. The selection of the amount of solution to be administered may be left to the discretion of the practitioner during individual procedures.
  • One exemplary dosage of agents is between 7 ⁇ and 15 ⁇ per injection site, although dosages less than 7 ⁇ ⁇ or more than 15 ⁇ ⁇ per injection site could be administered.
  • the objective of this study was to evaluate the stromal distribution of different volumes of a fluorescent solution following injection into human donor cornea using the syringe device 1 described herein.
  • Oregon Green 488 was used as the fluorescent solution.
  • Two sets of human donor cornea were procured, and prior to injection, the donor corneas were gently rinsed with sterile phosphate buffered saline.
  • Oregon Green 488 were loaded into the injector device and injected into the central region of human donor cornea.
  • Cornea #1 received 20 ⁇ ⁇ of Oregon Green 488 solution
  • cornea #2 received of Oregon Green 488 solution
  • cornea #3 received 30 ⁇ of Oregon Green 488 solution.
  • the distribution, depth, and uniformity of distribution were evaluated using confocal microscopy to examine the central cornea and each quadrant of the peripheral cornea.
  • Results for the 20 ⁇ ⁇ injection volume showed strong central cornea fluorescence at a depth of approximately 225 um, but weak distribution in peripheral quadrants surrounding the central cornea, and fluorescent intensity diminished beyond the 250 ⁇ depth.
  • results for the 25 ⁇ , and 30 ⁇ , injection volumes showed strong central cornea and peripheral cornea fluorescence at a depth of approximately 225 nL, and fluorescence intensity only slightly diminished in the peripheral cornea quadrants.
  • the syringe device 1 successfully delivered fluorescent solution to human donor cornea to a depth of approximately 225 ⁇ , and injection volumes of 25 ⁇ , and 30 ⁇ , provided uniform distribution of fluorescence across the entire corneal stroma to a depth of approximately 225 ⁇ .
  • the tube insert 13 may be loaded onto stabilizing pins (not shown) for stabilization.
  • the tube insert 13 may be stabilized in order to ensure that the tube insert 13 is disposed centrally with respect to a longitudinal axis of the barrel 6 of the syringe body 2.
  • plastic forming the syringe body 2 may then be molded around the tube insert 13.
  • the needle 4 may be molded into the plastic forming the syringe body 2. In one embodiment, the needle 4 may be molded into the need holding portion 7 of the syringe body 2.
  • the plastic may be injection molded around the tube insert 13. Additionally, the plastic forming the syringe body 2 may be transparent polycarbonate radiation stabilized, medical grade, Bayer Makrolon® 2558, or an engineering approved equivalent. Molding the plastic around the tube insert 13 in this manner confines the tube insert 13 to a core of the syringe body 2. Once the syringe body 2 is removed from the stabilizing pins, two holes 12a, 12b may remain in a lower portion of the barrel 6 where the stabilizing pins were located during the molding process. In some embodiments, the two holes 12a, 12b may be filled or, alternatively, left as open holes in the syringe device 1 and not filled before a practitioner operates the syringe device 1 during a treatment.
  • the markings 21 for indicating an amount of ophthalmic solution may be applied to the exterior of the barrel 6 of the syringe body 2.
  • the mold may have a surface finishing, such as an SPI B-l finish or better.
  • Forming at least the syringe body 2 in this manner avoids the limits imposed by using plastic molding to form the entire syringe body 2.
  • the syringe device 1 may be made economically with minimal labor, while allowing for the injection of very small volumes of ophthalmic solution into a portion of an eye during a treatment. This may be due to the small diameter of the tube insert 13, which, in some instances, may be made from a metal such as stainless steel.
  • applying the markings 21 on the barrel 6 of the syringe body 2 after the molding process provides an indicating means for a practitioner to easily determine the amount of ophthalmic solution injected and/or remaining in the syringe device tube insert 13 during a procedure.
  • syringe device 1 which is commercially viable for large-scale operations.
  • the syringe device 1 may require one needle 4 rather than a plurality of needles before being disposed of after treatment.
  • operating the syringe device 1 may be intuitive and thus simple for a trained practitioner such as a doctor.
  • a practitioner can easily and accurately deliver a desired dosage of ophthalmic solution to a portion of an eye, where the portion of the eye may be the stroma.
  • the disclosed syringe device 1 may be applicable for administering an ophthalmic solution to the eye of a patient.
  • the syringe device 1 may be configured to deliver ophthalmic solutions to the front (i.e. anterior) of the eye.
  • the disclosed syringe device 1 can be used to inject ophthalmic solutions to a subsurface region of the stroma.
  • Exemplary uses for such injections may include treatments for, and/or prevention of, "front-of-the-eye" conditions, such as myopia, hyperopia, astigmatism, keratectasia, and keratoconus, by administering agents that improve the structural integrity of the cornea, e.g., by increasing its rigidity.
  • Such uses may include stabilizing the cornea, correcting refractive error, and improving unaided visual acuity.
  • exemplary treatments may be administered in conjunction with refractive surgery procedures, such as LASIK, PRK, RK, and other surgical refractive procedures.
  • exemplary treatments may include, or may be associated with, non-surgical refractive procedures, such as orthokeratology and corneal rehabilitation.
  • the disclosed device 1 may be utilized to administer agents to the cornea for the purpose of rendering the cornea more malleable and/or pliable (e.g., corneal acylation). This procedure may be performed prior to a stabilization procedure not associated with a surgical treatment.
  • agents to the cornea for the purpose of rendering the cornea more malleable and/or pliable (e.g., corneal acylation). This procedure may be performed prior to a stabilization procedure not associated with a surgical treatment.
  • Possible agents shown to increase structural rigidity of the cornea include
  • compositions with proteins that crosslink collagen fibrils may include such proteins along with a pharmaceutically acceptable carrier.
  • decorin crosslinks the collagen fibrils by binding to each of two different fibrils to form a bridge therebetween.
  • Another such protein is transglutaminase, which crosslinks collagen fibrils by catalyzing the formation of a covalent bond between an amino acid in one collagen fibril and an amino acid in a second collagen fibril.
  • the disclosed syringe device may be utilized to inject compositions including decorin or transglutaminase.
  • such agents may be administered by the disclosed syringe device to the cornea subject to a refractive surgical procedure.
  • the treatment may be initiated before, during, and/or after the surgery.
  • Exemplary refractive surgical procedures may include, but are not limited to, Radial Keratotomy (RK), Photorefractive Keratoplasty (PRK), LASIK (Laser-Assisted In Situ Keratomileusis), Epi-LASIK, IntraLASIK, Laser Thermal Keratoplasty (LTK), and Conductive Keratoplasty.
  • the disclosed syringe device may be employed in methods of treating keratectasia, comprising administering to the stroma a composition comprising a protein that crosslinks collagen fibrils and a pharmaceutically acceptable carrier.
  • the treatment can be prophylactic, contemporaneous with a surgical procedure, postoperative, or can involve multiple
  • the keratectasia may develop following a refractive surgical procedure, such as LASIK, it may also develop in an eye that has not had a surgical procedure.
  • the disclosed syringe device may be employed in methods of treating keratoconus, comprising administering to the eye of a patient who has keratoconus a composition comprising a protein that crosslinks collagen fibrils and a pharmaceutically acceptable carrier.
  • Figure 7 presents the data for an individual patient who had an OD of -6.25 and an OS of -6.00.
  • the x-axis shows the time periods at which measurements were taken, i.e., at baseline and at various time points post surgery.
  • the Y-axis shows the results as a percentage of baseline corneal historesis.
  • Figure 8 shows the effects of decorin drops on corneal historesis for multiple patients.
  • Figure 8 groups the data for all five myopic patients in the study.
  • the disclosed syringe device may be used to inject other types of agents, such as antibiotics, anti-inflammatory agents, anti-allergy agents, antihistamines, or any other ophthalmic solution that is desired to be delivered to subsurface regions of the stroma.
  • agents such as antibiotics, anti-inflammatory agents, anti-allergy agents, antihistamines, or any other ophthalmic solution that is desired to be delivered to subsurface regions of the stroma.
  • embodiments herein are shown and discussed as being configured for applications involving injection of solutions to the eye, embodiments are envisioned that may be configured for injection anywhere in or on the body.
  • features of the disclosed apparatus such as needle insertion depth regulating means, various handle configurations and features, plunger actuating configurations, etc., may be adaptable for syringes used elsewhere in the body besides the eye.
  • various support structure or locator member configurations may be implemented according to the target area of injection.
  • Exemplary non-ophthalmic uses may include, but are not limited to, insulin injections, antibiotic injections, anti-inflammatory injections for skin inflammation, anti-allergy injections, injection of anti-viral agents, etc.
  • Additional possible uses may include surgical and non-surgical skin alterations (e.g., plastic/cosmetic surgery), for example, collagen, epithelial injections, Botox, etc.
  • skin alterations e.g., plastic/cosmetic surgery
  • the volume of the hollow cavity, size of the needle, depth of injection, and other various parameters of the disclosed syringe device may be selected appropriately for the area of the body being treated, and the type of agent injected.
  • the disclosed devices may be utilized to aspirate liquids from the eye or other parts of the body. Possible uses may include specimen collection for various uses.
  • the disclosed devices may be utilized to take tissue samples, blood samples for various testing, (e.g., glucose testing), and other fluid samples, etc. Needle sizes may be determined according to the desired application.
  • embodiments configured for collecting tissue samples may have a needle with a larger inner diameter than embodiments utilized solely for fluid collection.
  • the singular forms "a”, “an” and “the” include plural referents unless the context clearly dictates otherwise.
  • reference to "a subject polypeptide” includes a plurality of such polypeptides and reference to “the agent” includes reference to one or more agents and equivalents thereof known to those skilled in the art, and so forth.
  • dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

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Abstract

Cette invention concerne un appareil et un procédé d'administration d'une solution ophtalmique dans une partie d'œil, ladite partie d'œil pouvant être le stroma. L'appareil peut être un dispositif de type seringue comprenant un corps de seringue et un piston. Le corps de seringue peut en outre comprendre une bride de corps de seringue, un cylindre, et une partie porte-aiguille conçue pour contenir une aiguille. Le piston peut en outre comprendre une bride de piston, une partie à insérer, et une tige de piston. Un insert tubulaire ayant un diamètre relativement petit et destiné à contenir la solution ophtalmique peut être placé à l'intérieur du corps de seringue. Le cylindre peut comprendre des graduations indicatrices externes, la tige de piston s'alignant sur lesdites graduations pour indiquer la quantité de solution ophtalmique qui sera injectée dans la partie d'œil.
PCT/US2012/055339 2011-09-15 2012-09-14 Dispositif et procédé pour l'administration contrôlée d'une solution ophtalmique dans le stroma de l'œil WO2013040310A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015091818A1 (fr) * 2013-12-20 2015-06-25 Novo Nordisk A/S Indicateur mécanique de dose expulsée

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050154354A1 (en) * 2001-12-27 2005-07-14 Yoshihiko Kawasaki Cartridge syringe, cartridge and ophthalmologic syringe set having such syringe
US20100241102A1 (en) * 2009-03-23 2010-09-23 Colin Ma Intravitreal injection devices and methods of injecting a substance into the vitreous chamber of the eye
US7967772B2 (en) * 2004-01-12 2011-06-28 Iscience Interventional Corporation Injector for viscous materials

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050154354A1 (en) * 2001-12-27 2005-07-14 Yoshihiko Kawasaki Cartridge syringe, cartridge and ophthalmologic syringe set having such syringe
US7967772B2 (en) * 2004-01-12 2011-06-28 Iscience Interventional Corporation Injector for viscous materials
US20100241102A1 (en) * 2009-03-23 2010-09-23 Colin Ma Intravitreal injection devices and methods of injecting a substance into the vitreous chamber of the eye

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015091818A1 (fr) * 2013-12-20 2015-06-25 Novo Nordisk A/S Indicateur mécanique de dose expulsée

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