EP1924309A1 - Seringue oculaire - Google Patents

Seringue oculaire

Info

Publication number
EP1924309A1
EP1924309A1 EP06803774A EP06803774A EP1924309A1 EP 1924309 A1 EP1924309 A1 EP 1924309A1 EP 06803774 A EP06803774 A EP 06803774A EP 06803774 A EP06803774 A EP 06803774A EP 1924309 A1 EP1924309 A1 EP 1924309A1
Authority
EP
European Patent Office
Prior art keywords
barrel
needle
injection solution
syringe
less
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06803774A
Other languages
German (de)
English (en)
Inventor
Stephen Scypinski
Perry Calias
Richard R. Everett
David T. Shima
Wisam Breegi
Dana L. Litman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
(OSI) Eyetech Inc
Original Assignee
(OSI) Eyetech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by (OSI) Eyetech Inc filed Critical (OSI) Eyetech Inc
Publication of EP1924309A1 publication Critical patent/EP1924309A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61M5/19—Syringes having more than one chamber, e.g. including a manifold coupling two parallelly aligned syringes through separate channels to a common discharge assembly
    • 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
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M2005/3201—Coaxially assembled needle cannulas placed on top of another, e.g. needles having different diameters
    • 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
    • A61M5/24—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic
    • 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
    • A61M5/24—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic
    • A61M5/2448—Ampoule syringes, i.e. syringes with needle for use in combination with replaceable ampoules or carpules, e.g. automatic comprising means for injection of two or more media, e.g. by mixing
    • 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
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/3202—Devices for protection of the needle before use, e.g. caps
    • 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
    • A61M5/32—Needles; Details of needles pertaining to their connection with syringe or hub; Accessories for bringing the needle into, or holding the needle on, the body; Devices for protection of needles
    • A61M5/34—Constructions for connecting the needle, e.g. to syringe nozzle or needle hub
    • A61M5/347—Constructions for connecting the needle, e.g. to syringe nozzle or needle hub rotatable, e.g. bayonet or screw

Definitions

  • the present invention relates to methods of administering ophthalmic medicines and devices related thereto.
  • the invention relates to intravitreous injection using an ophthalmic syringe and needle.
  • 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.
  • IOP intra-ocular pressure
  • 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).
  • intravitreous injection of the vascular endothelial growth factor (VEGF) inhibitor, Macugen® has become available for the treatment of age-related macular degeneration.
  • intravitreous injections of triamcinolone acetonide are now commonly used for the treatment of macular edema.
  • VEGF vascular endothelial growth factor
  • 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.
  • 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.
  • the present invention provides a device for use in ophthalmology.
  • 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.
  • the invention relates to ophthalmic drug delivery devices and features a device for delivery of a therapeutic agent to the eye of a mammal.
  • 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.
  • a needle typically includes an elongated tube with an outside surface, a proximal end, a distal end and an open bore therethrough.
  • 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.
  • the hub is a Luer hub.
  • the needle may also be attached to the syringe via a ceramic coated tip (CCT) interface, i.e. 'press fit'.
  • CCT ceramic coated tip
  • the coating is a medicated coating.
  • the needle is a 27 gauge needle or smaller. In one embodiment the needle is a 30 gauge needle.
  • the needle has a length of less than 1 inch. In another embodiment, the needle has a length of about 0.5 inches.
  • 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.
  • 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.
  • 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.
  • the tip shield is synthetic isoprene, ethylene oxide (EtO) or hydrogen peroxide (H 2 O 2 ) permeable.
  • the syringe barrels, stoppers and plunger rod components and assemblies can also be gamma irradiated.
  • the needle tip shield comprises a polypropylene.
  • the needle tip shield comprises a styrene block thermoplastic elastomer.
  • the needles of the present invention are used for penetration of the scleral tissue for administration of the syringe contents into the vitreous.
  • the needles require a low penetration force.
  • the needles require a low penetration force with low variability.
  • the needles require a penetration force of less than 500 grams (g).
  • the needles require a penetration force of less than 100 grams (g).
  • the needles require a penetration force of less than 50 grams (g).
  • the needles require a penetration force with a variability range of
  • 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
  • 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.
  • the syringe barrel is typically made of glass or a thermoplastic material.
  • 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.
  • the syringe is a BD Hypak SCF® syringe.
  • the syringe is a single dose, pre-filled syringe.
  • the syringe barrel has a volume of 1 mL or less.
  • 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.
  • the final Luer formation is made using a platinum wire.
  • 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.
  • the ophthalmic injection solutions of the present invention are useful as microliter ( ⁇ L)-volume injections. Microliter ( ⁇ L)-volume injections may also be referred to as "ultra- low volume injections".
  • the ophthalmic injection solution to be delivered has a volume of about 1.0 mL (1000 ⁇ L) or less. In another embodiment the ophthalmic injection solution to be delivered has a volume of about 200 ⁇ L or less. In another embodiment the ophthalmic injection solution to be delivered has a volume of about 100 ⁇ L or less. In another embodiment the ophthalmic injection solution to be delivered has a volume of about 90 ⁇ L. In another embodiment the ophthalmic injection solution to be delivered has a volume of about 50 ⁇ L.
  • the ophthalmic solution contained within the syringe of the present invention has a 10 ⁇ m ⁇ size or larger sub-visible particulate count of less than or equal to about 60 particles per mL, a 25 ⁇ m-size or larger sub-visible particulate count of less than or equal to about 10 particles per mL, or a 50 ⁇ m-size or larger sub-visible particulate count of less than or equal to about 5 particles per mL.
  • the concentration of sub- visible particulate matter is less than or equal to about 150 ppb.
  • 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.
  • the ophthalmic solution contained within the syringe of the present invention has a lO ⁇ m-size or larger sub-visible particulate count of less than or equal to about 20 particles per mL, a 25 ⁇ m-size or larger sub-visible particulate count of less than or equal to about 5 particles per mL, or a 50 ⁇ m-size or larger sub-visible particulate count of less than or equal to about 2 particles per mL.
  • the concentration of sub-visible particulate matter contained within the syringe of the present invention is less than or equal to about 150 ppb.
  • the needle/syringe combination of the present invention has a low waste space.
  • 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-lokTM 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 ⁇ L. 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.
  • the elastomer is a synthetic isoprene blend
  • the reinforcement is an inert material
  • the curing system is a resin
  • the syringe tip cap comprises a chloro/bromobutyl rubber stopper.
  • Another aspect of the invention provides a syringe comprising more than one barrel.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • two cannulas, one affixed to one of each barrel may lead to the one needle.
  • 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.
  • 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.
  • FIG. 6 illustrates an apparatus comprising a first and second housing 61, 62 capable of accepting a first and second prefilled syringe 63, 64.
  • tandem syringe typically comprises two or more compartments within one external barrel.
  • 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.
  • 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).
  • 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.
  • compartment 71 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.
  • 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.
  • Porate 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.
  • proximal 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).
  • Drop 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.
  • substantially constant pressure 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).
  • Standard- Volume Injection applies to an injection that is packaged in containers labeled as containing 100 mL or less.
  • Microliter-volume Injection or "Ultra-Low- Volume Injection” applies to an Injection that is packaged in containers labeled as containing 1.0 mL (1000 ⁇ L) or less.
  • 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.
  • therapeutic agent 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.
  • 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.
  • active treatment that is, treatment directed specifically toward improvement of a disease, pathological condition, or disorder
  • causal treatment that is, treatment directed toward removal of the cause of the disease, pathological condition, or disorder.
  • 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
  • supportive treatment that is, treatment employed to supplement another specific therapy directed toward the improvement of the disease, pathological condition, or disorder.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 C 2 ⁇ H 342 F 13 N 1 O 7 Na 28 O 188 P 2S (C 2 H 4 O) n (where n is approximately 900) and the molecular weight is approximately 50 kDa.
  • 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 !
  • Dosage levels of pegaptanib sodium on the order of about 1 ⁇ g/kg to 100 mg/kg of body weight per administration are useful in the treatment of neo vascular disorders.
  • 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.
  • 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.
  • 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.
  • Specific therapeutic agents also include the anti-PDGF aptamer ARC- 127 (Archemix
  • 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.
  • CAGGCUACGN CGTAGAGCAU CANTGATCCU GT SEQ ID NO: 10 from U.S. Patent No. 6,582,918, incorporated herein by reference in its entirety
  • 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.
  • the photodynamic therapy 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.
  • 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.
  • therapeutic agents include 4,9(1 l)-pregnadien-17 ⁇ ,21-diol-3,20-dione, 4,9(11)- pregnadien-17 ⁇ ,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, nitrofura
  • 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.
  • 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 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.
  • 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.
  • 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.
  • Macugen® (Eyetech Pharmaceuticals, NY, NY) is formulated at 0.3mg/90 ⁇ L, 0.03mg/90 ⁇ L or 0.003mg/90 ⁇ L 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.
  • 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.
  • 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).
  • Options A and B For patients with iodine allergy, investigators are required follow Option A, instilling one additional drop of antibiotic instead of povidone- iodine.
  • topical antibiotic drops Prior to treatment, topical antibiotic drops are administered 3 times separated by at least 5 minutes within one hour prior to treatment.
  • 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.
  • 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.
  • 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.
  • Group 1 HYPAK 1 mL long syringe 27Ga five-bevel Vz inch needle
  • Group 2 HYPAK 1 mL long syringe 29Ga five-bevel 1 A inch needle
  • Group 3 BD ImL TB syringe paired with a 30Ga 1 A 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)

Abstract

La présente invention a pour objet un dispositif destiné à un usage ophtalmologique. Plus particulièrement, la présente invention concerne un dispositif pour l’administration de produits oculaires dans le corps vitré. L’invention a également pour objet des procédés d’administration d’un ou de plusieurs médicaments à l’œil humain et de traitement d’une maladie, d’un trouble ou d’un état ophtalmique.
EP06803774A 2005-09-16 2006-09-18 Seringue oculaire Withdrawn EP1924309A1 (fr)

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PCT/US2006/036260 WO2007035621A1 (fr) 2005-09-16 2006-09-18 Seringue oculaire

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EP1924309A1 true EP1924309A1 (fr) 2008-05-28

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