WO2013149260A1 - Method for treatment of ocular disorders - Google Patents

Method for treatment of ocular disorders Download PDF

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Publication number
WO2013149260A1
WO2013149260A1 PCT/US2013/034857 US2013034857W WO2013149260A1 WO 2013149260 A1 WO2013149260 A1 WO 2013149260A1 US 2013034857 W US2013034857 W US 2013034857W WO 2013149260 A1 WO2013149260 A1 WO 2013149260A1
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WIPO (PCT)
Prior art keywords
ultrasound
eye
patient
microbubble
glaucoma
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Application number
PCT/US2013/034857
Other languages
French (fr)
Inventor
Mark S. Humayun
Original Assignee
Humayun Mark S
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Publication date
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Publication of WO2013149260A1 publication Critical patent/WO2013149260A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
    • 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
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/00781—Apparatus for modifying intraocular pressure, e.g. for glaucoma treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61F9/007—Methods or devices for eye surgery
    • A61F9/00736—Instruments for removal of intra-ocular material or intra-ocular injection, e.g. cataract instruments
    • A61F9/00745—Instruments for removal of intra-ocular material or intra-ocular injection, e.g. cataract instruments using mechanical vibrations, e.g. ultrasonic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N2007/0039—Ultrasound therapy using microbubbles

Definitions

  • the present invention relates to a method for treating a disease or disorder of the eye characterized by impaired ocular blood and/or aqueous flow, such as diabetic retinopathy or glaucoma.
  • the method involves administering a microbubble composition and applying ultrasound to the eye of a patient in need thereof.
  • the present invention also includes a system and kit for use in carrying out the method.
  • Impairment of ocular blood flow can result from a number of diseases and disorders, including but not limited to, diabetic retinopathy and glaucoma.
  • Diabetic retinopathy remains the major cause of vision impairment and blindness in adults suffering from diabetes. Nearly all patients with type 1 diabetes will develop some manifestation of diabetic retinopathy; for example in type 2 diabetic patients 80% of insulin-dependent patients and 50% of patients not requiring insulin therapy will have DR within 20 to 25 years following disease onset (Curtis TM, Gardiner TA, Stitt AW. Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis? Eye (Lond). 2009: 23: 1496-1508). With the global incidence of diabetes projected to rise from 150 million to approximately 300 million by the year 2025, diabetic retinopathy represents a major health concern which will present ever-increasing burdens on the health care delivery system.
  • diabetic retinopathy The major underlying pathophysiology of diabetic retinopathy is consistent with the effects of diabetes on small vessel disease elsewhere in the body (e.g., nephropathy, neuropathy). More specifically, vasoconstrictor molecules have been implicated to mediate in part the decrease in retinal blood flow during diabetic induction (Zhu Q, Xu X, Xia X, Gu Q, Ho PC. Role of protein Kinase C on the alteration of retinal endotheim-1 in streptozotocin-induced diabetic rats. Exp Eye Res. 2005; 81 :200-6).
  • high glycemic index can lead to a chronic, low-grade inflammation, damage to pericytes, platelet aggregation and ultimately to venostasis and capillary occlusion (Joussen AM, Pouiaki V, Le ML, Koizumi K, Esser C, Janicki H,et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J. 2004; 8: 1450-2).
  • the earliest detectable changes in diabetic retinopathy are the morphologic appearance of microaneurysms and capillary occlusion.
  • Diabetic retinopathy is currently managed with destructive laser treatments and/or monthly intraocular injections.
  • Destructive laser treatment involves the local or pan retinal application of destructive laser photocoagulation to microaneurysm/ischemic retinal regions (Early Treatment Diabetic Retinopathy Study Research Group.Eariy photocoagulation for diabetic retinopathy. ETDRS Report Number 9. Ophthalmology. 1991;98:66-785; The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical Application of Diabetic Retinopathy Study (DRS) Findings, DRS Report Number 8. Ophthalmology. 1981;88:583-600).
  • Diabetic retinopathy is also treated with repeated intraocular injections of either antiangiogenics (e.g., Lucentis® and Avastin®) or steroids (e.g., triamcinolone acetonide).
  • antiangiogenics e.g., Lucentis® and Avastin®
  • steroids e.g., triamcinolone acetonide
  • current therapies require repeated treatments with limited success in improving visual acuity.
  • treatment may also lead to multiple blind spots (scotomas) and impact peripheral visual field and dark adaptation.
  • intraocular implants containing steroids have been investigated clinically, but have the serious side effects of inducing cataracts and glaucoma.
  • Glaucoma is a term used to refer to a group of disorders of the eye typically involving damage to the optic nerve, leading to vision loss and possibly, blindness. Glaucoma is normally associated with increased fluid pressure in the eye (aqueous humor). There are two basic types of glaucoma, open angle and closed angle. The angle refers to the area between the iris and cornea, through which fluid must flow to escape via the trabecular meshwork. Patients with closed angle glaucoma are more likely to seek treatment quickly, due to the associated discomfort, which tends to limit permanent damage to vision. Conversely, patients with open angle, chronic glaucoma tend to progress at a slower rate and may not seek medical attention until the disease has progressed more significantly.
  • Intraocular pressure can be lowered by the use of eye drops containing pharmaceutical agents. Compliance remains an issue, however, as do undesirable side effects. Most studies have reported little effect or improvement of optic nerve blood flow when topical medications are used. Improved flow with medication use most likely is a result of decreased intraocular pressure and improved perfusion pressure.
  • the present invention includes a method, system and kit for treating a disease or disorder of the eye characterized by impaired ocular blood flow, involving administering a microbubble composition to the patient and applying ultrasound to a patient in need thereof.
  • the present invention is a method for treating glaucoma, involving administering a therapeutically effective amount of a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
  • the present invention is a method for treating diabetic retinopathy, involving administering a therapeutically effective amount of amicrobubble composition to a patient in need thereof and applying ultrasound to the eye.
  • the present invention is a method for improving ocular blood in a patient suffering from glaucoma or diabetic retinopathy, involving administering a therapeutically effective amount microbubble composition and applying ultrasound to the eye.
  • the present invention is a method for treating glaucoma or diabetic retinopathy involving administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of about 10 MHz or less using an extraocular probe over a period of time from about 30 to about 45 minutes.
  • microbubble composition may be administered by any suitable method including, for example, intravascular administration or administration directly to the eye.
  • Fig. 1 is a graph showing reduction of intraocular pressure in a clinical study of nine (9) patients treated by intravenous administration of microbubbles and extraocular ultrasound according to Example 1.
  • the present invention is directed as a method, system and kit for treating a disease or disorder of the eye characterized by impaired ocular blood flow in a patient in need thereof, involving administering a microbubble composition and applying ultrasound to the eye of a patient in need thereof.
  • the method results in improved visual acuity, improved blood flow to a previously impaired ocular region, decreased macular edema, reduced intraocular pressure (IOP), improved visual field, decreased neovascularization or combinations thereof.
  • Microbubbles are gas-filled bubbles in the micron size range.
  • microbubble composition refers to a composition comprising a plurality of microbubbles.
  • microbubbles as contrast agents in diagnostic ultrasound is well- known.
  • a microbubble passes through an ultrasound energy field, it undergoes translations and size oscillations (static or inertial cavitation), which generates harmonic signals that are able to increase the acoustic impedance mismatch between the blood and surrounding tissue, thereby improving the diagnostic vascular ultrasound (Nanda NC, Schlief R, Goldberg BB. Advances in echo imaging using contrast enhancement. 2nd ed. Dordrecht: Kluwer Academic Publishers, 1997).
  • Contrast- enhanced ultrasound can be used to image blood perfusion in organs, measure blood flow rate in the heart and other organs, among other imaging applications.
  • sonothrombolysis More recently, the use of microbubbles and ultrasound for thrombolysis (“sonothrombolysis”) has been studied.
  • the basic concept of sonothrombolysis is that that during the ultrasound application, certain ultrasound parameters can produce cavitational energy that disassembles, or destroys, the clot (Tachibana K, Tachibana S. Albumin microbubble echo-contrast material as an enhance for ultrasound accelerated thrombolysis. Circulation 1995; 92: 1148-1150; Porter TR, LeVeen RF, Fox R, et al. Thrombolytic enhancement with perfluorocarbon-exposed sonicated dextrose albumin microbubbles. Am Heart J.
  • Sonothrombolysis can be used to enhance thrombolytic drug therapy or as a stand alone treatment.
  • the use of sonothrombolysis in patients with an acute cerebral- vascular ischemic has been studied clinically. These initial trials included the administration of tissue plasminogen activator (tPA) in combination with the microbubbles, and a continuous application of transcranial ultrasound.
  • tPA tissue plasminogen activator
  • Alexandrov AV, Mikulik R, Ribo M, Sharma VK, Lao AY, Tsivgoulis G, Sugg RM, Barreto A, Sierzenski P, Malkoff MD, Grotta JC A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke Stroke.
  • gas microbubbles may show strong oscillatory motion provided the frequency of the incident ultrasound is close to the resonant (fundamental) frequency of the microbubbles.
  • MI > 0.5 ultrasound at the microbubble resonance frequency will cause the bubbles to rupture.
  • microbubble used in the present invention may be any suitable microbubble. They generally have an outer shell and a hollow core encapsulating a gas, where different microbubbles may be characterized by the composition of their member or shell, the composition of their gas core and whether or not they are targeted or contain additional agents (e.g., therapeutic agents).
  • the microbubble shell may include, without limitation, a lipophilic monolayer surfactant, a lipid bilayer (liposome), albumin, galactose, gelatin, polyglutaminic acid or other lipid or polymer material.
  • the microbubble shell is formed from more than one compound or material.
  • the gas core of the microbubble used in the present invention may be air, a heavy gas or nitrogen.
  • the gas is air, perfluoropropane, perfluorobutane, dodecafluoropentane, octafluoropropane, perfluorocarbon, sulphur hexafluoride, perfluorohexane or perfluorobutane.
  • the gas core may contain more than one gas.
  • the microbubble diameter size may be, for example, about 1 to about 10 micrometeres, about 3 to about 7 micrometers, or about 3, about 4, about 5, about 6 or about 7 micrometers.
  • the microbubble used in the present invention is a perflutren lipid microsphere, composed of octafluoropropane encapsulated in an outer lipid shell (e.g., Defmity®, Lantheus).
  • the microbubble used in the present invention is a 1-2 micron-CsFg perflutren-lipid microsphere (e.g., MRX-801 , Cerevast).
  • the microbubble used in the present invention is targeted.
  • the surface of the microbubble contains a ligand that specifically binds to a particular molecular marker of interest.
  • targeted microbubbles can be prepared by attaching targeting ligands to the lipid, protein or polymer shell coating of gas-filled microbubbles using covalent or non-covalent binding techniques (Klivanov et al. Med Biol Eng Comput. 2009 Aug;47(8):875-82). Representing, non-limiting molecular targets include fibrin and/or proteins associated with clots.
  • the microbubbles may be, for example, targeted to activated platelets.
  • the microbubble is a clot-targeted or thrombus-targeted microbubble.
  • the microbubble is a platelet-targeted microbubble.
  • the microbubble used in the present invention is modified by the introduction of one or more therapeutic agents.
  • the microbubble may be coated or filled with a therapeutic agent, with ultrasonic energy activating the coating or creating oscillations or explosions to release the agent, using any suitable coating or linking technology.
  • the therapeutic agent may be any suitable agent, such as a small molecule, a carbohydrate, a peptide, a protein, an oligonucleotide or other biologic.
  • therapeutic agents suitable for use in the method of the present invention include TPA or rTPA (alteplase, reteplase, and tenecteplase (TNKase)) or vasodilators (e.g., prostaglandins, nitrates).
  • TPA or rTPA (alteplase, reteplase, and tenecteplase (TNKase)) or vasodilators (e.g., prostaglandins, nitrates).
  • the microbubble composition utilized in the present invention comprising gas-filled microbubbles in an aqueous carrier (e.g., saline or another physiologically acceptable liquid).
  • an aqueous carrier e.g., saline or another physiologically acceptable liquid.
  • the microbubble concentration is about 20, about 30, about 40, about 50, about 60, about 70, about 80 or about 90%.
  • injectable compositions generally contain high concentrations of microbubbles, in a minimal amount of carrier for the composition to be injected.
  • the composition may comprise a single microbubble type or more than one microbubble type.
  • the microbubble composition may contain one more additional excipients or other active agents.
  • the composition may include viscosity modifiers, buffers, stabilizers, chelators, air solubility modifiers, osmotic agents, salts and/or sugars.
  • Preferred solutions have a pH of about 7 and are isotonic.
  • the present method relies upon the use of ultrasound to activate microbubbles or to locate the area to be treated, or both.
  • ultrasound can be used to confirm placement of microbubbles at the treatment site and/or to confirm successful treatment.
  • the treatment is diffuse. In another embodiment, the treatment is localized, i.e., the ultrasound is utilized to locate the area to be treated.
  • Ultrasonic techniques have also been utilized in surgical procedures on the eye for imaging structure and/or tissue of a surgical site. See, e.g., U.S. Pat. No. 6,676,607 to de Juan, Jr. et al., the contents of which are incorporated herein by reference in their entirety.
  • the ultrasound probe is an extraocular probe.
  • the ultrasound probe is configured for use on the eyebrow or closed eyelid of the patient being treated.
  • the ultrasound probe may be secured to the closed eyelid by any suitable means, including, without limitation, an adhesive or an apparatus worn by the patient to secure the probe in place physically (e.g., a strap).
  • the ultrasound probe is configured for internal or intraocular use.
  • the ultrasound probe is configured for use on the eye surface, similar to a contact lens.
  • the ultrasound probe is used in conjunction with a water- or gel-filled bath configured to be positioned within the eye.
  • the ultrasound probe may be attached to the bath or simply rest within in the bath.
  • the ultrasound probe of the present invention is advantageously configured to obviate the need for the user or operator to hold the device as the method is performed, either at all or for more than a limited duration (e.g., less than about 60 minutes, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes or about 5 minutes).
  • the shape of the ultrasound probe may vary according to the conditions of use.
  • the ultrasound probe is a disc, half-circle, crescent, wedge or doughnut shape.
  • the ultrasound probe may optionally include a sensing means, to permit the ultrasound machine or user to determine if the probe is in contact with the eye, for example the eyebrow, eyelid or eye surface.
  • the sensing means may be any suitable means, including but not limited to, a means to sense or measure pressure or resistance at the probe tip.
  • the sensing means is a mechanical or electrical spring.
  • the ultrasound probe of the present invention is configured to deliver or provide ultrasound energy and optionally, optical imaging capabilities.
  • the device may be used for any purpose where ultrasound function is desirable or where dual function (ultrasound and optical imaging) is desirable, including, but not limited to, therapeutic or diagnostic purposes.
  • the device is an ultrasound probe for use in treating ocular disorders such retinal vein occlusion.
  • specially designed probes which have the ability to image and also activate the microbubbles, therapies can be effected in the eye, while minimizing collateral damage.
  • Such a probe is described in co-owned and co-pending U.S. patent application Ser. No. 12/061,120 filed 2 Apr. 2008 and entitled "Thrombolysis In Retinal Vessels with Ultrasound," incorporated in its entirety herein by reference.
  • a pulsed-wave Doppler system with a PMN-PT needle transducer has been developed to measure the blood flow velocity in selected retinal vessels. See, e.g., Emanuel J. Gottling, et al, "PMN-PT High Frequency Ultrasonic Needle Transducers for Pulsed Wave Doppler In The Eye,” 2005 IEEE Ultrasonics Symposium (IEEE 2005), the contents of which are incorporated herein by reference in their entirety.
  • the ultrasound component comprises a source of sonic energy.
  • the frequency and/or range of frequencies used may be any one or more of those deemed useful to one of skill in the art for use in imaging and/or therapeutic applications.
  • the ultrasound may be applied generally or in a focused or directed manner.
  • the intensity, duration and resonant frequency may be altered according to the particular result desired, for example, diagnostic imaging versus therapeutic use as discussed further below.
  • the method of the present invention involves administering a microbubble composition and applying ultrasound to the eye of a patient in need thereof.
  • the patient may be a human or non-human patient. In a particular embodiment, the patient is human.
  • the method of the present invention can be used to provide treatment, protection or amelioration of a disease or disorder of the eye.
  • the disease or disorder is characterized by reduced ocular blood flow.
  • the patient may suffer from one or more diseases or disorders of the eye characterized by reduced ocular blood flow
  • the patient suffers from glaucoma. In another embodiment, the patient suffers from diabetic retinopathy. In a particular embodiment, the patient suffers from glaucoma and diabetic retinopathy.
  • the patient does not have retinal vein occlusion (RVO).
  • RVO retinal vein occlusion
  • the patient has RVO but has been diagnosed with one or more additional ocular diseases or disorders characterized by reduced blood flow.
  • the patient suffers from glaucoma and RVO.
  • the patient suffers from diabetic retinopathy and RVO.
  • the disease or disorder is characterized by increased ocular pressure
  • the patient may suffer from one or more diseases or disorders of the eye characterized by increased ocular pressure.
  • the disease or disorder is glaucoma.
  • the microbubble composition may be administered to the patient using any suitable strategy, either systemically or locally.
  • the microbubble composition may be administered to the patient by intravitreal injection, injection into the eye (vitreous cavity, subretinal, or anterior chamber) or intravascularly, including intravenously.
  • the microbubble composition is administered by intra vitreal injection.
  • the microbubble composition is administered intravascularly
  • the microbubble composition is administered intranveously.
  • the microbubbles are administered by a single bolus injection. In another embodiment, the microbubbles are administered via intermittent bolus injection or continuous infusion. In a preferred embodiment, the microbubbles are administered intravenously by continuous infusion.
  • the microbubble composition is administered to the patient in a therapeutically effective amount.
  • the amount of microbubble composition administered to the patient may vary, as would be understood by one of skill in the art, based on a variety of factors including the indication and the physical characteristics (including health status) of the patient..
  • two vials of microbubbles are administered, each containing lxlO 10 microbubbles per vial.
  • no more than one bag of IV fluids with 2-6mls of microbubbles is given in any one day.
  • the ultrasound probe may be any suitable ultrasound probe, including those disclosed herein.
  • the ultrasound probe is an external probe.
  • the ultrasound probe is an intraocular probe.
  • the ultrasound is applied as single pulses or pulse trains (defined as single application) within a second that are then repeated every second over a time frame of minutes/hours (defined as multiple applications, representing one therapeutic course). Furthermore, similar courses over a period of days/weeks/months are then considered multiple therapeutic courses. Hence, the ultrasound may be applied in a single application or multiple applications within a given therapeutic course or within multiple therapeutic courses.
  • the ultrasound is applied for about 0.1 to about 0.5 seconds. For example, about 0.1, about 0.2, about 0.3, about 0.4 or about 0.5 seconds.
  • the total time period over which multiple applications are applied may vary, from about 5 to about 90 minutes, about 5 to about 45 minutes, about 20 to about 40 minutes, about 25 to about 35 minutes, or about 30 to about 90 minutes.
  • the ultrasound applications occur over a period of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85 or about 90 minutes.
  • the total time period over which multiple applications are applied is from about 30 to about 45 minutes.
  • the mechanical index at which the ultrasound is applied may vary.
  • a suitable range would be, for example, about 0.1-1.0 MI.
  • the mechanical index is greater than about 1.0 MI.
  • the mechanical index is about 0.1, about 0.2, about 0.25, about 0.29, about 0.3, about 0.35, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9 or about 1.0 MI.
  • the mechanical index is in the range of about 0.1 to about 0.5, about 0.2 to about 0.4, or about 0.25 to about 0.35 MI.
  • the mechanical index is about 0.5 MI.
  • the frequency at which the ultrasound is applied may be vary.
  • a suitable range would be, for example, about 1 to about 10, about 2 to about 8, about 4 to about 6, or about 5 to about 7 MHz.
  • the frequency is greater than about 10 MHz.
  • the frequency is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5 or about 10 MHz. In a particular embodiment, the frequency is about 8 MHz.
  • ultrasound is applied at a frequency of less than about 10 MHz. In a particular embodiment, the ultrasound is applied at a frequency of less than about 10, less than about 9, less than about 8, less than about 7, less than about 6, less than about 5, less than about 4, less than about 3, less than about 2 or less than about 1.0 MHz.
  • the ultrasound is applied at about 0.5 MI once every second for only 40 microseconds, over a ten (10) minute period.
  • the present invention is a method for treating glaucoma, involving administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz over a time period of about 30 and about 45 minutes.
  • the present invention is a method for treating glaucoma, involving administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz once every second for 40 microseconds over a time period of about 30 and about 45 minutes.
  • the present invention is a method for treating glaucoma, involving intraveneously administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz once every second for 40 microseconds over a time period of about 30 and about 45 minutes.
  • the present invention is a method for treating diabetic retinopathy, involving administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10MHz over a time period of about 30 to about 45 minutes.
  • the present invention is a method for treating diabetic retinopathy, involving administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz once every second for 40 microseconds over a time period of about 30 to about 45 minutes.
  • the present invention is a method for treating diabetic retinopathy, involving intravenously administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz once every second for 40 microseconds over a time period of about 30 to about 45 minutes.
  • Ultrasound may be applied by extraocular ultrasound probes or intraocular ultrasound probes.
  • the lid may be open or closed when an extraocular ultrasound probe is utilized.
  • the present invention is a method for treating glaucoma, involving administering (e.g., intravenously) a perfluorocarbon- lipid microbubble composition and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz over a time period of about 30 and about 45 minutes using an extraocular probe.
  • the present invention is a method for treating diabetic retinopathy, involving administering (e.g., intravenously) a perfluorocarbon- lipid microbubble composition and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz over a time period of about 30 to about 45 minutes using an extraocular probe.
  • a topical ultrasound gel is applied to the ocular surface prior to ultrasound treatment.
  • ultrasound is applied through a transverse access on the lateral fornix to avoid energy attenuation caused by the lens.
  • the probe may be maintained at that angle for the rest of the treatment period.
  • the ultrasound probe is applied to the inferior conjunctival surface aiming at the midvitreous cavity.
  • the patient method involves placement of a saline well or water bath within the eye of the patient.
  • the well or bath is a small soft contact lenslike structure. It is placed on the eye of the patient, having first been anesthetized by use of topical anesthetic drug placed in the eye as a topical drop (e.g. proparacaine). Then the ultrasound probe is place on the water bath.
  • topical anesthetic drug placed in the eye as a topical drop (e.g. proparacaine).
  • the ultrasound probe is place on the water bath.
  • the water bath or well is used when treatment is directed to the front of the eye. Following the procedure, the water bath is removed much like a soft contact lens is removed.
  • the method of the present invention will result in one or more of: (i) improved visual acuity; (ii) improved blood flow to a previously impaired region as measure on retinal angiography, Doppler ultrasound, or phase contrast optical coherence tomography (OCT); (iii) decreased macular edema as measured by OCT ; (iv) reduced intraocular pressure (IOP) of at least 2mmHg as measured by corneal applanation tonometry; (v) changes in visual field (improvement in central of peripheral visual fields as measured on automated perimetry) and/or (iv) decreased neovascularization of iris or retina as determined by angiography and fundus photography.
  • OCT phase contrast optical coherence tomography
  • the method results in improved blood flow to a previously impaired region.
  • Evidence of improved blood flow may be determined by, for example, diagnostic (Doppler) ultrasound and/or ophthalmoscopic exam. If either or both show an increase of blood flow, then no more treatment cycles will be administered.
  • the method results in improved optic disease and/or retrobulbar blood flow.
  • the method results in improvement of episcleral blood flow.
  • the method results in an improvement in ocular blood flow of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95 or about 100%.
  • the present invention is a method of improving ocular blood flow in a patient suffering from diabetic retinopathy by administering a microbubble composition and applying ultrasound to the eye.
  • the present invention is a method of improving ocular blood flow in a patient suffering from glaucoma by administering a microbubble composition and applying ultrasound to the eye.
  • the method results in decreased macular edema.
  • Macular edema can be measured by OCT.
  • the method results in a decrease of macular edema of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95 or about 100%.
  • the present invention is a method of decreasing macular edema in a patient suffering from diabetic retinopathy by administering a microbubble composition and applying ultrasound to the eye.
  • the present invention is a method of decreasing macular edema in a patient suffering from glaucoma by administering a microbubble composition and applying ultrasound to the eye.
  • the method results in improved visual acuity.
  • the method increases visual acuity about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95 or about 100%.
  • the present invention is a method of improving visual acuity in a patient suffering from diabetic retinopathy by administering a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
  • Example 4 provides results from a clinical study evidencing improved visual acuity in 2/3 (66%) of patients treated according to this embodiment of the present invention.
  • the present invention is a method of improving visual acuity in a patient suffering from glaucoma by administering a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
  • the method results in changes in visual field. Changes in the visual field, as measured using an automated perimetry, such as the Humphrey (24-2 or 30-2, Zeiss).
  • the present invention is a method of improving visual field patient suffering from diabetic retinopathy by administering a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
  • the present invention is a method of improving visual field in a patient suffering from glaucoma by administering a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
  • the method of the present invention requires fewer intraocular injections than drug therapies currently in use (e.g., anti-VEGF drugs such Lucentis (Genentech-Roche)).
  • drug therapies e.g., anti-VEGF drugs such Lucentis (Genentech-Roche)
  • the present invention is a system incorporating the various elements necessary to carry out the claimed method.
  • the present invention is a kit that includes the components necessary to form the microbubbles for use in the present invention (either individually or pre-mixed) and an ultrasound probe for use in the method of the present invention.
  • the kit also includes instructions for preparing (as necessary) and administering the microbubble composition according to the present invention.
  • the subjects were preferred for infusion, and for continuous monitoring via EKG for the duration of the procedure.
  • diagnostic ultrasound was applied through closed or open eyelids after topical anesthetic drop of proparacine and an ultrasound gel application. Pulse and Color Doppler were used to evaluate the retinal circulation before treatment.
  • the vehicle was shaken for forty five (45) seconds. Two -six (6) mis of vehicle content were added to 100 ml of ringer solution at the beginning of the therapeutic application of ultrasound and then infused IV 75-150ml/hr.
  • the microbubble contrast agent (Definity) was administered and ultrasound was simultaneously applied at OA- 0.5MI (mechanical index). The ultrasound was applied in this mode once every second for only 40 microseconds, over a ten (10) minute period.
  • the ocular blood flow is evaluated with the ultrasound machine or by investigator assessment using ophthalmoscopy.
  • the above treatment was continued until the occlusion is opened or the infusion fluid volume was finished.
  • ultrasound was applied through a transverse access on the lateral fornix to avoid energy attenuation caused by the lens.

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Abstract

The present invention is a method for treating a disease or disorder of the eye characterized by impaired ocular blood and/or aqueous flow, such as diabetic retinopathy or glaucoma. The method involves administering a microbubble composition to a patient in need thereof and applying ultrasound to the eye of a patient in need thereof. The present invention also includes a system and kit for use in carrying out the method.

Description

METHOD FOR TREATMENT OF OCULAR DISORDERS
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to U.S. Provisional Patent Application No. 61/618,227, filed March 30, 2012, the contents of which are incorporated by reference in their entirety.
FIELD OF THE INVENTION
The present invention relates to a method for treating a disease or disorder of the eye characterized by impaired ocular blood and/or aqueous flow, such as diabetic retinopathy or glaucoma. The method involves administering a microbubble composition and applying ultrasound to the eye of a patient in need thereof. The present invention also includes a system and kit for use in carrying out the method.
BACKGROUND OF THE INVENTION
Proper ocular function is dependent upon adequate blood supply. When blood flow to the eye is impaired, the result is ischemia and hypoxia which can lead to loss of visual acuity and even blindness. Impairment of ocular blood flow can result from a number of diseases and disorders, including but not limited to, diabetic retinopathy and glaucoma.
Diabetic retinopathy (DR) remains the major cause of vision impairment and blindness in adults suffering from diabetes. Nearly all patients with type 1 diabetes will develop some manifestation of diabetic retinopathy; for example in type 2 diabetic patients 80% of insulin-dependent patients and 50% of patients not requiring insulin therapy will have DR within 20 to 25 years following disease onset (Curtis TM, Gardiner TA, Stitt AW. Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis? Eye (Lond). 2009: 23: 1496-1508). With the global incidence of diabetes projected to rise from 150 million to approximately 300 million by the year 2025, diabetic retinopathy represents a major health concern which will present ever-increasing burdens on the health care delivery system.
The major underlying pathophysiology of diabetic retinopathy is consistent with the effects of diabetes on small vessel disease elsewhere in the body (e.g., nephropathy, neuropathy). More specifically, vasoconstrictor molecules have been implicated to mediate in part the decrease in retinal blood flow during diabetic induction (Zhu Q, Xu X, Xia X, Gu Q, Ho PC. Role of protein Kinase C on the alteration of retinal endotheim-1 in streptozotocin-induced diabetic rats. Exp Eye Res. 2005; 81 :200-6). Additionally, high glycemic index can lead to a chronic, low-grade inflammation, damage to pericytes, platelet aggregation and ultimately to venostasis and capillary occlusion (Joussen AM, Pouiaki V, Le ML, Koizumi K, Esser C, Janicki H,et al. A central role for inflammation in the pathogenesis of diabetic retinopathy. FASEB J. 2004; 8: 1450-2). The earliest detectable changes in diabetic retinopathy are the morphologic appearance of microaneurysms and capillary occlusion.
Diabetic retinopathy is currently managed with destructive laser treatments and/or monthly intraocular injections. Destructive laser treatment involves the local or pan retinal application of destructive laser photocoagulation to microaneurysm/ischemic retinal regions (Early Treatment Diabetic Retinopathy Study Research Group.Eariy photocoagulation for diabetic retinopathy. ETDRS Report Number 9. Ophthalmology. 1991;98:66-785; The Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical Application of Diabetic Retinopathy Study (DRS) Findings, DRS Report Number 8. Ophthalmology. 1981;88:583-600). Diabetic retinopathy is also treated with repeated intraocular injections of either antiangiogenics (e.g., Lucentis® and Avastin®) or steroids (e.g., triamcinolone acetonide). In each instance, current therapies require repeated treatments with limited success in improving visual acuity. In the case of laser photocoagulation, treatment may also lead to multiple blind spots (scotomas) and impact peripheral visual field and dark adaptation. More recently, intraocular implants containing steroids have been investigated clinically, but have the serious side effects of inducing cataracts and glaucoma.
Glaucoma is a term used to refer to a group of disorders of the eye typically involving damage to the optic nerve, leading to vision loss and possibly, blindness. Glaucoma is normally associated with increased fluid pressure in the eye (aqueous humor). There are two basic types of glaucoma, open angle and closed angle. The angle refers to the area between the iris and cornea, through which fluid must flow to escape via the trabecular meshwork. Patients with closed angle glaucoma are more likely to seek treatment quickly, due to the associated discomfort, which tends to limit permanent damage to vision. Conversely, patients with open angle, chronic glaucoma tend to progress at a slower rate and may not seek medical attention until the disease has progressed more significantly. Worldwide, there will be 60.5 million people with glaucoma in 2013, in its most common presentations, increasing to 79.6 million by 2020. Bilateral blindness will be present in 4.5 million people with open angle glaucoma and 3.9 million people with angle closure glaucoma in 2013, rising to 5.9 and 5.3 million people in 2020, respectively (H A Quigley, A T Broman. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006; 90:262- 267).
Numerous circulatory abnormalities of the eye have been identified in subjects with glaucoma (Grunwald JE, Piltz JR, Hariprasad SM, DuPont J. Optic nerve and choroidal circulation in glaucoma. Invest Ophthalmol Vis Sci 1998;39:2329 -2336; Grunwald JE, Piltz JR, Hariprasad SM, DuPont J, Maguire MG. Optic nerve blood flow in glaucoma: effect of systemic hypertension. Am J Ophthalmol 1999;127:516 -522; Grunwald JE, Riva CE, Stone RA, Keates EU, Petrig BL. Retinal autoregulation in open-angle glaucoma. Ophthalmology 1984;91 :1690 -1694; Kaiser HJ, Schoetzau A, Stumpfig D, Flammer J. Blood-flow velocities of the extraocular vessels in patients with hightension and normal-tension primary open-angle glaucoma.Am J Ophthalmol 1997;123:320 -327). In a previous study using laser Doppler flowmetry, a > 25% decrease in blood flow was detected in the temporal neuroretinal rim and cup of subjects with glaucoma compared with controls. Studies suggest that impairment of blood flow may develop early in the glaucomatous process and not solely result from glaucoma damage. Studies have also shown that elevation in episcleral venous pressure results in decreased drainage of fluid via the trabecular and non-trabecular means in the anterior part of the eye (i.e. angle of eye) (Artur Llobet, Xavier Gasull, and Arcadi Gual. Understanding Trabecular Meshwork Physiology: A Key to the Control of Intraocular Pressure? News Physiol Sci 18: 205-209, 2003).
Current treatments for glaucoma include both pharmaceutical and surgical approaches. Intraocular pressure can be lowered by the use of eye drops containing pharmaceutical agents. Compliance remains an issue, however, as do undesirable side effects. Most studies have reported little effect or improvement of optic nerve blood flow when topical medications are used. Improved flow with medication use most likely is a result of decreased intraocular pressure and improved perfusion pressure.
US Patent Application Publication No. 20090030323 (Fawzi et al) teaches the use of contrast-enhanced ultrasound to locate areas of blockage within retinal vessels and to break up clots that are causing damage.
It is one object of the present invention to provide a method for treating diseases or disorders of the eye characterized by impaired ocular blood flow, such as diabetic retinopathy or glaucoma.
It is a further object of the present invention to provide a method for improving ocular blood in a patient suffering from glaucoma or diabetic retinopathy.
It is a still further object of the present invention to provide a method for reducing intraocular pressure in a patient suffering from glaucoma.
It is yet another object of the present invention to provide a method for improving visual acuity in a patient suffering from diabetic retinopathy.
It is another object of the present invention to provide a system for treating diseases or disorders of the eye characterized by impaired ocular blood flow, such as glaucoma or diabetic retinopathy.
It is yet another object of the present invention to provide a kit for treating diseases and disorders of the eye characterized by impaired ocular blood flow, such as glaucoma or diabetic retinopathy.
These and other objects of the invention shall be evident to one of skill in the art.
SUMMARY OF THE INVENTION
The present invention includes a method, system and kit for treating a disease or disorder of the eye characterized by impaired ocular blood flow, involving administering a microbubble composition to the patient and applying ultrasound to a patient in need thereof. In one embodiment, the present invention is a method for treating glaucoma, involving administering a therapeutically effective amount of a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
In another embodiment, the present invention is a method for treating diabetic retinopathy, involving administering a therapeutically effective amount of amicrobubble composition to a patient in need thereof and applying ultrasound to the eye.
In a further embodiment, the present invention is a method for improving ocular blood in a patient suffering from glaucoma or diabetic retinopathy, involving administering a therapeutically effective amount microbubble composition and applying ultrasound to the eye.
It is a still further object of the present invention to provide a method for reducing intraocular pressure in a patient suffering from glaucoma, involving administering a therapeutically effective amount of a microbubble composition and applying ultrasound to the eye.
It is another object of the present invention to provide a method for improving visual acuity in a patient suffering from diabetic retinopathy, involving administering a therapeutically effective amount of a microbubble composition and applying ultrasound to the eye.
In a particular embodiment, the present invention is a method for treating glaucoma or diabetic retinopathy involving administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of about 10 MHz or less using an extraocular probe over a period of time from about 30 to about 45 minutes.
The microbubble composition may be administered by any suitable method including, for example, intravascular administration or administration directly to the eye. BRIEF DESCRIPTION OF DRAWINGS
Fig. 1 is a graph showing reduction of intraocular pressure in a clinical study of nine (9) patients treated by intravenous administration of microbubbles and extraocular ultrasound according to Example 1.
DETAILED DESCRIPTION
The present invention is directed as a method, system and kit for treating a disease or disorder of the eye characterized by impaired ocular blood flow in a patient in need thereof, involving administering a microbubble composition and applying ultrasound to the eye of a patient in need thereof. Without being bound by any particular theory, the method results in improved visual acuity, improved blood flow to a previously impaired ocular region, decreased macular edema, reduced intraocular pressure (IOP), improved visual field, decreased neovascularization or combinations thereof.
I. Microbubbles/Ultrasound Contrast Agents
Microbubbles are gas-filled bubbles in the micron size range. As used herein, the term "microbubble composition" refers to a composition comprising a plurality of microbubbles.
The use of microbubbles as contrast agents in diagnostic ultrasound is well- known. When a microbubble passes through an ultrasound energy field, it undergoes translations and size oscillations (static or inertial cavitation), which generates harmonic signals that are able to increase the acoustic impedance mismatch between the blood and surrounding tissue, thereby improving the diagnostic vascular ultrasound (Nanda NC, Schlief R, Goldberg BB. Advances in echo imaging using contrast enhancement. 2nd ed. Dordrecht: Kluwer Academic Publishers, 1997). Contrast- enhanced ultrasound can be used to image blood perfusion in organs, measure blood flow rate in the heart and other organs, among other imaging applications.
More recently, the use of microbubbles and ultrasound for thrombolysis ("sonothrombolysis") has been studied. The basic concept of sonothrombolysis is that that during the ultrasound application, certain ultrasound parameters can produce cavitational energy that disassembles, or destroys, the clot (Tachibana K, Tachibana S. Albumin microbubble echo-contrast material as an enhance for ultrasound accelerated thrombolysis. Circulation 1995; 92: 1148-1150; Porter TR, LeVeen RF, Fox R, et al. Thrombolytic enhancement with perfluorocarbon-exposed sonicated dextrose albumin microbubbles. Am Heart J. 1996; 132:964-968; Birnbaum Y, Iakobishvili Z, Porter A, et al. Microparticl-containing oncotic solutions augment in-vitro clot disruption by ultrasound. Thromb Res 2000; 98:549-557). Specifically, when the microbubble passes through an ultrasound energy field, it undergoes static cavitation, which generates harmonic emissions which also releases energy and agitates the fluid in which the bubbles are dissolved, improving the delivery and penetration of alteplase into the clot (Am J Cardiovasc Drugs. 2010;10(1):5-10. © 2010; Prokop AF, Soltani A, Roy RA. Cavitational mechanisms in ultrasound-accelerated fibrinolysis. Ultrasound Med Biol 2007; 33 (6): 924-33). If the ultrasound negative pressure is increased, the bubble collapses (inertial cavitation), leading to intense localized stresses and microjets, which may cause mechanical fragmentation of the thrombus (Dijkmans PA, Juffermans LJ, Musters RJ, et al. Microbubbles and ultrasound: from diagnosis to therapy. Eur J Echocardiogr 2004; 5 (4): 245-56).
Sonothrombolysis can be used to enhance thrombolytic drug therapy or as a stand alone treatment. The use of sonothrombolysis in patients with an acute cerebral- vascular ischemic has been studied clinically. These initial trials included the administration of tissue plasminogen activator (tPA) in combination with the microbubbles, and a continuous application of transcranial ultrasound. Alexandrov AV, Mikulik R, Ribo M, Sharma VK, Lao AY, Tsivgoulis G, Sugg RM, Barreto A, Sierzenski P, Malkoff MD, Grotta JC A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke Stroke. 2008 May; 39(5): 1464-9. Epub 2008 Mar 20; Molina CA, Barreto AD, Tsivgoulis G, Sierzenski P, Malkoff MD, Rubiera M, Gonzales N, Mikulik R, Pate G, Ostrem J, Singleton W, Manvelian G,Unger EC, Grotta JC, Schellinger PD, Alexandrov AV. Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial. Ann Neurol. 2009 Jul;66(l):28-38). The acoustic power of the ultrasound generally determines the behavior of the microbubble. At low acoustic power (MI < 0.1), microbubbles act as point scatterers. At intermediate acoustic power (0.1 < MI < 0.5) gas microbubbles may show strong oscillatory motion provided the frequency of the incident ultrasound is close to the resonant (fundamental) frequency of the microbubbles. At high acoustic power (MI > 0.5), ultrasound at the microbubble resonance frequency will cause the bubbles to rupture.
The microbubble used in the present invention may be any suitable microbubble. They generally have an outer shell and a hollow core encapsulating a gas, where different microbubbles may be characterized by the composition of their member or shell, the composition of their gas core and whether or not they are targeted or contain additional agents (e.g., therapeutic agents).
Any compound or composition that aids in the formation and maintenance of a membrane or shell by forming a layer at the interface between the gas and liquid phases may be used to form the microbubble used in the present invention. The microbubble shell may include, without limitation, a lipophilic monolayer surfactant, a lipid bilayer (liposome), albumin, galactose, gelatin, polyglutaminic acid or other lipid or polymer material. In certain embodiment, the microbubble shell is formed from more than one compound or material.
The gas core of the microbubble used in the present invention may be air, a heavy gas or nitrogen. In a particular embodiment, the gas is air, perfluoropropane, perfluorobutane, dodecafluoropentane, octafluoropropane, perfluorocarbon, sulphur hexafluoride, perfluorohexane or perfluorobutane. In certain embodiments, the gas core may contain more than one gas.
The microbubble diameter size may be, for example, about 1 to about 10 micrometeres, about 3 to about 7 micrometers, or about 3, about 4, about 5, about 6 or about 7 micrometers.
In a particular embodiment, the microbubble used in the present invention is a perflutren lipid microsphere, composed of octafluoropropane encapsulated in an outer lipid shell (e.g., Defmity®, Lantheus). In another particular embodiment, the microbubble used in the present invention is a 1-2 micron-CsFg perflutren-lipid microsphere (e.g., MRX-801 , Cerevast).
In one embodiment, the microbubble used in the present invention is targeted. For example, the surface of the microbubble contains a ligand that specifically binds to a particular molecular marker of interest. Specifically, targeted microbubbles can be prepared by attaching targeting ligands to the lipid, protein or polymer shell coating of gas-filled microbubbles using covalent or non-covalent binding techniques (Klivanov et al. Med Biol Eng Comput. 2009 Aug;47(8):875-82). Representing, non-limiting molecular targets include fibrin and/or proteins associated with clots. The microbubbles may be, for example, targeted to activated platelets.
In one embodiment, the microbubble is a clot-targeted or thrombus-targeted microbubble.
In a particular embodiment, the microbubble is a platelet-targeted microbubble.
In one embodiment, the microbubble used in the present invention is modified by the introduction of one or more therapeutic agents. For example, the microbubble may be coated or filled with a therapeutic agent, with ultrasonic energy activating the coating or creating oscillations or explosions to release the agent, using any suitable coating or linking technology. The therapeutic agent may be any suitable agent, such as a small molecule, a carbohydrate, a peptide, a protein, an oligonucleotide or other biologic. Representative, non-limiting examples of therapeutic agents suitable for use in the method of the present invention include TPA or rTPA (alteplase, reteplase, and tenecteplase (TNKase)) or vasodilators (e.g., prostaglandins, nitrates).
In one embodiment, the microbubble composition utilized in the present invention comprising gas-filled microbubbles in an aqueous carrier (e.g., saline or another physiologically acceptable liquid). In certain embodiments, the microbubble concentration is about 20, about 30, about 40, about 50, about 60, about 70, about 80 or about 90%. Injectable compositions generally contain high concentrations of microbubbles, in a minimal amount of carrier for the composition to be injected.
The composition may comprise a single microbubble type or more than one microbubble type. In addition to the microbubble component, the microbubble composition may contain one more additional excipients or other active agents. For example, the composition may include viscosity modifiers, buffers, stabilizers, chelators, air solubility modifiers, osmotic agents, salts and/or sugars. Preferred solutions have a pH of about 7 and are isotonic.
Any suitable method may be used to form the microbubble composition used in the present invention including, for example, sonication, gas injection or mechanical formation.
II. Ultrasound
The present method relies upon the use of ultrasound to activate microbubbles or to locate the area to be treated, or both. In certain instances, ultrasound can be used to confirm placement of microbubbles at the treatment site and/or to confirm successful treatment.
In one embodiment, the treatment is diffuse. In another embodiment, the treatment is localized, i.e., the ultrasound is utilized to locate the area to be treated.
Ultrasonic techniques have also been utilized in surgical procedures on the eye for imaging structure and/or tissue of a surgical site. See, e.g., U.S. Pat. No. 6,676,607 to de Juan, Jr. et al., the contents of which are incorporated herein by reference in their entirety.
In one embodiment, the ultrasound probe is an extraocular probe. In a specific embodiment, the ultrasound probe is configured for use on the eyebrow or closed eyelid of the patient being treated. The ultrasound probe may be secured to the closed eyelid by any suitable means, including, without limitation, an adhesive or an apparatus worn by the patient to secure the probe in place physically (e.g., a strap).
In another embodiment, the ultrasound probe is configured for internal or intraocular use. In a specific embodiment, the ultrasound probe is configured for use on the eye surface, similar to a contact lens. In a particular embodiment, the ultrasound probe is used in conjunction with a water- or gel-filled bath configured to be positioned within the eye. The ultrasound probe may be attached to the bath or simply rest within in the bath. In a particular embodiment, the ultrasound probe of the present invention is advantageously configured to obviate the need for the user or operator to hold the device as the method is performed, either at all or for more than a limited duration (e.g., less than about 60 minutes, about 45 minutes, about 30 minutes, about 15 minutes, about 10 minutes or about 5 minutes).
The shape of the ultrasound probe may vary according to the conditions of use. In a specific embodiment, the ultrasound probe is a disc, half-circle, crescent, wedge or doughnut shape. The ultrasound probe may optionally include a sensing means, to permit the ultrasound machine or user to determine if the probe is in contact with the eye, for example the eyebrow, eyelid or eye surface. The sensing means may be any suitable means, including but not limited to, a means to sense or measure pressure or resistance at the probe tip. In a particular embodiment, the sensing means is a mechanical or electrical spring.
The ultrasound probe of the present invention is configured to deliver or provide ultrasound energy and optionally, optical imaging capabilities. The device may be used for any purpose where ultrasound function is desirable or where dual function (ultrasound and optical imaging) is desirable, including, but not limited to, therapeutic or diagnostic purposes. In a particular embodiment, the device is an ultrasound probe for use in treating ocular disorders such retinal vein occlusion. Using specially designed probes, which have the ability to image and also activate the microbubbles, therapies can be effected in the eye, while minimizing collateral damage. Such a probe is described in co-owned and co-pending U.S. patent application Ser. No. 12/061,120 filed 2 Apr. 2008 and entitled "Thrombolysis In Retinal Vessels with Ultrasound," incorporated in its entirety herein by reference. A pulsed-wave Doppler system with a PMN-PT needle transducer has been developed to measure the blood flow velocity in selected retinal vessels. See, e.g., Emanuel J. Gottlieb, et al, "PMN-PT High Frequency Ultrasonic Needle Transducers for Pulsed Wave Doppler In The Eye," 2005 IEEE Ultrasonics Symposium (IEEE 2005), the contents of which are incorporated herein by reference in their entirety.
The ultrasound component comprises a source of sonic energy. The frequency and/or range of frequencies used may be any one or more of those deemed useful to one of skill in the art for use in imaging and/or therapeutic applications. The ultrasound may be applied generally or in a focused or directed manner. The intensity, duration and resonant frequency may be altered according to the particular result desired, for example, diagnostic imaging versus therapeutic use as discussed further below.
III. Method of Treatment
The method of the present invention involves administering a microbubble composition and applying ultrasound to the eye of a patient in need thereof. The patient may be a human or non-human patient. In a particular embodiment, the patient is human. The method of the present invention can be used to provide treatment, protection or amelioration of a disease or disorder of the eye.
In one embodiment, the disease or disorder is characterized by reduced ocular blood flow. The patient may suffer from one or more diseases or disorders of the eye characterized by reduced ocular blood flow
In one embodiment, the patient suffers from glaucoma. In another embodiment, the patient suffers from diabetic retinopathy. In a particular embodiment, the patient suffers from glaucoma and diabetic retinopathy.
Other diseases and disorders that are associated with impaired retinal blood flow to the optic nerve include ocular hypertension and ischemic optic neuropathies (Sohan Hayreh, "Ischemic optic neuropathy", Progress in Retinal and Eye Research (2009) 28(l):34-62).
In one embodiment, the patient does not have retinal vein occlusion (RVO).
In another embodiment, the patient has RVO but has been diagnosed with one or more additional ocular diseases or disorders characterized by reduced blood flow. In a particular embodiment, the patient suffers from glaucoma and RVO. In a particular embodiment, the patient suffers from diabetic retinopathy and RVO.
In another embodiment, the disease or disorder is characterized by increased ocular pressure The patient may suffer from one or more diseases or disorders of the eye characterized by increased ocular pressure. In a particular embodiment, the disease or disorder is glaucoma.
The microbubble composition may be administered to the patient using any suitable strategy, either systemically or locally. In one embodiment, the microbubble composition may be administered to the patient by intravitreal injection, injection into the eye (vitreous cavity, subretinal, or anterior chamber) or intravascularly, including intravenously.
In exemplary embodiments, the microbubble composition is administered by intra vitreal injection.
In other embodiments, the microbubble composition is administered intravascularly
In a particular embodiment, the microbubble composition is administered intranveously.
In one embodiment, the microbubbles are administered by a single bolus injection. In another embodiment, the microbubbles are administered via intermittent bolus injection or continuous infusion. In a preferred embodiment, the microbubbles are administered intravenously by continuous infusion.
The microbubble composition is administered to the patient in a therapeutically effective amount. The amount of microbubble composition administered to the patient may vary, as would be understood by one of skill in the art, based on a variety of factors including the indication and the physical characteristics (including health status) of the patient.. In one embodiment, two vials of microbubbles are administered, each containing lxlO10 microbubbles per vial. In one embodiment, no more than one bag of IV fluids with 2-6mls of microbubbles is given in any one day.
The ultrasound probe may be any suitable ultrasound probe, including those disclosed herein. In one embodiment, the ultrasound probe is an external probe. In another embodiment, the ultrasound probe is an intraocular probe.
The ultrasound is applied as single pulses or pulse trains (defined as single application) within a second that are then repeated every second over a time frame of minutes/hours (defined as multiple applications, representing one therapeutic course). Furthermore, similar courses over a period of days/weeks/months are then considered multiple therapeutic courses. Hence, the ultrasound may be applied in a single application or multiple applications within a given therapeutic course or within multiple therapeutic courses.
For a single application, the ultrasound is applied for about 0.1 to about 0.5 seconds. For example, about 0.1, about 0.2, about 0.3, about 0.4 or about 0.5 seconds. The total time period over which multiple applications are applied may vary, from about 5 to about 90 minutes, about 5 to about 45 minutes, about 20 to about 40 minutes, about 25 to about 35 minutes, or about 30 to about 90 minutes. In exemplary embodiments, the ultrasound applications occur over a period of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85 or about 90 minutes.
In a particular embodiment, the total time period over which multiple applications are applied is from about 30 to about 45 minutes.
The mechanical index at which the ultrasound is applied may vary. A suitable range would be, for example, about 0.1-1.0 MI. In one embodiment, the mechanical index is greater than about 1.0 MI. In one embodiment, the mechanical index is about 0.1, about 0.2, about 0.25, about 0.29, about 0.3, about 0.35, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9 or about 1.0 MI. In exemplary embodiments, the mechanical index is in the range of about 0.1 to about 0.5, about 0.2 to about 0.4, or about 0.25 to about 0.35 MI.
In a specific embodiment, the mechanical index is about 0.5 MI.
The frequency at which the ultrasound is applied may be vary. A suitable range would be, for example, about 1 to about 10, about 2 to about 8, about 4 to about 6, or about 5 to about 7 MHz. In a particular embodiment, the frequency is greater than about 10 MHz.
In exemplary embodiments, the frequency is about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, about 8, about 8.5, about 9, about 9.5 or about 10 MHz. In a particular embodiment, the frequency is about 8 MHz.
In one embodiment, ultrasound is applied at a frequency of less than about 10 MHz. In a particular embodiment, the ultrasound is applied at a frequency of less than about 10, less than about 9, less than about 8, less than about 7, less than about 6, less than about 5, less than about 4, less than about 3, less than about 2 or less than about 1.0 MHz.
In one embodiment, the ultrasound is applied at about 0.5 MI once every second for only 40 microseconds, over a ten (10) minute period. In a particular embodiment, the present invention is a method for treating glaucoma, involving administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz over a time period of about 30 and about 45 minutes.
In a specific embodiment, the present invention is a method for treating glaucoma, involving administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz once every second for 40 microseconds over a time period of about 30 and about 45 minutes.
In a particular specific embodiment, the present invention is a method for treating glaucoma, involving intraveneously administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz once every second for 40 microseconds over a time period of about 30 and about 45 minutes.
In a particular embodiment, the present invention is a method for treating diabetic retinopathy, involving administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10MHz over a time period of about 30 to about 45 minutes.
In a particular embodiment, the present invention is a method for treating diabetic retinopathy, involving administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz once every second for 40 microseconds over a time period of about 30 to about 45 minutes.
In a specific embodiment, the present invention is a method for treating diabetic retinopathy, involving intravenously administering a perfluorocarbon-lipid microbubble composition to a patient in need thereof and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz once every second for 40 microseconds over a time period of about 30 to about 45 minutes. Ultrasound may be applied by extraocular ultrasound probes or intraocular ultrasound probes. The lid may be open or closed when an extraocular ultrasound probe is utilized.
In a specific embodiment, the present invention is a method for treating glaucoma, involving administering (e.g., intravenously) a perfluorocarbon- lipid microbubble composition and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz over a time period of about 30 and about 45 minutes using an extraocular probe.
In a particular embodiment, the present invention is a method for treating diabetic retinopathy, involving administering (e.g., intravenously) a perfluorocarbon- lipid microbubble composition and applying ultrasound to the eye at an acoustic power of about 1.0 MI or less at a frequency of less than about 10 MHz over a time period of about 30 to about 45 minutes using an extraocular probe.
In exemplary embodiments, a topical ultrasound gel is applied to the ocular surface prior to ultrasound treatment. In one embodiment, ultrasound is applied through a transverse access on the lateral fornix to avoid energy attenuation caused by the lens. Once the optic nerve is visualized and vascular flow in the nerve is confirmed by ultrasound, the probe may be maintained at that angle for the rest of the treatment period. In exemplary embodiments, the ultrasound probe is applied to the inferior conjunctival surface aiming at the midvitreous cavity.
In one embodiment, the patient method involves placement of a saline well or water bath within the eye of the patient. The well or bath is a small soft contact lenslike structure. It is placed on the eye of the patient, having first been anesthetized by use of topical anesthetic drug placed in the eye as a topical drop (e.g. proparacaine). Then the ultrasound probe is place on the water bath. Preferably, the water bath or well is used when treatment is directed to the front of the eye. Following the procedure, the water bath is removed much like a soft contact lens is removed.
The method of the present invention will result in one or more of: (i) improved visual acuity; (ii) improved blood flow to a previously impaired region as measure on retinal angiography, Doppler ultrasound, or phase contrast optical coherence tomography (OCT); (iii) decreased macular edema as measured by OCT ; (iv) reduced intraocular pressure (IOP) of at least 2mmHg as measured by corneal applanation tonometry; (v) changes in visual field (improvement in central of peripheral visual fields as measured on automated perimetry) and/or (iv) decreased neovascularization of iris or retina as determined by angiography and fundus photography.
In a particular embodiment, the method results in improved blood flow to a previously impaired region. Evidence of improved blood flow may be determined by, for example, diagnostic (Doppler) ultrasound and/or ophthalmoscopic exam. If either or both show an increase of blood flow, then no more treatment cycles will be administered. In a particular embodiment, the method results in improved optic disease and/or retrobulbar blood flow. In another particular embodiment, the method results in improvement of episcleral blood flow.
In one embodiment, the method results in an improvement in ocular blood flow of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95 or about 100%.
In a specific embodiment, the present invention is a method of improving ocular blood flow in a patient suffering from diabetic retinopathy by administering a microbubble composition and applying ultrasound to the eye.
In another specific embodiment, the present invention is a method of improving ocular blood flow in a patient suffering from glaucoma by administering a microbubble composition and applying ultrasound to the eye.
In another embodiment, the method results in decreased macular edema. Macular edema can be measured by OCT. In one embodiment, the method results in a decrease of macular edema of about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95 or about 100%.
In a specific embodiment, the present invention is a method of decreasing macular edema in a patient suffering from diabetic retinopathy by administering a microbubble composition and applying ultrasound to the eye.
In another specific embodiment, the present invention is a method of decreasing macular edema in a patient suffering from glaucoma by administering a microbubble composition and applying ultrasound to the eye.
In another embodiment, the method results in improved visual acuity. In one embodiment, the method increases visual acuity about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95 or about 100%.
In a specific embodiment, the present invention is a method of improving visual acuity in a patient suffering from diabetic retinopathy by administering a microbubble composition to a patient in need thereof and applying ultrasound to the eye. Example 4 provides results from a clinical study evidencing improved visual acuity in 2/3 (66%) of patients treated according to this embodiment of the present invention.
In a specific embodiment, the present invention is a method of improving visual acuity in a patient suffering from glaucoma by administering a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
In a still further embodiment, the method results in changes in visual field. Changes in the visual field, as measured using an automated perimetry, such as the Humphrey (24-2 or 30-2, Zeiss).
In a specific embodiment, the present invention is a method of improving visual field patient suffering from diabetic retinopathy by administering a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
In another specific embodiment, the present invention is a method of improving visual field in a patient suffering from glaucoma by administering a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
Advantageously, the method of the present invention requires fewer intraocular injections than drug therapies currently in use (e.g., anti-VEGF drugs such Lucentis (Genentech-Roche)).
In another embodiment, the present invention is a system incorporating the various elements necessary to carry out the claimed method.
In a further embodiment, the present invention is a kit that includes the components necessary to form the microbubbles for use in the present invention (either individually or pre-mixed) and an ultrasound probe for use in the method of the present invention. The kit also includes instructions for preparing (as necessary) and administering the microbubble composition according to the present invention.
The following examples are mere illustrations of the present invention and not intended to in any way limit the scope. EXAMPLES
Examples 1: Clinical study A
A clinical study was performed. Three subjects had been diagnosed with glaucoma and RVO. One subject had been diagnosed with diabetic retinopathy and RVO.
The subjects were preferred for infusion, and for continuous monitoring via EKG for the duration of the procedure. Once the subject was prepared, diagnostic ultrasound was applied through closed or open eyelids after topical anesthetic drop of proparacine and an ultrasound gel application. Pulse and Color Doppler were used to evaluate the retinal circulation before treatment.
The vehicle was shaken for forty five (45) seconds. Two -six (6) mis of vehicle content were added to 100 ml of ringer solution at the beginning of the therapeutic application of ultrasound and then infused IV 75-150ml/hr. The microbubble contrast agent (Definity) was administered and ultrasound was simultaneously applied at OA- 0.5MI (mechanical index). The ultrasound was applied in this mode once every second for only 40 microseconds, over a ten (10) minute period.
After this 10 minute interval the ocular blood flow is evaluated with the ultrasound machine or by investigator assessment using ophthalmoscopy. The above treatment was continued until the occlusion is opened or the infusion fluid volume was finished. As much as was possible, given patient eye movement, ultrasound was applied through a transverse access on the lateral fornix to avoid energy attenuation caused by the lens.
Once the optic nerve was visualized and vascular flow in the nerve was confirmed by ultrasound, the probe was maintained at that angle for the duration of the treatment period. Where diagnostic ultrasound and/or ophthalmoscopic exam showed an increase of blood flow, no further treatment cycles were administered. If the retinal blood flow does not increase as determined by the diagnostic Doppler ultrasound, additional cycles of ultrasound were administered to the subject, but not more than the infusion of one bag of IV fluids with 2-6mls of microbubbles in any one day. Example 2: Post Treatment Monitoring
Following the completion of the ultrasound cycles, subjects were kept at the clinic for at least 30 minutes for post-procedure monitoring. The monitoring included electrocardiography and supervision of the subject's condition for any adverse signs or symptoms. The subject were sent home once the Investigators determined it was safe to do so.
Subjects returned to the clinic for follow-up visits in accordance with the schedule: (i) 1 Day post-procedure; (ii) weekly for the first four (4) weeks after the procedure; (iii) monthly for six (6) months following the procedure.
Evaluations were completed as detailed in Table 1. At the follow-up visits, all subjects were queried for any changes or new developments in their health status, including any new medications.
Table 1 : Follow-up Evaluation for Glaucoma and Diabetic Retinopathy subjects
Figure imgf000022_0001
The results shown in Figure 1 are based on follow up over more than 3 months as indicated, and evidence almost 3-4mmHG of sustained IPO reduction.
Example 3 : Retreatment
If retinal circulation was not restored after one week, the subjects were scheduled for a retreatment procedure. The procedure was the same as described in Example 1 , each completed one week apart.
Example 4: Clinical Study B
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000027_0001
Figure imgf000027_0002
Figure imgf000028_0001
Figure imgf000028_0002

Claims

We Claim:
1. A method for treating glaucoma by administering a therapeutically effective amount of a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
2. The method of claim 1, wherein the microbubble composition is administered intravascularly.
3. The method of claim 2, wherein the microbubble composition is administered intranveously.
4. The method of claim 1, wherein the microbubble composition is administered by injection into the eye.
5. The method of claim 1, wherein the ultrasound is applied at a mechanical index of 1.0 MI or less.
6. The method of claim 5, wherein the ultrasound is applied at a mechanical index of about 0.5 MI or less.
7. The method of claim 1, wherein the ultrasound is applied over a time period of about 30 to about 45 minutes.
8. The method of claim 1, wherein the microbubble composition comprises perflutren lipid microspheres in an aqueous carrier.
9. The method of claim 1, wherein the microbubbles are clot-targeted.
10. A method for treating diabetic retinopathy, involving administering a therapeutically effective amount of a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
11. The method of claim 10, wherein the microbubble composition is administered intravascularly.
12. The method of claim 11, wherein the microbubble composition is administered intranveously.
13. The method of claim 10, wherein the microbubble composition is administered by injection into the eye.
14. The method of claim 10, wherein the ultrasound is applied at a mechanical index of 1.0 MI or less.
15. The method of claim 14, wherein the ultrasound is applied at a mechanical index of about 0.5 MI or less.
16. The method of claim 1, wherein the ultrasound is applied over a time period of about 30 to about 45 minutes.
17. The method of claim 10, wherein the microbubble composition comprises perflutren lipid microspheres in an aqueous carrier.
18. The method of claim 1, wherein the microbubbles are clot-targeted.
19. A method for reducing intraocular pressure in a patient suffering from glaucoma by administering a therapeutically effective amount of a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
21. A method for reducing intraocular pressure in a patient suffering from glaucoma by administering a therapeutically effective amount of a microbubble composition to a patient in need thereof and applying ultrasound to the eye.
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