WO2010097800A1 - Combinaison synergique de composés bioactifs pour diminuer la pression intraoculaire - Google Patents

Combinaison synergique de composés bioactifs pour diminuer la pression intraoculaire Download PDF

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Publication number
WO2010097800A1
WO2010097800A1 PCT/IL2010/000166 IL2010000166W WO2010097800A1 WO 2010097800 A1 WO2010097800 A1 WO 2010097800A1 IL 2010000166 W IL2010000166 W IL 2010000166W WO 2010097800 A1 WO2010097800 A1 WO 2010097800A1
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peptides
ocular hypotensive
ocular
hypotensive peptides
cells
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PCT/IL2010/000166
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English (en)
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Muhammad Abdulrazik
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Muhammad Abdulrazik
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Priority claimed from IL197323A external-priority patent/IL197323A0/en
Priority claimed from IL197324A external-priority patent/IL197324A0/en
Application filed by Muhammad Abdulrazik filed Critical Muhammad Abdulrazik
Publication of WO2010097800A1 publication Critical patent/WO2010097800A1/fr
Priority to US13/107,874 priority Critical patent/US20110305710A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors (Somatomedins), e.g. IGF-1, IGF-2

Definitions

  • Glaucoma is one of the worldwide leading causes of blindness. According to recent estimates, about 50 million people worldwide suffer from glaucoma while several millions of new glaucoma cases are expected each year. Glaucoma is a silent disease that may run undetected for many years to be diagnosed only at advanced stages with considerable damage to retinal ganglion cells and nerve fiber layer of the retina, (see: Glaucoma. In Basic and Clinical Science Course Section 10; American Academy of Ophthalmology, 2007-2008 ed.). Many pharmacological and surgical interventions have been used to slow down the progression of glaucoma but none of these interventions could cure or even arrest the progression of this neurodegenerative disease that could deteriorate to severe loss of vision and blindness.
  • the glaucomas are generally divided into open-angle and closed-angle, primary and secondary, and further classified into acute and chronic forms. More than 80% of all glaucomas are chronic open angle glaucoma cases (COAG). Elevated intraocular pressure (IOP) is a long appreciated major risk factor for glaucoma. However, cumulating evidence from recent decades strongly suggests the contribution of mechanisms independent of intraocular pressure in the pathogenesis of this neurodegenerative disease. So far, the available interventions can treat only one single risk factor of glaucoma, the elevated intraocular pressure.
  • Antiglaucoma drug classes that are approved for clinical use include prostaglandin analogues, beta-blockers, alpha2-adrenergic agonists, carbonic anhydrase inhibitors, miotics (direct cholinergic agonists and cholinesterase inhibitors) and nonselective adrenergic agonists (epinephrine and its derivatives) (See: 2006 Physicians' Desk Reference (PDR) for Ophthalmic medicines).
  • Established antiglaucoma drugs that decrease aqueous production rate include nonselective beta adrenergic antagonists, selective beta-1 adrenergic antagonists, nonselective adrenergic agonists, alpha-2 adrenergic agonists and carbonic anhydrase inhibitors. Many other compounds have been reported to decrease aqueous humor production rate but are not approved for clinical use.
  • Examples are calcium channel antagonists (verapamil, nifedipine), nitrovasodilators, atrial natriuretic factor, serotonergic receptor (5-HT1A) antagonists (ketanserin), angiotensin converting enzyme (ACE) inhibitors, Hl -antihistamines (antazoline, pyrilamine), delta 9-tetrahydrocannabinol (a component of marijuana), cardiac glycosides (ouabain, digoxin), cyclic GMP (8-Bromo cyclic GMP).
  • Established antiglaucoma drugs that increase aqueous outflow rate include nonselective adrenergic agonists, alpha-2 adrenergic agonists (increase uveal outflow), miotics (increase trabecular outflow) and prostaglandin analogues (increase uveal outflow).
  • mice that have been reported to increase aqueous humor outflow rate include hyaluronidase, proteases, matrix metalloproteinases, transforming growth factor-beta, cytochalasin B, cytochalasin D, ethacrynic acid, tienilic acid, staurosporine, latrunculins, ethyleneglycol bis (aminoethylether) tetraacetate (EGTA) and EDTA.
  • EGTA ethyleneglycol bis (aminoethylether) tetraacetate
  • EDTA ethyleneglycol bis (aminoethylether) tetraacetate
  • these compounds are not approved for clinical use. While some of the currently available pharmacologic interventions in clinical ophthalmology can provide a significant lowering of intraocular pressure, none of these agents could cure or even arrest the progression of glaucomas. In cases were profound manipulations of the trabecular outflow are indicated, such
  • An object of the present invention is to provide a novel drug for lowering or preventing increase in intraocular pressure.
  • the inventor of the present invention have earned to a surprising finding that placenta growth factor, insulin growth factor, and euglycemic levels of insulin have a substantial ocular hypotensive effect which was additive when those peptides were administered as combined local treatment to the eye. Subsequentlt an extensive study was carried out with a view to clarify the correlation of those peptides with intraocular pressure and glaucoma prevention and treatment. Placenta growth factor and insulin like growth factor have shown substantial ocular hypotensive effect when administered to the eye in the invented method. Regarding insulin for instance, the inventor has finally found out that insulin by itself is a potent agent for euglycemic lowering of intraocular pressure, not through the secondary effect of hypoglycemia.
  • the invention provides synergestic combination of ocular hypotensive peptides, where those pepides are selected from euglycemic-insulin, insulin like growth factor, placenta growth factor, their isoforms, their analoges, their gene-engineered modifications, and combinations thereof for lowering of intraocular pressure, for increasing success rate of surgical procedures for the treatment or prevention of glaucoma, and for neuroprotection of retinal ganglion cells.
  • euglycemic amount of insulin and "euglycemic insulin” administration in the present invention refers to the administration of insulin or insulin substitute in amounts and in a way that achieves the goal of lowering intraocular pressure and treating or preventing glaucoma and ocular hypertension while avoiding significant effects on the blood glucose levels and the induction of hypoglycemia.
  • Frier et al teaches that hypoglycemia can lower intraocular pressure through "profound autonomic discharge provoked by acute hypoglycaemia" (Frier et al., Br. Med. J. (Clin. Res. Ed.) 7 March 1987,
  • Koivikko et al. (Diabetes, vol. 54, March 2005, pages744-750) provides support to this distinction between “euglycemic insulin” and “hypoglycemic insulin” interventions and their effects on the autonomic system.
  • Koivikko et al. studied the effect of hypoglycemic and euglycemic insulin clumps on the vagal indexes (parasystemic part of the autonomic system) and came to conclusion that "the observed changes in vagal indexes during the hypoglycemic clamp were caused by hypoglycemia itself but not caused by hyperinsulinemia" (page 748, right column, 2 d paragraph [Effect of Hyperinsulinemia], lines 11-13).
  • lowering intraocular pressure by "euglycemic insulin” intervention means that this goal is achieved by direct effect of insulin on target ocular tissues and not through the indirect effect of hypoglycemia on intraocular pressure through the autonomic system.
  • intraocular pressure in the present invention refers to measurement of the pressure of the fluid that fills the eye globe, the aqueous humor, which is determined by the interplay between the rate of aqueous humor production inside the eye and the resistance to aqueous outflow as it exits the eye through the anterior chamber angle towards the schlemm's canal.
  • the rate of aqueous formation is 2.5 ⁇ L/minute while that in the rabbit eye is approximately 3 to 4 ⁇ L/minute.
  • Normal IOP measurements in the human eye according to widely acceptable consensus, range between 10 and 21 mm of mercury, with an average of 16.
  • the Goldmann equation is a simplified hydraulic algorithm that views aqueous flow as passive non-energy-dependent bulk fluid movement down a pressure gradient (between intraocular pressure [IOP] and episcleral venous pressure [EPV]), with aqueous leaving the eye through the trabecular route.
  • IOP intraocular pressure
  • EPV episcleral venous pressure
  • Aqueous Flow (Trabecular Outflow Facility).([IOP]-[EVP])
  • any part of the trabecular outflow pathway consisting of the trabecular meshwork, the pericanalicular connective tissue, the endothelial lining of Schlemm's canal, Schlemm's canal itself, the collecting channels and aqueous veins, may virtually contribute to the resistance to aqueous outflow.
  • the theoretical resistance to aqueous outflow in this region is negligible.
  • the endothelial cells of Schlemm's canal form a continuous monolayer that run mostly in an equatorial direction. This endothelial lining, similarly to lymphatic vessels, is perfused from outward to inward and the pressure gradient wave moves from the basement membrane to the basal side of the endothelial cell.
  • the endothelial cells of the inner wall of Schlemm's canal also develop cytoplasmic processes that interdigitate with similar processes of underlying cells of a second row underneath the canal endothelium.
  • the endothelial cells of Schlemm's canal are bound together by tight junctions.
  • glaucoma in the present invention refers to an eye disorder characterized by increased intraocular pressure, excavation of the optic nerve head and gradual loss of the visual field.
  • An abnormally high intraocular pressure is commonly known to be detrimental to the eye, and there are clear indications that, in glaucoma patients, this probably is the most important factor causing degenerative changes in the retina.
  • the pathophysiological mechanism of open angle glaucoma is, however, still unknown. In one particular form of glaucoma, low tension glaucoma, damage may occur at intraocular pressure levels otherwise regarded as physiologically normal.
  • ocular hypertension in the present invention refers to clinical situation in individuals with an abnormally high intraocular pressure without any manifest defects in the visual field or optic nerve head. Such conditions are usually referred to as ocular hypertension.
  • Individuals with ocular hypertension carry the risk of conversion to glaucoma with the risk being correlated to higher intraocular pressure measurements. Therefore, offering treatment to lower intraocular pressure to subjects with ocular hypertension to prevent conversion to glaucoma is the subject of ongoing debate on the timing of such intervention.
  • the death of retinal ganglion cells is the hallmark of glaucoma, and the cascade of events that lead to cell death include the vrelease of excitatory neurotoxins.
  • Neuroprotective agents should have the ability to prevent or arrest the cascade of events that lead to cell death. At a preclinical setting, successful neuroprotective agent should allow the neutralization of excitatory neurotoxins. Neroprotection may also prevent "retinal ganglion cell pressure-induced death” . Reported evidence that suggest that elevated intraocular pressure could be a direct trigger of retinal ganglion cell death. (Sappington RM, Chan M, Calkins DJ. Invest Ophthalmol Vis Sci.
  • therapeutically effective amount in the present invention refers to an amount of a compound of the present invention that when administered to the subject in need of therapy it will decrease or prevent the increase in intra ocular pressure in such a magnitude that the clinically desired level of intraocular pressure will be reached or maintained.
  • therapeutically-effective amount is that amount of the present pharmaceutical composition which produces a desired result or exerts a desired influence on the particular condition being treated.
  • compositions incorporating the same ingredient may be used in preparing compositions incorporating the same ingredient to provide for variations in species (animal, human, etc.) body weight, age of the subject to be treated, the severity of the condition, the duration of the treatment and the mode of administration
  • pharmaceutically acceptable derivative in the present invention refers to any non-toxic salt, ester, salt of an ester, or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an active metabolite or residue thereof.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • Suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
  • Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium, and N.sup.+ (C.sub.1-4 alkyl) .sub.4 salts, "subject in need of such treatment” in the present invention refers to an animal, preferably a mammal, and most preferably a human in need of such treating or preventing, as judged by their clinical assessment, "increasing the success rate of glaucoma surgical procedures" in the present invention refers to one embodiment of the present invention were the composition of the present invention is administered substantially together with the performance of the following surgical procedures for the treatment of glaucoma.
  • composition of the present invention will be administered through different routs of drug delivery in therapeutically effective amount to achieve the following: (a) torn provide lowering of intraocular pressure as adjuvant to the surgical procedure itself, (b) to prevent spikes of elevated intraocular pressure that is a frequent side effect of the postsurgical period in some surgical procedures, (c) to provide enhanced permeability to the filtering surfaces of the surgical procedures as adjuvant effect and to prevent failed surgery due to failed filtration function of the filtering surfaces after surgery in some cases.
  • substantially together in the present invention refers to the administration of two interventions either simultaneously or within a period of time where the subject would receive the benefit of both separate interventions including taken together (simultaneous) or with a few seconds to at least about 24 hours of one another (not-simultaneous, but co-administered).
  • laser iridotomy in the present invention refers to a surgical incision into the iris, an intraocular tissue that forms a diaphragm that separates the posterior chamber of the eye from the anterior chamber.
  • aqueous humor flows through the pupil which is the only natural opening through the iris that is otherwise none permeable to aqueous humor flow.
  • laser iridoplasty in the present invention refers to a surgical procedure for the treatment of some glaucoma patients aiming at retracting the peripheral iris via the thermal effect of the laser to widen the iridocorneal angle and facilitate aqueous outflow through this angle
  • surgical iridectomy in the present invention refers to surgical removal of part of the iris indicated when aqueous humor flow through the pupil is compromised and there is a need to create an alternative opening through the iris to allow shunting of the aqueous between posterior and anterior ocular chambers to prevent pressure build up in the posterior chamber
  • laser trabeculoplasty and “selective laser trabeculoplasty” in the present invention refers to the use of a very focused beam of light to treat the angle of the
  • the two types of laser trabeculoplasty are Argon laser trabeculoplasty (ALT) which uses Argon laser, and Selective laser trabeculoplasty (SLT) that uses a lower level laser to open the drainage angle of the eye.
  • ALT Argon laser trabeculoplasty
  • SLT Selective laser trabeculoplasty
  • filtering surgery in the present invention refers to the surgical procedure were a very small piece of the wall of the eye (the sclera) is being removed, aiming at allowing the aqueous humor to drain through the hole that is being created that hopefully will result in substantial lowering of the intraocular pressure.
  • the most common type of filtering procedure is called a trabeculectomy.
  • trabeculectomy the opening in the sclera takes the form of a hinging flap that is tightened over a hole (in penetrating trabeculectomy) or a very thin residual of the sclera (in none penetrating trabeculectomy), "fistulizing procedures" in the present invention refers to a general name for all surgeries that create an alternate pathway for aqueous humor outflow.
  • needleling in the present invention refers to needle-assisted cystitomy of a failed filtering bleb following trabeculectomy surgery for glaucoma.
  • Filtering bleb is a space created under the conjunctiva of the eye over the site of the trabeculectomy to serve as a receiver reservoir for the aqueous humor that is draining through the trabeculectomy and it serves as a transit station before allowing the aqueous to drain further away from the filtering bleb.
  • the bleb takes the form of bulge in the conjunctival surface.
  • Pathological processes like fibrosis turn successful bleb into a non-functioning bleb that is more like a cyst than a filtering bleb.
  • a cystitomy is performed with a fine needle, usually combined with subconjunctival injection of 5-fluorouracil as anti-fibrotic agent.
  • the procedure is referred to also as “needling revision" of poorly functioning filtering blebs, "glaucoma drainage device” in the present invention refers to a tube that leads to a reservoirwerein the tube is inserted into the anterior chamber of the eye without touching the cornea while the reservoir is implanted subconjunctively .
  • several polymers with deferent properties havre been utilized to manufacture the tube and the receiving reservoir.
  • cyclodiathermy in the present invention refers to the destruction of a portion of the ciliary body by diathermy aiming at decreasing the production rate of aqueous humor by the ciliary body and eventually decreasing intraocular pressure
  • cyclocryotherapy in the present invention refers to the destruction of a portion of the ciliary body by cryotherapy aiming at decreasing the production rate of aqueous humor by the ciliary body and eventually decreasing intraocular pressure
  • ocular in the present invention refers to administering drug directly to the eye.
  • peripheral in the present invention refers to administrating drugs to the orbital space that surrounds the eye globe
  • orbital in the present invention refers to drug administration to the relatively deaper orbital tissues
  • topical in the present invention refers to administering drugs to the surface of the eye.
  • This goal is achieved by the application to the eye surface one or more of the following: “eye-drops”, “sprayed formulations”, “suspensions”, “ointments”, “gels”, “hydrogels”, “viscosified solution”, “formulation loaded in contact lens”, “formulation loaded in collagen shield”, and “formulation loaded in ocular insert”, (see: Abdulrazik M, Behar-Cohen F, Benita S. Drug Delivery Systems for Enhanced Ocular Absorption.
  • corneaal and intra-corneal in the present invention refers to administering a drug to the cornea while taking necessary measures to minimize drug penetration through other ocular tissues.
  • the composition of the invention is administered in repeated small volume applications (of few micro-liters each) on the corneal surface to allow penetration through the cornea while minimizing penetration through the conjunctival surface, aiming at allowing drug accumulation in the anterior chamber and eventually the drainage of the dug to the assumed site of action, the schlemm's canal.
  • composition of the present invention is implanted or injected to the stroma of the cornea (upper third), through the cornea into the anterior chamber of the eye, or to the scleral tissue adjacent to the schlemm's canal.
  • “Subconjunctival” in the present invention refers to administering drug behind the conjunctiva.
  • subtenon in the present invention refers to drug administration directly to the subtenon space by injecting, pumping, or implanting drugs or drug delivery systems directly to the subtenon space or by allowing intimate contact of these systems with the tenon's fascia.
  • Tenon's fascia is a tissue that takes the form of a coating that surrounds the globe and extraocular muscles and is situated under the conjunctiva.
  • “episcleral” in the present invention refers to drug administration directly to the episcleral tissue by injecting, pumping, or implanting drugs or drug delivery systems directly to the episclera tissue or allowing intimate contact of these systems with the episclera.
  • the episclera is a fine vascularized tissue the form an external lining of the sclera
  • "intra-scleral” in the present invention refers to to drug administration directly to the sclera tissue by injecting, pumping, or implanting drugs or drug delivery systems directly to the sclera tissue or allowing intimate contact of these systems with the sclera.
  • “Intracameral” in the present invention refers to drug administration into the anterior chamber of the eye.
  • the anterior chamber is the most anterior compartment of the eye filled with aqueous humor, that flows in from the posterior chamber of the eye were it is being secreted by the ciliary body, with the posterior surface of the cornea as its anterior border and the anterior surface of the iris as its posterior border.
  • the intracameral drug administration could be accomplished by injection, pumping, or by implants.
  • "Intravitreal" in the present invention refers to administering drugs into the vitreous cavity.
  • the vitreous cavity is the space that consists most of the volume of the core of the eye with the lens and its suspension system (the zonules) as its anterior border and the retina and its coating as the peripheral border.
  • the intravitreal drug administration could be accomplished by injection, pumping, or by implants, "peribulbar or retrobulbar injections or implants" in the present invention refers to drug administration to the space that surrounds the eye, the orbital space.
  • Priorbital injections are injections to the orbital space that surrounds the eye and usually means the more anterior orbital space, while retrobulbar injections is performed with long-enough needle to reach the deep orbital space. In both cases, the orbital space serves as drug reservoir for later drug permeation towards the ocular tissues.
  • glaucoma filtering bleb in the present invention refers to the space created under the conjunctiva of the eye over the site of the trabeculectomy to serve as a receiver reservoir for the aqueous humor that is draining through the trabeculectomy and it serves as a transit station before allowing the aqueous to drain further away from the filtering bleb.
  • the bleb takes the form of bulge in the conjunctival surface
  • sclerotomy pocket of trabeculectomy in the present invention refers to the space under the hinging sclera flap in trabeculectomy surgery for glaucoma.
  • the opening in the sclera takes the form of a hinging flap that is tightened over a hole (in penetrating trabeculectomy) or a very thin residual of the sclera (in none penetrating trabeculectomy).
  • the composition of the invention is applied by injection, pumping, or implantation to the filtering bleb or the sclerotomy pocket of trabeculectomy to achieve (i) permeability enhancement of the filtering surfaces and (ii) sustained lowering of intraocular pressure
  • "administration is on an as needed basis” in the present invention refers to a preferred embodiment wherein the composition of the current invention is administered on an as needed basis, well known to those skilled in the art as pro re nata dosing. Insulin
  • Insulin is composed of two, alpha and beta, peptide chains with several inter and intra chain disulphide bonds.
  • the three-dimensional structure of the insulin molecule (insulin monomer), essentially the same in solution and in solid phase, exists in two main conformations. These differ in the extent of helix in the B chain which is governed by the presence of phenol or its derivatives.
  • the insulin monomer In acid and neutral solutions, in concentrations relevant for pharmaceutical formulation, the insulin monomer assembles to dimers and at neutral pH, in the presence of zinc ions, further to hexamers. Many crystalline modifications of insulin have been identified but only those with the hexamer as the basic unit are utilized in preparations for therapy. The insulin hexamer forms a relatively stable unit but some flexibility remains within the individual molecules.
  • the intrinsic flexibility at the ends of the B chain plays an important role in governing the physical and chemical stability of insulin. Insulin may undergo structural transformations resulting in aggregation and formation of insoluble insulin fibrils. Physical modifications of the secondary to quaternary structures (denaturation, aggregation, and precipitation) are known to affect insulin and insulin preparations during storage and use. A variety of chemical changes of the primary structure have been suggested to produce insulin derivatives with favorable stability. Although the exact mechanism of fibril formation is still obscure, it is now clear that the initial step is an exposure of certain hydrophobic residues, normally buried in the three-dimensional structure, to the surface of the insulin monomer. Therefore, most methods stabilizing insulin against fibrillation share the property of being able to counteract associated insulin from being disassembled.
  • PlGF vascular endothelial growth factor
  • PlGF had a negligible role in physiological angiogenesis and vascular development but do play a role in pathological angiogenesis.
  • PlGF and VEGFR-I are minimally expressed in adult quiescent vasculature, but are markedly upregulated during pathological conditions (Carmeliet et al., Nat Med. 2001 ;7(5):575-83). Shih et al have demonstrated that PlGF-I intervention didn't carry the risk of provoking retinal neovascularization (Shih et al., J CHn Invest. 2003;l 12(l):50-7).
  • IGF Insulin-Like Growth Factor
  • IGF-I is a single chain peptide with three intermolecular disulfide bridges. IGF-I is the primary protein involved in responses of cells to growth hormone (GH). IGF-I is produced in response to GH and then induces subsequent cellular activities, particularly on bone growth. Subsequent studies have demonstrated, however, that IGF- 1 has autocrine and paracrine activities in addition to the initially observed endocrine activities on bone.
  • the IGF-I receptor like the insulin receptor, has intrinsic tyrosine kinase activity. Owing to their structural similarities IGF-I can bind to the insulin receptor but does so at a much lower affinity than doe's insulin itself.
  • Insulin, PlGF, and/or IGF may undergo structural transformations resulting in aggregation and formation of insoluble Insulin, PlGF, and/or IGF fibrils.
  • Physical modifications of the secondary to quaternary structures denaturation, aggregation, and precipitation are known to affect Insulin, PlGF, and/or IGF and their preparations during storage and use.
  • a variety of chemical changes of the primary structure have been suggested to produce Insulin, PlGF, and/or IGF derivatives with favorable stability.
  • the initial step is an exposure of certain hydrophobic residues, normally buried in the three-dimensional structure, to the surface of the PlGF-I and/or IGF-I monomer.
  • the Insulin, PlGF, and/or IGF to be used to achieve the subject matter of the present invention could be native (e.g., wild-type, naturally occurring, or allelic variant) Insulin, PlGF, and/or IGF, synthetic Insulin, PlGF, and/or IGF, semisynthetic Insulin, PlGF, and/or IGF. active dimeric form of Insulin, PlGF, and/or IGF, active multimeric form of Insulin, PlGF, and/or IGF, Insulin, PlGF, and/or IGF isoforms and isomers, Insulin, PlGF, and/or IGF with modified stereochemistry.
  • insulin, PlGF, and/or IGF may be needed to achieve the subject matter of the present invention for any particular subject in need of therapy, depending upon a variety of factors, including type, severity and course of the Glaucoma or ocular hypertension being treated, as well as the bioavailability characteristics of insulin, PlGF, and/or IGF preparation administered, concurrent treatment with other co-administered therapeutic agents, and other relevant circumstances.
  • Insulin, PlGF, and/or IGF could be administered once or at multiple times. Multiple administrations could be performed at intervals ranging from ONCE-PER-MINUTE, THROGH hourly, And could be daily, weekly, biweekly, monthly, biyearly, yearly.
  • Insulin, PlGF, and/or IGF could be administered independently or co-administered with one or more additional therapeutic agent disclosed herein.
  • Combination therapy insulin, PlGF, and/or IGF could be conjugated to another drug, transport vector, or permeability enhancing peptide by avidin-biotin technology, polyethylene glycol linkers or other chemical linkers.
  • Combination therapies according to this invention exert a synergistic effect. The use of such combinations is also advantageous to reduce the dosage of a given conventional therapeutic agent that would be required for a desired therapeutic or prophylactic effect.
  • Combinations treatments may also reduce or eliminate the side effects of conventional single agent therapies.
  • Combinations may also increase the efficacy of a conventional agent without increasing the associated toxicity.
  • a combination therapy is consisting of insulin, PlGF, and/or IGF co-administered or conjugated to at least one conventional antiglaucoma drug selected from the group consisting of a prostaglandin analogues, beta-blockers, alpha2-adrenergic agonists, carbonic anhydrase inhibitors, miotics and nonselective adrenergic agonists (epinephrine and its derivatives).
  • a prostaglandin analogues beta-blockers
  • alpha2-adrenergic agonists carbonic anhydrase inhibitors
  • miotics and nonselective adrenergic agonists epinephrine and its derivatives.
  • a combination therapy is consisting of insulin, PlGF, and/or IGF co-administered or conjugated to at least one compound that possess antiglaucoma or anti ocular hypertensive activity, selected from the group consisting of calcium channel antagonists, preferably verapamil and nifedipine, potassium channel antagonists, nitrovasodilators , nitroglycerin, isosorbide dinitrate, nitroprusside, minoxidil, atrial natriuretic factor, phenylimino-imidazoles, serotonergic receptor antagonists, preferably ketanserin, angiotensin converting enzyme (ACE) inhibitors, Hl -antihistamines, preferably antazoline and pyrilamine, delta 9-tetrahydrocannabinol, cardiac glycosides, preferably ouabain and digoxin), A3 subtype adenosine receptor antagonists, a cAMP modulator, cyclic GMP,
  • Corticosteroids are being used locally or systemically for a wide range of indications in clinical ophthalmology.
  • One particular complication with this therapeutic regimen is steroid induced glaucoma.
  • Steroid induced glaucoma is a form of open angle glaucoma that usually is associated with topical steroid use, but has been reported also following inhaled, oral, intravenous, periocular, or intravitreal steroid preparations.
  • the incidence of this complication varies, being 6-30% among the normal population using topical steroids, but this estimates was reportedly more than doubled in cases with family history of glaucoma.
  • Drug induced glaucoma is similar to steroid induced glaucoma but this name is used when the causative drug is other than a corticosteroid.
  • insulin, PlGF, and/or IGF alone or in one of the aforementioned combinations, is coadministered or conjugated to a corticosteroid.
  • insulin, PlGF, and/or IGF alone or in one of the aforementioned combinations, is coadministered or conjugated to a drug that can cause drug- induced glaucoma.
  • Neovascular glaucoma is a term used to describe secondary glaucoma that develops following the growth of neovascular tissue at the sites of aqueous humor outflow. This condition is usually secondary to ischemic disorders like diabetic retinopathy, central retinal vein occlusion, severe carotid artery disease, severe ischemic retinopathies due to sickle cell disease, and central retinal artery occlusion.
  • insulin, PlGF, and/or IGF-I alone or in one of the aforementioned combinations, is coadministered with or conjugated to an antiangiogenic compound as a combination therapy to treat or prevent neovascular glaucoma.
  • the combination therapy that comprises insulin, PlGF, and/or IGF, alone or in one of the aforementioned combinations, together with a antiangiogenic agent is meant to prevent a possible neovascularization side effect of the insulin, PlGF, and IGF intervention itself.
  • Polypeptides are hydrophilic macromolecules that are virtually impermeable through ocular barriers that are characterized by lipophilic cell membranes and intercellular pores that are too small to allow the permeation of most polypeptides.
  • Permeability enhancing agents are compounds that, when coadministered with or conjugated to ocular hypotensive peptides of the present invention produces an increase in transport of this polypeptide across ocular barriers.
  • the permeability enhancing agent is selected from the group consisting of bile salt, surfactant, chelating agent, phospholipid additive, medium-chain fatty acid, hydrophobic penetration enhancer, long-chain amphipathic molecule, cyclodextrin or beta-cyclodextrin derivative, N-acetylamino acid or salt, glycerol ester of acetoacetic acid, salicylic acid derivative, and enamine.
  • ocular hypotensive peptides of the present invention is co-administered with or conjugated to a permeability enhancing agent.
  • the permeability enhancing agent is a permeability enhancing peptide, preferably transferrin.
  • composition is formed by incorporating the ocular hypotensive peptides of the present invention, with the desired degree of purity, in a nontoxic formulation using one or more suitable and pharmaceutically acceptable carriers, excipients, dilutents, and stabilizers.
  • suitable and pharmaceutically acceptable carriers excipients, dilutents, and stabilizers.
  • Pharmaceutical compositions can be formulated by standard techniques widely available to the ordinarily skilled artisan.
  • Rational strategies can be devised for stabilization of the ocular ocular hypotensive peptides of the present invention.
  • Several strategies for protein stabilization are widely available to the ordinary skilled artisan, depending on the mechanism involved.
  • active insulin, PlGF and IGF conformations could be stabilized by introducing a disulfide bond between chains of a polypeptide or between two polypeptides.
  • One strategy to achieve this goal is by introducing point mutations to cystine in the relevant polypeptide chains (See, for example: Reiter Y. et al. NaI. Biotech.; vol. 14: pp. 1239-1245, 1996).
  • Example of protein stabilizing strategies in a solid formulation is the water content control. Water content could be controlled to keep the water activity in the formulation at optimal levels that prevent polypeptide destabilization interactions.
  • cross-linking methodologies could be used to stabilize a desired active conformation. Examples of cross-linking methodologies include UV-cross-linking, and treatment of protein with formamide or glutaraldehyde.
  • protein stabilizing strategies in a solid formulation is the use of sucrose and sucrose based polymers, to provide significant protection against peptide or protein aggregation during solid- phase incubation and to enhance the stability of solid proteins embedded within polymer matrices.
  • Compounds such as gelatin and collagen can also serve as stabilizing or bulking agents to reduce denaturation and aggregation of proteins.
  • solubilization agents could be also serve as stabilizing agents that significantly inhibits protein aggregation, such as cyclodextrins, cyclodextrin dimers, trimers and tetramers, which selectively bind hydrophobic side chains of polypeptides.
  • Example of protein stabilizing strategies in solution formulations is the use of various additives such as polyols, amino acids, collagen, gelatin, and various salts.
  • additives such as polyols, amino acids, collagen, gelatin, and various salts.
  • Several other compounds have shown the ability to reduce the aggregation of polypeptides and proteins. Examples of such compounds are dextrans, diethylaminoethyl dextran, carboxymethyl cellulose, glycopeptides, polyamino acids, and polyethylene glycol.
  • the stability of protein is enhanced by the inhibition of enzymatic degradation processes.
  • some bile salts and fusidic acid derivatives are capable of inhibition proteolytic degradation of proteins. Since divalent cations are co-factors for many proteases, some chelating agents, such as EDTA, can be used in suitable concentrations that ensure efficient inhibition of relevant proteases.
  • some mucoadhesive polymers have also the capability of divalent cation complexation. Examples of such mucoadhesive polymers are polyacrylates and polycarbophil.
  • Boro-amino acids which are produced by incorporating the boron atom, can form a tetrahedral boronate ion and could be a mimetic of peptides in their transition state and serve as amino- peptidases substrate. Therefore boro-amino acid could provide peptide sparing effect in tissues rich of amino-peptidases hydrolysis activity by acting as reversible inhibitors of such enzymes. Several other peptide mimetics could be used selectively to block the interaction between active peptides and degradation enzymes.
  • salts The formation of salts of a composition is way of modulating its physicochemical properties to allow for favorable drug disposition.
  • Pharmaceutically acceptable salt should be non-toxic and should not alter the biological activity of the active composition.
  • a selected pharmaceutically acceptable salt of a peptide could be prepared by widely available to the ordinary artisan. Examples include the treatment of the free base with an inorganic or organic acid.
  • Inorganic acids could be selected from group consisting of hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfamic acid, sulfonic acid, sulfuric acid, and mixtures thereof.
  • Organic acids could be selected from group consisting of acetic acid, alpha- hydroxy acid, aspartic acid, benzenesulfonic acid, benzoic acid, cinnamic acid, citric acid, cyclohexylsulfamic acid, cyclohexylsulfonic acid, ethanesulfonic acid, fumaric acid, galacturonic acid, glucuronic acid, glutamic acid, glycolic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, oxalic acid, p-toluenesulfonic acid, pyranosidyl acid, pyruvic acid, quinic acid, salicylic acid, succinic acid,
  • Examples of pharmaceutically acceptable salts of a peptide include acetate, acrylate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-l,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, chlorobenzoate, citrate, cyclohexylsulfamate, cycloexylsulfonate, decanoate, dihydrochloride, dihydrogenphosphate, dinitrobenzoate, diphosphate, edetate, edislyate, estolate, esylate, ethanesulfonate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne
  • Additives to ophthalmic formulations of bioactive peptides optionally include preservatives, buffers, tonicity agents, antioxidants, stabilizers, wetting and clarifying agents, viscosity increasing agents, and antibacterial, antiviral, or antifungal agents.
  • preservatives include benzalkonium chloride, benzethonium, phenylethyl alcohol, chlorobutanol, thimerosal and the like.
  • buffers include boric acid, sodium and potassium bicarbonate, sodium and potassium borates, sodium and potassium carbonate, sodium acetate, sodium biphosphate, Tris, and the like.
  • tonicity agents are dextran, dextrose, glycerin, potassium chloride, propylene glycol, sodium chloride and the like.
  • antioxidants include sodium and potassium bisulfite, sodium and potassium metabisulfite, sodium thiosulfate, thiourea and the like.
  • stabilizers include EDTA, EGTA, DTPA, DOTA, ethylene diamine, bipyridine, 1,10- phenanthrolene, crown ethers, aza crown, catechols, dimercaprol, D-penicillamine and deferoxamine.
  • wetting and clarifying agents include polysorbate 80, polysorbate 20, poloxamer 282 and tyloxapol.
  • viscosity increasing agents include dextran, gelatin, glycerin, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, lanolin, methylcellulose, petrolatum, polyethylene glycol, polyvinyl alcohol, polyvinyl polyvinylpyrrolidone, carboxymethyl cellulose and the like.
  • Necessary antibacterial, antiviral, or antifungal agents are added in sufficient amounts to the above excipients according to guidelines well known to the skilled artisan.
  • Aqueous formulations are based on water, buffered water, saline, glycine, hyaluronic acid and the like. Aqueous formulations may be used as is, or lyophilized. Lyophilized preparation is being revived prior to administration by adding sterile solution.
  • Ointment formulations are based on ingredients such as petrolatum, paraffin, oleic acid, mineral oil, lanolin, glycerol, polysorbates, glycol ethers, polyethylene glycols and waxes.
  • Aerosol formulations have usually three main components. Beside active compound and propellant, the aerosol formulations are based on esters, such as glycerides, of fatty acids, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids. Surfactants and cosolvents are usually needed to prevent unwanted aggregation of the active compound.
  • esters such as glycerides
  • fatty acids such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids.
  • surfactants and cosolvents are usually needed to prevent unwanted aggregation of the active compound.
  • Solid formulations usually utilize pharmaceutical grades of cellulose, lactose, polysaccharide, starch, sucrose, and the like.
  • polysaccharides useful for solid formulations are alginate, carboxymethyl cellulose, carboxymethyl chitosan, carrageenan, crosscarmellose, curdlan, gellan, gum Arabic, hydroxypropyl carboxymethyl cellulose, karaya gum, mesquite gum, pectin, poly acrylic acid, xanthan, and the like. Methods described herein can be generally adapted for use with such ingredients.
  • Example of strategies for the modulation of the physicochemical properties of polysaccharides is the acylation of gellans. Acylated gellan tends to form soft, elastic, transparent and flexible gels.
  • de-acylated gellans are hard, relatively non-elastic brittle gels.
  • Active compound in a solid formulation can be attached to a backbone either directly or by a linker arm.
  • the backbone can be composed of monomer units that are covalently or non-covalently linked. Examples of covalent backbones include oligosaccharides, peptides, lipids and other cross-linked monomers.
  • Poly lactic acid (PLA) and poly glycolic acid (PGA) and their copolymer (PLGA) are among the most widely used biodegradable polymers. They are approved for human use by worldwide health authorities and are degraded into nontoxic compounds (lactic acid and glycolic acid, respectively) following hydrolysis and enzymatic cleavage.
  • Biodegradable polymeric systems were used as colloidal systems and inserts, and also as an ophthalmic drug delivery system (DDS) for subconjunctival, scleral, intracameral, or intravitreal application.
  • DDS ophthalmic drug delivery system
  • Nonbiodegradable polymers allow the design of long term sustained release DDS but carry the disadvantage of subsequent intervention to remove the DDS at the end of its functioning life.
  • the active compound can be incorporated in collagen shields or contact lenses that can serve as time release DDS on the ocular sureface.
  • Collagen shields are manufactured from porcine scleral tissue and commercially available (bio-Cor, Bauch and Lomb) with three dissolution times of 12, 24, and 72 hours, depending on the level of collagen crosslinking induced during the manufacture process.
  • Hydrophilic drugs are entrapped within the collagen matrix when the dry shield is soaked in aqueous solution of the drug while water insoluble drugs are incorporated into the shield during the manufacturing process.
  • the commercially available shields consist of a contact-lens-shaped dry product which can absorb fluid up to 60% water content when soaked in aqueous solution, and is biodegradable in a time frame according to the programmed dissolution time.
  • Therapeutic contact lenses can act as a pre-corneal drug reservoir allowing for higher drug concentrations to be in contact with ocular surface.
  • Liposomes are vesicles consisting of an aqueous compartment core surrounded by a lipid bilayer that mimics a cell membrane.
  • the aqueous core can be surrounded by either a single lipidic bilayer (unilamellar liposomes) or concentric multiple bilayers (multilamellar liposomes).
  • Liposomes with multiple bilayers are termed 'multilamellar vesicles' (MLV)
  • the unilamellar liposomes are termed 'small unilamellar vesicles' (SUV) or 'large unilamellar vesicles' (LUV) according to their size (less or more than 100 nm accordingly).
  • the bilayer of the liposomes is formed from a double array of phospholipids with their lipophilic tails facing each other and their hydrophilic heads embedded either in the aqueous core or in the aqueous solution that separate vesicles from each other.
  • the typical liposome bilayer components are phophatidylecholine (PC) as the main backbone and a small amount of cholesterol (Choi) to improve the stability of the bilayer array.
  • PC phophatidylecholine
  • Choi cholesterol
  • other amphiphiles such as negatively charged phospholipids (phosphatidylethanolamine (PE), phosphatidylserine, etc.) or cationic lipids (stearylamine, DOTAP, etc.) can be used to achieve the desired electrostatic bilayer properties.
  • PE phosphatidylethanolamine
  • DOTAP cationic lipids
  • PEG polyethyleneglycol
  • RES reticuloendothelial system
  • Liposomes are usually prepared by the reverse phase evaporation method or its modification, consisting of vigorous mechanical mixing of the water phase and low boiling-point organic solvents that contain the phospholipids and other bilayer components. Liposomes can incorporate a wide variety of molecules and peptides. Hydrophilic compounds should be incorporated in the aqueous phase while lipophilic compounds are added to the bilayer components. Because the lipid bilayer occupies only a small volume, the incorporating capacity of liposomes for lipophilic drugs is far more limited than for hydrophilic drugs. However, pro-drug strategy can allow the incorporation of lipophilic drugs in the aqueous phase and vice versa.
  • Micelles can allow the incorporation of lipophilic drugs in the aqueous phase and vice versa.
  • Amphiphilic molecules can assemble into nanoscopic supramolecular structures with a hydrophobic core and a hydrophilic shell micellar arrangement. As surfactant concentration is increased in aqueous solutions, the separated molecules aggregate into micelles upon reaching a concentration interval known as the critical micellar concentration (CMC).
  • CMC critical micellar concentration
  • nonpolar molecules are solubilized within the internal micelle hydrophobic core, polar molecules are adsorbed on the micelle surface and substances with intermediate polarity are distributed along surfactant molecules in intermediate positions.
  • Micellar ocular drug delivery systems are based on non-toxic and non-irritant materials and are stable enough to achieve a reasonable shelf life.
  • the non-ionic triblock copolymers like poly ethylene oxide- poly propylene oxide-polyethylene oxide (PEO-PPO-PEO), are among the most widely used polymeric micelles. Emulsions
  • Oil in water emulsions are two-phase systems formed by the dispersion of oil (the internal phase) in water (the external phase) and stabilized by at least one surfactant.
  • Submicron emulsion (SME), and nanoemulsion are interchangeable terms used to describe a kinetically stable emulsion system characterized by a droplet size in the nano-range.
  • Microemulsion is a term used to emphasis certain properties of an emulsion.
  • Microemulsions are also a nano-range two-phase systems prepared from oil, water and surfactant, but usually more surfactants are used (up to 10% compared to 1% in simple emulsions).
  • Co-surfactants in microemulsions are required to achieve very low interfacial tensions that allow self emulsif ⁇ cation and enhanced thermodynamic stability.
  • the surface charge of the emulsion could be negatively charged, neutral or positively charged.
  • Nanocapsules are colloid systems with an oil core and biodegradable polymeric coating. Nanocapsules can be prepared by different approaches like, interfacial precipitation, interfacial polymerization, interfacial deposition, and self assembly procedures. The dispersion stability are mainly determined by the nature of outer coating and the type of the used surfactant. Particulate drug delivery systems (Micro/Nano Particles)
  • particulate drug delivery systems can offer more possibilities for controlled drug release. Furthermore, particulate systems are basically more stable than other colloidal systems, and since they can be freeze-dried for long term storage, extended shelf life is feasible.
  • Particulate carriers meet the basic needs of advanced ocular drug carriers, being nontoxic, non-immunogenic, biocompatible, uniform and biodegradable in a predictable pace. In addition, they have the ability to provide protection for the delivered molecules while interacting with the ocular tissues. Examples of materials used for the preparation of nanoparticles are biodegradable polymers (PLGA and the like), chitosan, albumin, solid lipid, and gold.
  • nanoparticles with a sterically stabilizing layer can modulate their in vivo biodistribution and lower their tendency to aggregate with biomolecules. Longer residence times on the ocular surface can be achieved if the nanoparticles are coated with a mucoadhesive or charged polymer. Dendrimers
  • Dendrimers is a name used for polyamidoamine (PAMAM, StarburstTM), polypropyleneimine- diaminobutane (DAB), polypropyleneimine- diaminoethane (DAE), polyethyleneoxide-carbosilane (CSi- PEO), polyether, and similar macromolecules with a highly branched globular nanometric structure that comprises branches radiating from a central core. Dendrimers vary in the flexibility of branches and type of peripheral functional groups. Branches can terminate at charged and uncharged amino, carboxyl or hydroxyl groups. Most of the described dendrimers are liquid or semi-solid polymers that are not soluble in aqueous solutions and their in vivo toxicity remains a concern.
  • Dendrimers are classified and designated according to the surface terminating group quality and quantity. For amine and sodium carboxylate terminating groups, the designation is PAMPAM; for amine and carboxylic acid groups, DAB; for amine groups, PEA; for polyethyleneoxide, CSi-PEO; and finally, for carboxylate and malonate groups, 'Polyether'.
  • Full generations (Gl, 2, 3, etc.) describe amine terminating groups (except for 'Polyether' Go or G2 where it refers to carboxylate and malonate groups, and for PAMAM G2(0H) and G4(0H) where it refers to hydroxyl group), while the half generations (G1.5, 2.5, 3.5, etc.) describe carboxylic acid or sodium carboxylate terminating groups.
  • Improved loading capacity of dendrimer can be achieved by the process of 'activation', a term used to describe a process comprising a heat treatment in a solvent that manipulates the structure of dendrimers where some branches are trimmed away, while keeping the general topology and size, resulting in more flexible molecules.
  • the reduced structural density in the intramolecular core allows higher levels of drug loading and enhanced penetration capabilities.
  • “physical penetration enhancers” in the present invention refers to the enhancement of drug penetration through tissue barriers by wide array of interventions that share the common ground of delivering energy that its strong enough to cause a very short and reversible change in the properties and configuration of cell membrane and tissue barriers in a way that will allow co-administered drugs to benefit from the temporarily lifting of barrier function in order to get access to highly protected compartments.
  • some technologies further utilizes electrostatic gradient to allow a powered-mobilization of ionized drugs down the electrostatic gradient. Iontophoresis is a method used to enhance the delivery of charged molecules across tissue barriers that are relatively impermeable for ionized compounds. This rapid and noninvasive technique utilizes low electrical current to drive ionized molecules across barriers.
  • the main factors influencing iontophoretic drug delivery are the molecular weight, charge and lipophilicity of the drug, current density, the duration of treatment, pH and the permeability of the tissue.
  • One electrode is placed on the eye while the other is placed on a remote tissue. Therefore, ionic drugs are delivered from electrodes by current of the same polarity measured in milliamperes (mA).
  • mA milliamperes
  • the negative pole cathode
  • the positive pole anode
  • the total delivered electric charge is proportional to the delivered drug.
  • the optimal setting that the operator should seek must allow for maximum delivery while minimizing the current level.
  • the efficiency of a iontophoretic device can be described in terms of the total amount of charge that must be passed to obtain the desired clinical effect (i.e. induction of local anesthesia upon delivery of Hdocaine) and quantified in units of mA minutes, calculated by multiplying the electrical current and the application time.
  • Electroporation comprises the use of electric pulses to induce transient changes in the cell membrane architecture that turn it into more permeable barrier.
  • chemical penetration enhancers in the present invention refers to the enhancement of drug penetration through tissue barriers by wide array of interventions that share the common ground of being able to disturb at least in part the barrier functions of that tissue and thus removing obstacles that limits drug penetration to the tissue.
  • the barrier effects of chemical penetration enhancers should be short lived to avoid consequences that can affect normal function of the tissue.
  • biological penetration enhancers in the present invention refers to the enhancement of drug penetration through a biological barriers by wide array of interventions that share the common ground of being able to favor the influx of the drug and minimize the efflux.
  • tissue loosening agents and "hyaluronidase and hyaluronidase analogs or equivalents” in the present invention refers to the use of agents to loosen up the surrounding extracellular matrix at the site of drug administration , aiming to significantly improve the distribution of the drug in ocular tissues and eventually enhancing its penetration.
  • tissue loosening agents and "hyaluronidase and hyaluronidase analogs or equivalents” in the present invention refers to the use of agents to loosen up the surrounding extracellular matrix at the site of drug administration , aiming to significantly improve the distribution of the drug in ocular tissues and eventually enhancing its penetration.
  • “delivery of said insulin PlGF and/or IGF is further assisted by antibody conjugated to” and "avidine- biotin or streptavidin-biotin system” in the present invention refers to the use of antibody assisted drug delivery wherein the antibody is attached to the drug delivery system by tailored linkers and the antibody selection should allow the specific targeting of the desired tissue.
  • Methods to conjugate antibodies to liposomes, emulsions, polymeric drug delivery systems, and to naked proteins, peptides, plasmids and oligonucleotide, for site-specific targeting are widely available for the skilled artisan. For example, by utilizing an efficiently internalized antibody, the conjugated drug, either naked or with a carrier, will be delivered inside targeted cells.
  • pegylation in the present invention refers to the process of covalent attachment of poly(ethylene glycol) polymer chains to another molecule, normally a drug or therapeutic protein. PEGylation is routinely achieved by incubation of a reactive derivative of PEG with the target macromolecule.
  • the covalent attachment of PEG to a drug or therapeutic protein can "mask" the agent from the host's immune system increase the hydrodynamic size (size in solution) of the agent which prolongs its circulatory time by reducing renal clearance.
  • PEGylation can also provide water solubility to hydrophobic drugs and proteins, "temporary punctal occlusion”, “permanent punctual occlusion”, “vascular constrictors”, “increased drug formulation adhesion to ocular tissues”, and "optimizing the volume of the administered drug formulation to prevent over spillage” in the present invention refers to methods and means to avoid systemic distribution of the locally administered active composition, in order to avoid unwanted side effects. Such methods are easily accessible and widely available to the skilled artisan.
  • the widely accepted methods includes temporary punctal occlusion, permanent punctual occlusion, use of vascular constrictors, increased drug formulation adhesion to ocular tissues, and optimizing the volume of the administered drug formulation to prevent over spillage, (see: Abdulrazik M, Behar-Cohen F, Benita S. Drug Delivery Systems for Enhanced Ocular Absorption. In Enhancement in Drug Delivery, Touitou E, Barry BW, Eds., Taylor and Francis, pp. 489-526, 2006)
  • cells that were converted into insulin PlGF and/or IGF-producing cells refers to converting cells that reside in-situ or those who can accumulate at the site of action of insulin PlGF and/or IGF, into insulin PlGF and/or IGF -producing cells.
  • embryonic stem cells and “adult stem cells” in the present invention refers to the utilizing of stem cells as insulin PlGF and/or IGF -producing cells.
  • Stem cells are subdivided into embryonic stem cells and adult stem cells.
  • Embryonic stem cells have pluripotent plasticity and can differentiate to any specialized cell line. They are derived from embryos that develop from eggs that have been fertilized by an in vitro fertilization process (IVF) and then donated for research purposes with informed consent of the donors.
  • IGF in vitro fertilization process
  • Adult stem cell is an undifferentiated cell found among differentiated cells in a tissue or organ, can renew itself, and can differentiate to yield the major specialized cell types of the tissue or organ.
  • Well known methods in the art teach ways of controlling stem cell differentiation in cell culture for specific purposes including cell-based therapies.
  • a suitable gene delivery system should be tailored for each mission to meet the unique requirements and to overcome hurdles.
  • a plasmid-based system such as transfection methods combined with electroporation may be used to produce stable cell lines by selection to meet the target of mediating a long-term constitutive gene expression, while a transient expression system could utilize a cationic liposome-plasmid complex.
  • some viral vectors including some Adenovirus subtypes (e.g., fiber-modified Ad vectors, tropism-modified Ad5 vectors, and AdK7 vector), have shown favorable characteristics related to stem cell gene therapy like ease of vector preparation, high transduction efficiency, and the transient expression ability (See: Kawabata K, et al., Molecular Pharmaceutics, 2006;3(2):95-103).
  • Adenovirus subtypes e.g., fiber-modified Ad vectors, tropism-modified Ad5 vectors, and AdK7 vector
  • PlGF and/or IGF -producing cells that eventually could be used in transplantation therapy for diabetic patients.
  • Another reported example includes replacing the dopamine-producing cells in the brains of
  • viral gene delivery vector and “non-viral gene delivery vector” in the present invention refers to assisted gene delivery process. These two categories differ primarily in their assembling process. While viral vector is assembled in a cell, nonviral vector is constructed at in vitro setting. Viral vectors are highly efficient in gene delivery. The desired therapeutic gene is incorporated in the viral coding sequence of replication-defective viruses. Viral vectors include adenovirus, adeno-associated virus, lentivirus, retrovirus, and herpes simplex virus, beside other less frequently used viruses.
  • Adenovirus is an icosahedral virus that contains a large DNA genome. Contrary to retrovirus, adenovirus can infect both dividing and nondividing cells. Gene expression using adenovirus lasts for only a short time because adenoviral genome is not integrated into the host DNA.
  • Adeno-associated virus is a small nonpathogenic DNA virus. It is pathogenic only in the presence of a helper virus, such as adenovirus or herpes virus. In the absence of a helper virus, AAV instead incorporates its genome into the chromosomes of the host cells. Both dividing and non-dividing cells can be infected by AAV.
  • the main disadvantage of AAV is that sufficiently high viral titer is hard to obtain.
  • the virus also has a limited packaging size of about 5 kb.
  • Retrovirus is an eukaryotic RNA virus in the family Retroviridae that has RNA as its genome. It uses viral enzymes to copy its genome into DNA and integrate into the host chromosome. Although recent advances in lentivirus vectors have enabled transduction of nondividing cells, long-term gene expression can he achieved with this vector only in the cycling cells.
  • Herpes simplex virus is a double-stranded DNA virus with a genome measuring more than 150 kb.
  • HSV can infect a variety of dividing and nondividing cells. A very high viral titer can also he produced. However, HSV causes some cytotoxicity.
  • the limitations of viral vectors like insufficient pharmaceutical quantities (viral titers), toxicity, and the potential replication of competent viruses, make synthetic vectors an attractive alternative.
  • Advantages of nonviral vectors include their nonimmunogenicity low acute toxicity, simplicity, and feasibility to be produced on a large scale. Still, nonviral vectors suffer from lower efficiency than viral vectors in gene transfer and their transient gene expressions. Many approaches for gene therapy by nonviral vectors have been proposed including gene transfer with naked DNA. Gene transfer with naked DNA carries the advantages of its simplicity and lack of toxicity.
  • “physical gene delivery methods” in the present invention refers to the creation of transient injuries or defects on cell membranes that allows DNA to enter the cells by diffusion. Such methods include mechanical, electric (iontophoresis and electroporation), ultrasonic, hydrodynamic (hydrodynamic gene transfer), or laser energy.
  • Shooting DNA into cells is one example that can be carried out by using a physical method such as bioballistic particle bombardment or gene gun.
  • the gene gun uses gold particles coated with DNA and this approach is an ideal method for gene transfer to superficial or surgically exposed ocular tissues. DNA coated gold particles, which are accelerated by pressurized gas and expelled onto cells or a tissue. The momentum allows the gold particles to penetrate a few millimeters deep into a tissue and release DNA into cells on the path.
  • Electroporation moves DNA along the electric field and can be practical in any ocular tissue into which a pair of electrodes can be inserted. Reportedly, the effective distance between the electrodes, is in the range of 1 cm. Therefore, when targeting deep tissues, a surgical procedure is usually required to place the electrodes. Electroporation can be effective in delivering DNA as large as 100 kb. Overall, a short time interval between DNA administration and electroporation is beneficial to minimize DNA degradation by extracellular nucleases.
  • a single electroporation assisted gene transfer can lead to a long-term gene expression.
  • Ultrasound energy creates membrane pores and facilitates intracellular gene transfer through passive diffusion of DNA across the membrane pores.
  • Ultrasound can facilitate gene transfer at cellular and tissue levels.
  • the efficacy of ultrasound assisted transfection is determined by frequency, strength, and the duration of ultrasound treatment.
  • the efficacy could be further increased by ultrasound enhancing agents that comprise air-filled microbubbles that rapidly expand and shrink under ultrasound irritation. The consequent local shock waves cause transient changes in the permeability of neighboring cell membranes.
  • Hydrodynamic gene delivery is based on brisk injection of naked plasmid DNA into selected body compartment at injected volume and injection pace that creates an overflow situation that transiently alters the permeability of the compartment barriers to the injected DNA, presumably by creation of transient membrane defects in neighboring cells.
  • a direct gene transfer to the cytoplasm is achieved without endocytosis.
  • this method can be effective in delivering DNA as large as 150 kb.
  • gene transfer to the endothelium of schlemm's canal can be achieved by fast injection of DNA solution into the lumen of schlemm's canal.
  • the injection could be accomplished by using a ballooned catheter and carrying out occlusion-assisted infusion to the whole or specific parts of the schlemm's canal.
  • Treatment of ocular tissue with hyaluronidase or similar tissue loosening agents prior to injection of plasmid DNA to loosen up the surrounding extracellular matrix can significantly improve the distribution of plasmid DNA in the tissue and enhance transfection.
  • cationic carriers for gene delivery in the present invention refers to the utilization of cationic carriers for the formulation of DNA into condensed particles.
  • Cell membrane is a major obstacle that faces DNA before getting access into the cytoplasm and migrating into the nucleus, where gene expression takes place.
  • DNA is an anionic macromolecule
  • cationic carriers are useful for the formulation of DNA into condensed particles.
  • the reduced size of DNA-containing particles carries the obvious advantage of more efficient passage to the cytoplasm of target cells through the cell membrane via endocytosis, macropinocytosis, or phagocytosis.
  • DNA cationic carriers include cationic polymers (polyplexes), cationic lipids (lipoplexes), peptides, and lipid-polymer cationic hybrids.
  • Cationic polymers that are effective candidates for the formation of polyplexes for gene delivery include cationic chitosan, poly-L-lysine, cationic dextran, polyallylamine, polypropylamine, polyamidoamine, and polyethylenimine.
  • polyethylenimine is one of the most active polymers for gene delivery.
  • Protein and peptide vectors for gene transfer into cells include cationic proteins and cationic peptides, like arginine-rich peptides derived from protamine, synthetic arginine-rich peptides, and lysine-rich peptides.
  • Short cationic peptides can be utilized as membrane-penetrating molecules to enhance the efficiency of polyplex-mediated gene delivery.
  • antibody mediated gene delivery and “avidine-biotin or streptavidin-biotin” in the present invention refers to antibody assisted target-specific gene delivery. Conjugation to antibody or avidin can further provide the possibility of target-specific gene delivery. See also: (Curtis AM, Ed.. Viral vectors for gene therapy: methods and protocols, Humana Press, 2002), (Kazunari T, Kazunari K, Takuro N, Eds., Non-viral gene therapy: Gene design and delivery, Springer, 2005), (Gao X, Kim KS, Liu D. AAPS J. 2007;9(1):E92-104)
  • the aforementioned strategies may be used for introducing gene modifications to non-ocular, ocular, and periocular tissues, like cells adjacent to the schlemm's canal and lacrimal gland cells, as well as stem cells, to reach the target of regional or in-situ insulin, insulin, PlGF and/or IGF production by these gene modified cells on long- or short-term basis.
  • concentration of the insulin, PlGF and/or IGF composition which is supplied to the subject in need by means such as topical, corneal, intracameral, intravitreal should be sufficiently high to obtain the desired lowering of intraocular pressure.
  • the concentration of insulin, PlGF and/or IGF in the administered composition is preferably between 10 and 1000 nmol/1 more preferably between 50 and 500 nmol/1.
  • the studied insulin preparations were: (Eli Lilly) humalog mix 25, (Eli Lilly )-humalog, (Eli LiIIy)- humulin 70/30, (Eli Lilly )-humulin n (nph), (Eli Lilly)-humulin r (regular), (Novo Nordisc)-novomix 50, (Novo Nordisk)-insulatard hm nph, (Novo Nordisk)-actrapid, (Novo Nordisk-mixtard 30, (Novo Nordisk)-mixtard, (Novo Nordisk)-levemir, (Novo Nordisk)-novomix (Novo Nordisk)-novomix 70, (Novo Nordisk)-novorapid, (Sanofi Aventis)-apidra, AND (Sanofi Aventis)-lantus.
  • the studies subjects were diabetic patients, one healthy human volunteer, Lewis rats and alb
  • intraocular pressure measurements were significantly lower than baseline values only in 5 patients. After 2 months reduction in intraocular pressure was higher than 15% from baseline in all cases. At the end of 3 months the reduction in intraocular pressure ranged from 24% up to 35% from baseline. This level of intraocular pressure reduction was maintained in the following months.
  • a 48-year-old male human volunteer have received twice daily doses of 50 micro-liters of (Eli LiIIy)- humulin 70/30 to the conjunctival sac of the right eye. Blood glucose was monitored 3 times per day and subjective tolerability score was documented daily.
  • the topical insulin was well tolerated and blood glucose levels remained without statistically significant change from baseline.
  • EXAMPLE 7 (Effect on Permeability) Ongoing studies on time to clear fluorescine from the anterior chamber of the eye have shown that the rate of the fluorescent legend clearance from the anterior chamber was almost doubled for the insulin treated eyes compared to balanced salt solution and denaturized insulin treated eyes. Similar trend was observed in studies of flourescine clearance from filtering bleb. The clearance of flourescine was more than 1.6 times faster for the insulin treated bleb compared to balanced salt solution and denaturized insulin treated blebs.
  • Example 8 The present study aimed at investigating the effect of insulin on IOP.
  • Methods Type 2 diabetes patients, with no diabetic retinopathy and without therapy that could affect IOP, were periodically examined starting from 3 weeks before the initiation of SC insulin therapy. Animal studies on 48 female albino rabbits were done to investigate the tolerability of ocular insulin administration and insulin effect on IOP. Controls and negative controls received denaturated insulin and balanced salt solution (BSS) respectively.
  • BSS balanced salt solution
  • BMI body mass index
  • IOP Humans: Goldmann applanation tonometer
  • Rabbits Tonopen AVIA, Reichert
  • blood glucose level at time of IOP measurement Optium-Xceed, Abbott
  • CCT central corneal thickness
  • EXAMPLE 9 Nonpenetrating trabeculectomy was performed in 28 rabbit eyes. At the end of the procedure a sustained release formulation was injected into the sclera pocket, comprising PlGF-I (4 eyes), IGF-I (4 eyes), a combination of PlGF-I and IGF-I (4 eyes), denaturated PlGF-I (4 eyes), denaturated IGF-I (4 eyes), denaturated combination of PlGF-I and IGF-I (4 eyes), and blank formulation (4 eyes).
  • the rank order of greater hypotensive effect of the surgical procedure was PlGF- 1>P1GF-1& IGF-1>IGF- l>each of the control groups. There were no significant differences between scores in the control eyes.
  • EXAMPLE 10 (Success Rate of Filtering Bleb) 24 rabbits underwent trabeculectomy. Four rabbits were treated with daily PlGF-I injections to the filtering bleb, 4 others received denaturized PlGF-I and another 4 rabbits received same volume and same frequency of balanced salt solution (BSS). Four rabbits were treated with daily IGF-I injections to the filtering bleb, 4 others received denaturized IGF-I and another 4 rabbits received same volume and same frequency of BSS. The rank order of greater hypotensive effect of the surgical procedure was PlGF- l>IGF-l>BSS>denaturated formulations.
  • EXAMPLE 11 (Effect on Permeability) In a study on time to clear fluorescine from the anterior chamber of the eye, the rate of the fluorescent clearance from the anterior chamber was 1.5-1.7 times higher for the PlGF-I or IGF-I treated eyes compared to balanced salt solution and denaturated formulations treated eyes. Similar ratio of hypotensive merit were obtained in studies of flourescine clearance from filtering bleb.
  • EXAMPLE 12 once daily intracorneal injections in the rabbit eye of Insulin, PIGF-I or IGF-I showed a prominent ocular hypotensive effect.
  • the rank order of the ocular hypotensive effect was 3 agent combination>Insulin+PlGF>Insulin+IGF>PlGF+IGF>Insulin>PlGF>IGF>Denaturated formulations>BS S .

Abstract

Cette invention porte sur des compositions et des procédés pour diminuer la pression intraoculaire et sur un traitement et/ou une prévention de glaucome et d'hypertension oculaire. L'invention porte sur l'insuline, le facteur de croissance de type insuline, le facteur de croissance placentaire, leurs isoformes, leurs analogues, leurs modifications par génie génétique et leurs combinaisons pour diminuer la pression intraoculaire, pour augmenter le taux de succès de procédures chirurgicales pour le traitement et la prévention d'un glaucome, et pour la neuroprotection de cellules ganglionnaires de la rétine.
PCT/IL2010/000166 2009-02-26 2010-02-28 Combinaison synergique de composés bioactifs pour diminuer la pression intraoculaire WO2010097800A1 (fr)

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IL197323A IL197323A0 (en) 2009-02-26 2009-02-26 Novel method and compositions for prevention or treatment of glaucoma and ocular hypertension
IL197324A IL197324A0 (en) 2009-02-26 2009-02-26 Synergistic drug combinations for prevention or treatment of glaucoma and ocular hypertension
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011053803A3 (fr) * 2009-10-30 2011-08-11 The Ohio State University Particules biodégradables multifonctionnelles permettant un ciblage sélectionnable, une imagerie, et une administration thérapeutique, et leur utilisation pour le traitement de troubles oculaires
WO2013079713A1 (fr) * 2011-12-01 2013-06-06 Thrombogenics Nv Amélioration du résultat de la trabéculectomie
WO2015060812A1 (fr) * 2013-10-21 2015-04-30 Howard University Traitement d'une maladie oculaire par des inhibiteurs des transporteurs d'efflux
WO2017053566A1 (fr) * 2015-09-23 2017-03-30 Aerpio Therapeutics, Inc. Méthodes de traitement de la pression intraoculaire avec des activateurs de tie-2
WO2017191077A1 (fr) * 2016-05-04 2017-11-09 The Provost, Fellows, Foundation Scholars, & The Other Members Of Board, Of The College Of The Holy & Undiv. Trinity Of Queen Elizabeth Near Dublin Thérapie par arni pour le traitement et/ou la prévention du glaucome
CN109260458A (zh) * 2017-07-18 2019-01-25 百捷生物科技有限公司 胶原蛋白植入物在制备青光眼手术辅助复原物中的用途
US10253094B2 (en) 2016-07-20 2019-04-09 Aerpio Therapeutics, Inc. Antibodies that target human protein tyrosine phosphatase-beta (HPTP-beta) and methods of use thereof to treat ocular conditions
US10307292B2 (en) 2011-07-18 2019-06-04 Mor Research Applications Ltd Device for adjusting the intraocular pressure
US11253502B2 (en) 2019-04-29 2022-02-22 EyePoint Pharmaceuticals, Inc. Tie-2 activators targeting the Schlemm's canal
EP3927369A4 (fr) * 2019-02-20 2022-11-02 Eleos Pharmaceuticals, LLC Composition topique pour la cicatrisation améliorée de maladies oculaires

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5147647A (en) * 1986-10-02 1992-09-15 Sohrab Darougar Ocular insert for the fornix
US20050096257A1 (en) * 2003-08-27 2005-05-05 David Shima Combination therapy for the treatment of ocular neovascular disorders
US20070087001A1 (en) * 2005-10-19 2007-04-19 Center For Molecular Medicine And Immunology Inhibition of placenta growth factor (PLGF) mediated metastasis and/or angiogenesis
US20070117750A1 (en) * 2005-10-06 2007-05-24 Muhammad Abdulrazik Method for enhanced ocular drug penetration
US20070154465A1 (en) * 2005-12-30 2007-07-05 Alexandar Kharazi Stem cell therapy for retinal disease
US20070185203A1 (en) * 2004-03-01 2007-08-09 Rothbard Jonathan B Compositions and Methods for Treating Diseases
US20080131522A1 (en) * 2006-10-03 2008-06-05 Qing Liu Use of placental biomaterial for ocular surgery
US20080268051A1 (en) * 2007-04-30 2008-10-30 Allergan, Inc. High viscosity macromolecular compositions for treating ocular conditions

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5147647A (en) * 1986-10-02 1992-09-15 Sohrab Darougar Ocular insert for the fornix
US20050096257A1 (en) * 2003-08-27 2005-05-05 David Shima Combination therapy for the treatment of ocular neovascular disorders
US20070185203A1 (en) * 2004-03-01 2007-08-09 Rothbard Jonathan B Compositions and Methods for Treating Diseases
US20070117750A1 (en) * 2005-10-06 2007-05-24 Muhammad Abdulrazik Method for enhanced ocular drug penetration
US20070087001A1 (en) * 2005-10-19 2007-04-19 Center For Molecular Medicine And Immunology Inhibition of placenta growth factor (PLGF) mediated metastasis and/or angiogenesis
US20070154465A1 (en) * 2005-12-30 2007-07-05 Alexandar Kharazi Stem cell therapy for retinal disease
US20080131522A1 (en) * 2006-10-03 2008-06-05 Qing Liu Use of placental biomaterial for ocular surgery
US20080268051A1 (en) * 2007-04-30 2008-10-30 Allergan, Inc. High viscosity macromolecular compositions for treating ocular conditions

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CUNHA ET AL.: "Extra-pancreatic insulin production in RAt lachrymal gland after streptozotocin- induced islet B-cells destruction", BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, vol. 1770, no. ISSUE, August 2007 (2007-08-01), pages 1128 - 1135 *
HUBBELL ET AL.: "Multifunctional polyplexes as locally triggerable nonviral vectors", GENE THERAPY, vol. 13, no. ISSUE, October 2006 (2006-10-01), pages 1371 - 1372 *
RABINOVICH-GUILATT ET AL.: "Cationic vectors in ocular drug delivery", JOUMAL OF DRUG TARGETING, vol. 12, no. 9-10, December 2004 (2004-12-01), pages 623 - 633 *
ZOUKHRI ET AL.: "Mechanisms of murine lacrimal gland repair after experimentally induced inflammation", INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, vol. 49, no. ISSUE, October 2008 (2008-10-01), pages 4399 - 406 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011053803A3 (fr) * 2009-10-30 2011-08-11 The Ohio State University Particules biodégradables multifonctionnelles permettant un ciblage sélectionnable, une imagerie, et une administration thérapeutique, et leur utilisation pour le traitement de troubles oculaires
US10307292B2 (en) 2011-07-18 2019-06-04 Mor Research Applications Ltd Device for adjusting the intraocular pressure
WO2013079713A1 (fr) * 2011-12-01 2013-06-06 Thrombogenics Nv Amélioration du résultat de la trabéculectomie
US9089552B2 (en) 2011-12-01 2015-07-28 Thrombogenics Nv Improving trabeculectomy outcome by administering an anti-placental growth factor antibody
WO2015060812A1 (fr) * 2013-10-21 2015-04-30 Howard University Traitement d'une maladie oculaire par des inhibiteurs des transporteurs d'efflux
WO2017053566A1 (fr) * 2015-09-23 2017-03-30 Aerpio Therapeutics, Inc. Méthodes de traitement de la pression intraoculaire avec des activateurs de tie-2
US10952992B2 (en) 2015-09-23 2021-03-23 Aerpio Pharmaceuticals, Inc. Methods of treating intraocular pressure with activators of Tie-2
US11666558B2 (en) 2015-09-23 2023-06-06 EyePoint Pharmaceuticals, Inc. Methods of treating intraocular pressure with activators of Tie-2
WO2017191077A1 (fr) * 2016-05-04 2017-11-09 The Provost, Fellows, Foundation Scholars, & The Other Members Of Board, Of The College Of The Holy & Undiv. Trinity Of Queen Elizabeth Near Dublin Thérapie par arni pour le traitement et/ou la prévention du glaucome
US10253094B2 (en) 2016-07-20 2019-04-09 Aerpio Therapeutics, Inc. Antibodies that target human protein tyrosine phosphatase-beta (HPTP-beta) and methods of use thereof to treat ocular conditions
US10597452B2 (en) 2016-07-20 2020-03-24 Aerpio Pharmaceuticals, Inc. Methods of treating ocular conditions by administering humanized monoclonal antibodies that target VE-PTP (HPTP-beta)
US10604569B2 (en) 2016-07-20 2020-03-31 Aerpio Pharmaceuticals, Inc. Humanized monoclonal antibodies that target protein tyrosine phosphatase-beta (HPTP-β/VE-PTP)
US11136389B2 (en) 2016-07-20 2021-10-05 Aerpio Pharmaceuticals, Inc. Humanized monoclonal antibodies that target VE-PTP (HPTP-β)
US11180551B2 (en) 2016-07-20 2021-11-23 EyePoint Pharmaceuticals, Inc. Humanized monoclonal antibodies that target VE-PTP (HPTP-beta)
CN109260458A (zh) * 2017-07-18 2019-01-25 百捷生物科技有限公司 胶原蛋白植入物在制备青光眼手术辅助复原物中的用途
CN109260458B (zh) * 2017-07-18 2022-03-18 百捷生物科技有限公司 胶原蛋白植入物在制备青光眼手术辅助复原物中的用途
EP3927369A4 (fr) * 2019-02-20 2022-11-02 Eleos Pharmaceuticals, LLC Composition topique pour la cicatrisation améliorée de maladies oculaires
US11253502B2 (en) 2019-04-29 2022-02-22 EyePoint Pharmaceuticals, Inc. Tie-2 activators targeting the Schlemm's canal

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