WO2008059501A2 - Use of lipid conjugates in the treatment of diseases or disorders of the eye - Google Patents
Use of lipid conjugates in the treatment of diseases or disorders of the eye Download PDFInfo
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- WO2008059501A2 WO2008059501A2 PCT/IL2007/001407 IL2007001407W WO2008059501A2 WO 2008059501 A2 WO2008059501 A2 WO 2008059501A2 IL 2007001407 W IL2007001407 W IL 2007001407W WO 2008059501 A2 WO2008059501 A2 WO 2008059501A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/717—Celluloses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/718—Starch or degraded starch, e.g. amylose, amylopectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
- A61K47/544—Phospholipids
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- 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
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- This invention provides compounds and methods of use thereof for reducing the incidence, reducing the severity or pathogenesis, or treating a disease or disorder of the eye in a subject, including, inter alia, retinal detachment, macular degeneration, glaucoma or retinopathy, as well as contact lens solutions comprising said compounds.
- Phospholipase A2 catalyzes the breakdown of phospholipids at the sn-2 position to produce a fatty acid and a lysophospholipid.
- the activity of this enzyme has been correlated with various cell functions, particularly with the production of lipid mediators such as eicosanoid production (prostaglandins, thromboxanes and leukotrienes), platelet activating factor and lysophospholipids.
- Compounds for use in the present invention may offer a wider scope of protection of cells and organisms from injurious agents and pathogenic processes, including the prevention and treatment of eye diseases.
- diabetes In the United States, diabetes is responsible for 8% of legal blindness, making it the leading cause of new cases of blindness in adults 20-74 years of age. Each year, between 12,000 to 24,000 people lose their sight because of diabetes, making patients with diabetes 25 times more likely to lose vision than those who are not diabetic, according to the American Academy of Ophthalmology. In addition, diabetic retinopathy often leads to additional eye disorders such as retinal detachment, glaucoma cataract, and corneal disease, contributing to the high rate of blindness in diabetics.
- the invention provides a method of reducing the incidence, reducing the severity or pathogenesis of a disease or disorder of the eye in a subject comprising the step of contacting said subject with a compound comprising a lipid or phospholipid moiety bound optionally via a spacer to a physiologically acceptable monomer, dimer, oligomer, or polymer via an ester or amide bond, and/or a pharmaceutically acceptable salt or a pharmaceutical product thereof.
- the invention provides a method of treating a disease or disorder of the eye in a subject comprising the step of contacting said subject with a compound comprising a lipid or phospholipid moiety bound optionally via a spacer to a physiologically acceptable monomer, dimer, oligomer, or polymer via an ester or amide bond, and/or a pharmaceutically acceptable salt or a pharmaceutical product thereof.
- the invention provides a contact lens solution comprising a lipid or phospholipid moiety bound optionally via a spacer to a physiologically acceptable monomer, dimer, oligomer, or polymer via an ester or amide bond, and/or a pharmaceutically acceptable salt or a pharmaceutical product thereof.
- the invention provides a compound represented by the structure of the general formula (I):
- Ri, R 2 , or a combination thereof is a palmitic acid moiety
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is alginate, hydroxyethylstarch, polygeline, carboxymethylcellulose, or a combination thereof; and n is a number from 1 to 1000 or wherein
- Ri, R 2 , or a combination thereof is a myristic acid moiety
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is alginate, hydroxyethylstarch, polygeline, carboxymethylcellulose, or a combination thereof; and n is a number from 1 to 1000.
- the invention provides a compound represented by the structure of the general formula (I):
- Ri, R 2 , or a combination thereof is a palmitic acid moiety
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is alginate, hydroxyethylstarch, polygeline, carboxymethylcellulose, or a combination thereof; and n is a number from 2 to 1000 or wherein
- Ri, R 2 , or a combination thereof is a myristic acid moiety
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is alginate, hydroxyethylstarch, polygeline, carboxymethylcellulose, or a combination thereof; and n is a number from 2 to 1000.
- the invention provides a method of reducing the incidence, reducing the severity or pathogenesis of a disease or disorder of the eye in a subject comprising the step of contacting said subject with a compound comprising a lipid or phospholipid moiety bound optionally via a spacer to a physiologically acceptable monomer, dimer, oligomer, or polymer via an ester or amide bond, and/or a pharmaceutically acceptable salt or a pharmaceutical product thereof.
- the invention provides a method of suppressing or inhibiting, a disease or disorder of the eye in a subject, comprising the step of contacting a cell with a compound comprising a lipid or phospholipid moiety bound to a physiologically acceptable monomer, dimer, oligomer, or polymer, and/or a pharmaceutically acceptable salt or a pharmaceutical product thereof.
- the invention provides a method of treating a disease or disorder of the eye in a subject, comprising the step of contacting said subject with a compound comprising a lipid or phospholipid moiety bound optionally via a spacer to a physiologically acceptable monomer, dimer, oligomer, or polymer via an ester or amide bond, and/or a pharmaceutically acceptable salt or a pharmaceutical product thereof.
- the invention provides a method of preventing a disease or disorder of the eye in a subject, comprising the step of contacting said subject with a compound comprising a lipid or phospholipid moiety bound optionally via a spacer to a physiologically acceptable monomer, dimer, oligomer, or polymer via an ester or amide bond, and/or a pharmaceutically acceptable salt or a pharmaceutical product thereof.
- the invention provides for the use of a lipid or phospholipid moiety bound optionally via a spacer to a physiologically acceptable monomer, dimer, oligomer, or polymer via an ester or amide bond, in the preparation of a composition for suppressing, inhibiting, preventing or treating a disease or disorder of the eye in a subject.
- the invention provides for the use of a lipid or phospholipid moiety bound optionally via a spacer to a physiologically acceptable monomer, dimer, oligomer, or polymer via an ester or amide bond, in the preparation of a composition for reducing the incidence, reducing the severity or pathogenesis of a disease or disorder of the eye in a subject
- a disease or disorder of the eye refers to any one or more of the following conditions: retinal detachment, macular edema, retinopathy, age-related macular degeneration, macular cyst, macular hole, solar retinopathy, diabetic retinopathy, branch retinal vein occlusion, or Lebers congenital amaurosis.
- a disease or disorder of the eye refers to any one or more of the following conditions: corneal graft rejection, uveitis, inflammatory eye diseases, infectious eye diseases, ocular tumours, neovascular proliferative diseases, neovascular maculopathies, rheumatoid corneal melting disorders, or autoimmune disorders.
- the method of the present invention may be used to prevent or treat any disorder or disease of the eye or associated with the eye, or in another embodiment, any ophthalmic disorder, hi one embodiment, the methods of the present invention may be used to prevent, suppress, inhibit or treat episcleritis, scleritis, or a combination thereof. In another embodiment, the methods of the present invention may be used to prevent, suppress, inhibit or treat retinopathy, including, inter alia, diabetic retinopathy, glaucoma, macular degeneration, retinal detachment, or a combination thereof.
- the methods of the present invention may be used to prevent, suppress, inhibit or treat any one or more of the following diseases or disorders, or symptoms as a result thereof: achromatopsia/Maskun, amblyopia, anisometropia, Argyll Robertson pupil, astigmatism, anisometropia, blindness, chalazion, color blindness, achromatopsia/Maskun, esotropia, exotropia, floaters, vitreous detachment, Fuchs' dystrophy, hype ⁇ netropia, hyperopia, hypertensive retinopathy, ulceris, keratoconus, Leber's congenital amaurosis, Leber's hereditary optic neuropathy, macular edema, myopia, nyctalopia, ophthalmoplegia, including progressive external ophthalmoplegia and internal opthalmoplegia, opthalmoparesis, presbyopia,
- the methods of the present invention may be used to prevent, suppress, inhibit or treat any one or more of the following diseases or disorders, or symptoms as a result thereof: neovascular glaucoma, retrolental fibroplasias, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, Sjogrens syndrome, acne rosacea, phylectenulosis, syphilis, lipid degeneration, chemical burns, Mooren ulcer, Terrien's marginal degeneration, marginal keratolysis, polyarteritis, trauma, Wegeners sarcoidosis, scleritis, Steven's Johnson disease, periphigoid radial keratotomy, sickle cell anemia, syphilis, pseudoxanthoma elasticum, Paget' s disease, vein occlusion, artery occlusion, carotid obstructive
- the methods of the present invention may be used in combination with or to prevent or treat secondary effects of: intraocular lens replacement; ophthalmic enucleation, evisceration, exenteration, or a combination thereof; lacrimal sac surgeries; corneal pterygium; lamellar keratoplasty; penetrating keratoplasty, or a combination thereof, as well as any of the disorders or conditions mentioned herein.
- the disease or disorder of the eye affects the anterior region of the eye, while in another embodiment, it affects the posterior region of the eye, while in another embodiment, it affects both the anterior and posterior regions of the eye.
- the anterior segment includes the cornea, anterior chamber, iris and ciliary body (anterior choroid), posterior chamber and crystalline lens and the posterior seqment includes the retina with optic nerve, choroid (posterior choroid) and vitreous.
- eye disorders resulting from the pathologic conditions of structures in the anterior segment of the eye are dry eye syndrome, keratitis or corneal dystrophy, cataracts, and glaucoma.
- the disease or disorders of the posterior segment of the eye in general are retinal or choroidal vascular diseases or hereditary diseases such as Lebers congenital amaurosis.
- treating refers to both therapeutic treatment and prophylactic or preventive measures, wherein the object is to prevent or lessen the targeted pathologic condition or disorder as described hereinabove.
- treating may include suppressing, inhibiting, preventing, treating, or a combination thereof.
- “treating” refers, inter alia, to increasing time to sustained progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof.
- preventing refers, inter alia, to delaying the onset of symptoms, preventing relapse to a disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, or a combination thereof.
- suppressing or “inhibiting”, refers, inter alia, to reducing the severity of symptoms, reducing the severity of an acute episode, reducing the number of symptoms, reducing the incidence of disease-related symptoms, reducing the latency of symptoms, ameliorating symptoms, reducing secondary symptoms, reducing secondary infections, prolonging patient survival, or a combination thereof.
- symptoms are primary, while in another embodiment, symptoms are secondary.
- primary refers to a symptom that is a direct result of an eye disease
- secondary refers to a symptom that is derived from or consequent to a primary cause.
- the compounds for use in the present invention treat primary or secondary symptoms or secondary complications related to an eye disease. In another embodiment, the compounds for use in the present invention treat primary or secondary symptoms or secondary complications related to an eye disease or disorder.
- symptoms may be any manifestation of a disease or pathological condition, comprising inflammation, swelling, fever, pain, bleeding, itching, runny nose, coughing, headache, migraine, dizziness, blurry vision, decreased visual acuity, light sensitivity, etc., or a combination thereof.
- symptoms comprise itchy eyes, swollen eyelids, redness, irritation, watery eyes, mucoid discharge, pain, or a combination thereof.
- the compounds for use in the present invention are directed towards the resolution of symptoms of a disease or disorder of the eye.
- the compounds affect the pathogenesis underlying a disease or disorder of the eye.
- a disease or disorder of the eye may affect a cell, in one embodiment, a vertebrate cell, in another embodiment, a mammalian cell, and in another embodiment, a human cell. It is to be understood that compounds of the present invention may be efficacious in treating any cell type in which a disease or disorder of the eye or the causes of a disease or disorder of the eye may exert an effect.
- a compound for use in the present invention may localize to or act on a specific cell type.
- a compound for use in the present invention may be cytoprotective.
- a compound for use in the present invention may be inserted or partially inserted into a cell membrane.
- a compound for use in the present invention may be effective in treating a plurality of cell types.
- a disease or disorder of the eye is a primary or secondary symptom of an underlying illness, which in one embodiment, is an autoimmune disease.
- the underlying illness is rheumatoid arthritis, systemic lupus erythematosus, Kawasaki's Disease, ulcerative colitis, Crohn's Disease, ankylosing spondylitis, Behcet's syndrome, psoriasis, Reiter's syndrome, sarcoidosis, diabetes, multiple sclerosis, etc., or any combination thereof.
- the methods of the present invention may be used to treat a disease or disorder of the eye in a subject that is immunosuppressed, while in another embodiment, in a subject that is immunodeficient, while in another embodiment, in a subject that is immunocompetent.
- the methods of the present invention may be used to prevent or treat glaucoma.
- glaucoma is characterized by increased fluid pressure in the eye, which in one embodiment, is due to slowed fluid drainage from the eye.
- glaucoma may damage the optic nerve and other parts of the eye, lead to vision loss or blindness, or a combination thereof, hi one embodiment, glaucoma may refer to primary open angle glaucoma, normal pressure glaucoma, normal tension glaucoma, pigmentary glaucoma, pseudoexfoliation glaucoma, acute angle closure glaucoma, absolute glaucoma chronic glaucoma, congenital glaucoma, juvenile glaucoma, narrow angle glaucoma, chronic open angle glaucoma, simplex glaucoma, primary congenital glaucoma, secondary glaucoma, or a combination thereof.
- the methods of the present invention may be used to prevent or treat macular degeneration.
- macular degeneration is characterized by damage to or breakdown of the macula, which in one embodiment, is a small area at the back of the eye.
- macular degeneration causes a progressive loss of central sight, but not complete blindness.
- macular degeneration is of the dry type, while in another embodiment, it is of the wet type.
- the dry type is characterized by the thinning and loss of function of the macula tissue.
- the wet type is characterized by the growth of abnormal blood vessels behind the macula.
- the abnormal blood vessels hemorrhage or leak resulting in the formation of scar tissue if untreated.
- the dry type of macular degeneration can turn into the wet type.
- macular degeneration is age-related, which in one embodiment is caused by an ingrowth of chorioidal capillaries through defects in Bruch's membrane with proliferation of fibrovascular tissue beneath the retinal pigment epithelium.
- the methods of the present invention may be used to prevent or treat retinopathy.
- retinopathy refers to a disease of the retina, which in one embodiment is characterized by inflammation and in another embodiment, is due to blood vessel damage inside the eye.
- retinopathy is diabetic retinopathy which, in one embodiment, is a complication of diabetes that is caused by changes in the blood vessels of the retina.
- retinopathy is proliferative retinopathy, which in one embodiment, is characterized by the growth of new, abnormal blood vessels on the surface of the retina (neovascularization), hi one embodiment, neovascularization around the pupil increases pressure within the eye, which in one embodiment, leads to glaucoma, hi another embodiment, neovascularization leads to new blood vessels with weaker walls that break and bleed, or cause scar tissue to grow, which in one embodiment, pulls the retina away from the back of the eye (retinal detachment).
- the pathogenesis of retinopathy is related to non-enzymatic glycation, glycoxidation, accumulation of advanced glycation end-products, free radical-mediated protein damage, up-regulation of matrix metalloproteinases, elaboration of growth factors, secretion of adhesion molecules in the vascular endothelium, or a combination thereof.
- macular edema leads to macular edema, which in one embodiment, is swelling of the retina.
- macular edema is characterized by retinal blood vessels that develop tiny leaks, which in one embodiment, allow blood and fluid to seep from the retinal blood vessels, and fatty material (called exudate) to deposit in the retina.
- symptoms of macular edema comprise impaired or blurred vision.
- retinopathy refers to retinopathy of prematurity
- ROP reactive oxygen species
- retinopathy of prematurity is caused by a therapy necessary to promote the survival of a premature infant.
- retinopathy refers to arteriosclerotic retinopathy, which in one embodiment, is due to arteriosclerosis (hardening of the arteries).
- retinopathy refers to hypertensive retinopathy, which in one embodiment, is due to high blood pressure.
- retinopathy refers to solar retinopathy, while in another embodiment, it refers to drug-related retinopathy.
- the methods of the present invention may be used to prevent or treat retinal detachment, including, inter alia, rhegmatogenous, fractional, or exudative retinal detachment, which in one embodiment, is the separation of the retina from its supporting layers.
- retinal detachment is associated with a tear or hole in the retina through which the internal fluids of the eye may leak.
- retinal detachment is caused by trauma, the aging process, severe diabetes, an inflammatory disorder, neovascularization, or retinopathy of prematurity, while in another embodiment, it occurs spontaneously.
- bleeding from small retinal blood vessels may cloud the vitreous during a detachment, which in one embodiment, may cause blurred and distorted images.
- a retinal detachment can cause severe vision loss, including blindness.
- the useful pharmacological properties of the compounds for use in the present invention may be applied for clinical use, and disclosed herein as methods for the prevention or treatment of a disease.
- the biological basis of these methods may be readily demonstrated by standard cellular and animal models of disease, for example, as described in the Examples hereinbelow.
- the pharmacological activities of compounds for use in the present invention may contribute to the resistance of a treated cell to diseases of the eye.
- cell membrane stabilization may ameliorate or prevent tissue injury arising in the course of an eye disease.
- anti-oxidant action may limit oxidative damage to cell and blood components arising in the course of an eye disease.
- attenuation of chemokine levels may attenuate physiological reactions to stress that arise in the course of an eye disease.
- the compounds for use in the present invention described herein can be used to treat disease, through amelioration or prevention, of tissue injury arising in the course of pathological disease states by stabilizing cell membranes; limiting oxidative damage to cell and blood components; or attenuating physiological reactions to stress, as expressed in elevated chemokine levels.
- methods of the present invention involve treating a subject by, inter alia, controlling the expression, production, and activity of phospholipases such as PLA2; controlling the production and/or action of lipid mediators, such as eicosanoids, platelet activating factor (PAF) and lyso- phospholipids; amelioration of damage to cell surface glycosaminoglycans (GAG) and proteoglycans; controlling the production of oxidants, oxygen radicals and nitric oxide; protection of cells, tissues, and plasma lipoproteins from damaging agents, such as reactive oxygen species (ROS) and phospholipases; controlling the expression, production, and activity of cytokines, chemokines and interleukins; anti-oxidant therapy; anti-endotoxin therapy or any combination thereof.
- phospholipases such as PLA2
- lipid mediators such as eicosanoids, platelet activating factor (PAF) and lyso- phospholipids
- GAG cell surface glycosamino
- controlling refers to inhibiting the production and action of the above mentioned factors in order to maintain their activity at the normal basal level and suppress their activation in pathological conditions.
- eye disease is characterized by the presence of damaging agents, which comprise, inter alia, phospholipases, reactive oxygen species (ROS), free radicals, lysophospholipids, fatty acids or derivatives thereof, hydrogen peroxides, phospholipids, oxidants, cationic proteins, streptolysins, proteases, hemolysins, or sialidases.
- damaging agents comprise, inter alia, phospholipases, reactive oxygen species (ROS), free radicals, lysophospholipids, fatty acids or derivatives thereof, hydrogen peroxides, phospholipids, oxidants, cationic proteins, streptolysins, proteases, hemolysins, or sialidases.
- This invention encompasses administration of compounds as described herein or compositions comprising the same, for treating diseases of the eye.
- compositions of this invention are pharmaceutically acceptable.
- pharmaceutically acceptable refers to any formulation which is safe, and provides the appropriate delivery for the desired route of administration of an effective amount of at least one compound for use in the present invention. This term refers to the use of buffered formulations as well, wherein the pH is maintained at a particular desired value, ranging from pH 4.0 to pH 9.0, in accordance with the stability of the compounds and route of administration.
- any of the compositions of this invention will comprise a lipid conjugate, in any form or embodiment as described herein. In some embodiments, any of the compositions of this invention will consist of a lipid conjugate, in any form or embodiment as described herein. In some embodiments, of the compositions of this invention will consist essentially of a lipid conjugate, in any form or embodiment as described herein.
- the term "comprise” refers to the inclusion of the indicated active agent, such as the Compounds I- C, as well as inclusion of other active agents, and pharmaceutically acceptable carriers, excipients, emollients, stabilizers, etc., as are known in the pharmaceutical industry.
- the term “consisting essentially of” refers to a composition, whose only active ingredient is the indicated active ingredient, however, other compounds may be included which are for stabilizing, preserving, etc. the formulation, but are not involved directly in the therapeutic effect of the indicated active ingredient.
- the term “consisting essentially of may refer to components which facilitate the release of the active ingredient.
- the term “consisting” refers to a composition, which contains the active ingredient and a pharmaceutically acceptable carrier or excipient.
- a compound used in the methods of this invention may be administered alone or within a composition.
- compositions comprising compounds for use in the present invention in admixture with conventional excipients, i.e. pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral (e.g. oral) or topical application which do not deleteriously react with the active compounds may be used.
- suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, polyethylene glycols, gelatine, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, white paraffin, glycerol, alginates, hyaluronic acid, collagen, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose, polyvinyl pyrrolidone, etc.
- the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g.
- lubricants preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds.
- they can also be combined where desired with other active agents, e.g. vitamins.
- the therapeutic compositions of the instant invention comprise a compound of the instant invention and additional compounds effective in preventing or treating eye disease.
- the additional compounds comprise anti-inflammatory compositions, which in one embodiment are non-steroidal anti-inflammatory medications, antihistamines, antibiotics, corticosteroids, cromolyn sodium (sodium cromoglicate), mast-cell stabilizers, artificial tears, lubricants, or a combination thereof.
- antibiotics comprise chloramphenicol, fusidic acid, tetracycline, erythromycin, gentamycin, or a combination thereof.
- an additional compound is vitamin A.
- the therapeutic compositions of the instant invention are administered with other treatments that relieve symptoms.
- other treatments comprise application of cold compresses, while in another embodiment, warm compresses.
- the route of administration may be parenteral, enteral, or a combination thereof.
- the route may be intraocular, topical, transdermal, intradermal, subcutaneous, intraperitoneal, intravenous, intra-arterial, vaginal, rectal, intratumoral, parcanceral, transmucosal, intramuscular, intravascular, intraventricular, intracranial, inhalation, nasal aspiration (spray), sublingual, oral, aerosol or suppository or a combination thereof.
- the dosage regimen will be determined by skilled clinicians, based on factors such as exact nature of the condition being treated, the severity of the condition, the age and general physical condition of the patient, etc.
- intra-ocular application eye drops, ointments, lotions, creams, or coated eye patches may be used in one embodiment.
- intraocular application may comprise the use of contact lens comprising the compounds of the instant invention.
- intra-ocular application is used to treat an eye condition or disease.
- intra-ocular injection is used to treat an eye condition or disease.
- compounds may be administered intravitreally, in another embodiment, subretinally, while in another embodiment, intra-retinally, while in another embodiment, periocularly.
- compounds may be administered intracamerally into the anterior chamber or vitreous, via a depot attached to the intraocular lens implant inserted during surgery, or via a depot placed in the eye sutured in the anterior chamber or vitreous.
- injectable, sterile solutions preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories and enemas.
- Ampoules are convenient unit dosages.
- Such a suppository may comprise any agent described herein.
- solutions or suspensions of the compounds mixed and aerosolized or nebulized in the presence of the appropriate carrier suitable may comprise any agent described herein and, in one embodiment, may be used to treat diseases or conditions caused by airborne pathogens, which may in one embodiment, cause sinusitis or upper respiratory infections, in addition to eye diseases.
- an admixture of the compounds with conventional creams, lotions, or delayed release patches is acceptable.
- a cream or lotion may comprise any agent described herein, and, in one embodiment, may be used to treat an eye disease.
- Suitable enteral application particularly suitable are tablets, dragees, liquids, drops, or capsules.
- a syrup, elixir, or the like can be used when a sweetened vehicle is employed.
- Sustained or directed release compositions can be formulated, e.g. liposomes or those wherein the active compound is protected with differentially degradable coatings, e.g. by microencapsulation, multiple coatings, etc. It is also possible to freeze-dry the new compounds and use the lyophilisates obtained, for example, for the preparation of products for injection.
- the route of administration may be directed to an organ or system that is affected by an eye disease.
- compounds may be administered in intra-ocular form to treat an eye disease.
- the route of administration may be directed to a different organ or system than the one that is affected by an eye disease.
- compounds may be administered parenterally to treat an eye disease.
- the present invention provides for the use of compounds of the instant invention in various dosage forms suitable for administration using any of the routes listed hereinabove.
- the doses utilized for the above described purposes will vary, but will be in an effective amount to exert the desired effect.
- the term "pharmaceutically effective amount” refers to an amount of a compound of formulae A and I-LXXXVII as described hereinbelow, which will produce the desired alleviation in symptoms or other desired phenotype in a patient.
- the doses utilized for any of the above-described purposes will generally be from 1 to about 1000 milligrams per kilogram of body weight (mg/kg), administered one to four times per day, or by continuous IV infusion. When the compositions are dosed topically or intraocularly, they will generally be in a concentration range of from 0.1 to about 10% w/v, administered 1-4 times per day.
- the concentrations of the compounds will depend on various factors, including the nature of the condition to be treated, the condition of the patient, the route of administration and the individual tolerability of the compositions.
- the compounds of the invention may be administered acutely for acute treatment of temporary conditions, or may be administered chronically, especially in the case of progressive, recurrent, or degenerative disease.
- one or more compounds of the invention may be administered simultaneously, or in another embodiment, they may be administered in a staggered fashion. In one embodiment, the staggered fashion may be dictated by the stage or phase of the disease.
- the present invention offers methods for the treatment of disease based upon administration of lipids covalently conjugated through their polar head group to a physiologically acceptable chemical moiety, which may be of high or low molecular weight.
- the present invention has been illustrated in terms of the anti-disease activity of compounds for use in the present invention and methods of their use as pharmaceutical compositions in the treatment of disease.
- the following sections present some examples of the therapeutic compounds for use in the present invention and their chemical preparation.
- the compounds for use in the present invention or for the compositions of the present invention comprise a lipid or phospholipid moiety bound to a physiologically acceptable monomer, dimer, oligomer, or polymer.
- the physiologically acceptable monomer, dimer, oligomer, or polymer is salicylate, salicylic acid, aspirin, a monosaccharide, lactobionic acid, maltose, an amino acid, glycine, carboxylic acid, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid, fatty acid, dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesterylhemmisuccinate, a dipeptide, a disaccharide, a trisaccharide, an oligosaccharide, a polysaccharide, a hetero-polysaccharide, a homo-polysaccharide, a
- examples of polymers which can be employed as the conjugated moiety for producing compounds for use in the present invention for use in the methods of this invention may be physiologically acceptable polymers, including water-dispersible or -soluble polymers of various molecular weights and diverse chemical types, mainly natural and synthetic polymers, such as glycosaminoglycans, hyaluronic acids, heparin, heparin sulfates, chondroitin sulfates, chondroitin-6-sulfates, chondroitin-4-sulfates, keratins, keratin sulfates, dermatins, dermatan sulfates, dextrans, plasma expanders, including polygeline (“Haemaccel", degraded gelatin polypeptide cross-linked via urea bridges, produced by "Behring"), "hydroxyethylstarch” (Hetastarch, HES) and extrans, food and drug additives, soluble cellulose
- methylcellulose, carboxymethylcellulose), polyaminoacids, hydrocarbon polymers e.g. polyethylene
- polystyrenes polyesters
- polyamides polyethylene oxides (e.g. polyethyleneglycols, polycarboxyethyleneglycols, polycarboxylated polyethyleneglycols), polyvinnylpyrrolidones, polysaccharides, polypyranoses, alginates, assimilable gums (e.g. xanthan gum), peptides, injectable blood proteins (e.g. serum albumin), cyclodextrin, and derivatives thereof.
- hydrocarbon polymers e.g. polyethylene
- polystyrenes polyesters
- polyamides polyethylene oxides
- polyethyleneglycols polycarboxyethyleneglycols, polycarboxylated polyethyleneglycols
- polyvinnylpyrrolidones polysaccharides
- polypyranoses alginates
- examples of monomers, dimers, and oligomers which can be employed as the conjugated moiety for producing compounds for use in the present invention for use in the methods of the invention may be mono- or disaccharides, trisaccharides, oligopeptides, carboxylic acids, dicarboxylic acids, fatty acids, dicarboxylic fatty acids, salicylates, slicyclic acids, acetyl salicylic acids, aspirins, lactobionic acids, maltoses, amino acids, glycines, glutaric acids, succinic acids, dodecanoic acids, didodecanoic acids, bile acids, cholic acids, cholesterylhemisuccinates, and di- and trisaccharide unit monomers of polysaccharides, polypyranoses, and/or glycosaminoglycans including heparins, heparan sulfates, hyaluronic acids, chondroitins
- lipid compounds for use in the present invention are described by the general formula:
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms; and X is a physiologically acceptable monomer, dimer, oligomer or polymer; and n is the number of lipid molecules bound to a molecule of X, wherein n is a number from 1 to 1000. In another embodiment, n is a number from 2 to 1000.
- the invention provides low-molecular weight compounds, previously undisclosed and unknown to possess pharmacological activity, of the general formula described hereinabove.
- X is a mono- or disaccharide, carboxylated disaccharide, mono- or dicarboxylic acids, a salicylate, salicylic acid, aspirin, lactobionic acid, maltose, an amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid, fatty acid, dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesterylhemmisuccinate, a di- or tripeptide, an oligopeptide, a trisacharide, or a di- or trisaccharide monomer unit of heparin, heparan sulfate,
- X is any of the physiologically acceptable monomer, dimer, oligomer, or polymer, as described herein.
- X is conjugated to the lipid, phospholipid, or spacer via an ester bond.
- X is conjugated to the lipid, phospholipid, or spacer via an amide bond.
- n is a number from 1 to 1000. In another embodiment, n is a number from 1 to 500. In another embodiment, n is a number from 1 to 100. In another embodiment, n is a number from 1 to 50. In another embodiment, n is a number from 1 to 25. In another embodiment, n is a number from 1 to 10. In another embodiment, n is a number from 1-5. In another embodiment, n is a number from 1 to 4.
- n is a number from 1 to 3, In another embodiment, n is a number from 1 to 2. hi another embodiment, n is a number from 2 to 1000. In another embodiment, n is a number from 2 to 100. In another embodiment, n is a number from 2 to 200. In another embodiment, n is a number from 2 to 50. In another embodiment, n is a number from 2 to 25. In another embodiment, n is a number from 2-10. In another embodiment, n is a number from 2 to 5. In another embodiment, n is a number from 2 to 4, In another embodiment, n is a number from 2 to 3. In another embodiment, n is a number from 3 to 300. In another embodiment, n is a number from 10 to 400.
- n is a number from 50 to 500. In another embodiment, n is a number from 100 to 300. In another embodiment, n is a number from 300 to 500. In another embodiment, n is a number from 500 to 800. In another embodiment, n is a number from 500 to 1000.
- the ratio of lipid moieties covalently bound may range from one to one thousand lipid residues per polymer molecule, depending upon the nature of the polymer and the reaction conditions employed. For example, the relative quantities of the starting materials, or the extent of the reaction time, may be modified in order to obtain products with either high or low ratios of lipid residues per polymer, as desired.
- the set of compounds comprising phosphatidylethanolamine covalently bound to a physiologically acceptable monomer, dimmer, oligomer, or polymer is referred to herein as the PE- conjugates
- the phosphatidylethanolamine moiety is dipalmitoyl phosphatidylethanolamine.
- the phosphatidylethanolamine moiety is dimyristoyl phosphatidylethanolamine.
- related derivatives in which either phosphatidylserine, phosphatidylcholine, phosphatidylinositol, phosphatidic acid or phosphatidylglycerol are employed in lieu of phosphatidylethanolamine as the lipid moiety provide equivalent therapeutic results, based upon the biological experiments described below for the compounds for use in the present invention and the structural similarities shared by these compounds.
- the lipid or phospholipid moiety is phosphatidic acid, an acyl glycerol, monoacylglycerol, diacylglycerol, triacylglycerol, sphingosine, sphingomyelin, chondroitin-4-sulfate, chondroitin-6-sulfate, ceramide, phosphatidylethanolamine, phosphatidylserine, phosphatidylcholine, phosphatidylinositol, or phosphatidylglycerol, or an ether or alkyl phospholipid derivative thereof.
- derivatives relevant to this invention are compounds wherein at least one of the fatty acid groups of the lipid moieties at position Cl or C2 of the glycerol backbone are substituted by a long chain alkyl group attached by amide, ether or alkyl bonds, rather than ester linkages.
- the compounds for use in the present invention administered to the subject are comprised from at least one lipid moiety covalently bound through an atom of the polar head group to a monomelic or polymeric moiety (referred to herein as the conjugated moiety) of either low or high molecular weight.
- a monomelic or polymeric moiety referred to herein as the conjugated moiety
- an optional bridging moiety can be used to link the compounds for use in the present invention moiety to the monomer or polymeric moiety.
- the conjugated moiety may be a low molecular weight carboxylic acid, dicarboxylic acid, fatty acid, dicarboxylic fatty acid, acetyl salicylic acid, cholic acid, cholesterylhemisuccinate, or mono- or di-saccharide, an amino acid or dipeptide, an oligopeptide, a glycoprotein mixture, a di- or trisaccharide monomer unit of a glycosaminoglycan such as a repeating unit of heparin, heparan sulfate, hyaluronic acid, chondroitin- sulfate, dermatan, keratan sulfate, or a higher molecular weight peptide or oligopeptide, a polysaccharide, a hetero-polysaccharide, a homo-polysaccharide, a polypyranose, polyglycan, protein, glycosaminoglycan, or a glycoprotein mixture.
- the term "moiety” means a chemical entity otherwise corresponding to a chemical compound, which has a valence satisfied by a covalent bond.
- the monomer or polymer chosen for preparation of the compound may in itself have select biological properties.
- both heparin and hyaluronic acid are materials with known physiological functions.
- the compounds for use in the present invention formed from these substances as starting materials display a new and wider set of pharmaceutical activities than would be predicted from administration of either heparin or hyaluronic acid which have not been bound by covalent linkage to a phospholipid.
- phosphatidylethanolamine (PE) linked to hyaluronic acid (Compound XXII), to heparin (Compound XXIV), to chondroitin sulfate A (Compound XXV), to carboxymethylcellulose (Compound XXVI), to Polygeline (haemaccel) (Compound XXVII), to alginate (Compound LI), or to hydroxyethylstarch (Compound XXVIII)
- PE phosphatidylethanolamine linked to hyaluronic acid
- Compound XXIV to heparin
- to chondroitin sulfate A (Compound XXV)
- carboxymethylcellulose Compound XXVI
- Polygeline (haemaccel)
- Compound XXVII to alginate
- Compound LI or to hydroxyethylstarch
- a phospholipid such as phosphatidylethanolamine, or related phospholipids which differ with regard to the polar head group, such as phosphatidylserine (PS), phosphatidylcholine (PC), phosphatidylinositol (PI), and phosphatidylglycerol (PG)
- PS phosphatidylserine
- PC phosphatidylcholine
- PI phosphatidylinositol
- PG phosphatidylglycerol
- properties may include: greater lubrication, greater local persistence, greater anti-inflammatory properties, greater antioxidant activity, or a combination thereof.
- the biologically active compounds for use in the present invention described herein can have a wide range of molecular weights, e.g.
- the compound for use in the present invention is represented by the structure of the general formula (A):
- L is a lipid or a phospholipid
- Z is either nothing, ethanolamine, serine, inositol, choline, phosphate, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a physiologically acceptable monomer, dimer, oligomer, or polymer; and n is a number from 1 to 1000; wherein any bond between L, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (A):
- L is a lipid or a phospholipid
- Z is either nothing, ethanolamine, serine, inositol, choline, phosphate, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a physiologically acceptable monomer, dimer, oligomer, or polymer; and n is a number from 2 to 1000; wherein any bond between L, Z, Y and X is either an amide or an esteric bond.
- L is phosphatidyl
- Z is ethanolamine, wherein L and Z are chemically bonded resulting in phosphatidylethanolamine, Y is nothing, and X is carboxymethylcellulose.
- L is phosphatidyl
- Z is ethanolamine, wherein L and Z are chemically bonded resulting in phosphatidylethanolamine, Y is nothing, and X is a glycosaminoglycan.
- the phosphatidylethanolamine moiety is dipalmitoyl phosphatidylethanolamine.
- the phosphatidylethanolamine moiety is dimyristoyl phosphatidylethanolamine.
- the compound for use in the present invention is represented by the structure of the general formula (I):
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms.
- X is either a physiologically acceptable monomer, dimer, oligomer or a physiologically acceptable polymer; and n is a number from 1 to 1,000; wherein if Y is nothing the phosphatidylethanolamine is directly linked to X via an amide bond and if Y is a spacer, the spacer is directly linked to X via an amide or an esteric bond and to the phosphatidylethanolamine via an amide bond.
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms.
- X is either a physiologically acceptable monomer, dimer, oligomer or a physiologically acceptable polymer; and n is a number from 2 to 1 ,000; wherein if Y is nothing the phosphatidylethanolamine is directly linked to X via an amide bond and if Y is a spacer, the spacer is directly linked to X via an amide or an esteric bond and to the phosphatidylethanolamine via an amide bond.
- compounds for use in the methods of the invention comprise one of the following as the conjugated moiety X: acetate, butyrate, glutarate, succinate, dodecanoate, didodecanoate, maltose, lactobionic acid, dextran, alginate, aspirin, cholate, cholesterylhemisuccinate, carboxymethyl- cellulose, heparin; hyaluronic acid, chondroitin sulfate, polygeline (haemaccel), hydroxyethylstarch (Hetastarch, HES) polyethyleneglycol, polycarboxylated polyethylene glycol, a glycosaminoglycan, a polysaccharide, a hetero- polysaccharide, a homo-polysaccharide, or a polypyranose.
- the polymers used as starting material to prepare the PE-conjugates may vary in molecular weight from 1 to 2,000 kDa.
- Examples of phosphatidylethanolamine (PE) moieties are analogues of the phospholipid in which the chain length of the two fatty acid groups attached to the glycerol backbone of the phospholipid varies from 2-30 carbon atoms length, and in which these fatty acids chains contain saturated and/or unsaturated carbon atoms.
- alkyl chains attached directly or via an ether linkage to the glycerol backbone of the phospholipid are included as analogues of PE.
- the PE moiety is dipalmitoyl-phosphatidyl-ethanolamine.
- the PE moiety is dimyristoyl-phosphatidyl-ethanolamine.
- Phosphatidyl-ethanolamine and its analogues may be from various sources, including natural, synthetic, and semi-synthetic derivatives and their isomers.
- Phospholipids which can be employed in lieu of the PE moiety are N- methyl-PE derivatives and their analogues, linked through the amino group of the N-methyl-PE by a covalent bond; N,N-dimethyl-PE derivatives and their analogues linked through the amino group of the N,N-dimethyl-PE by a covalent bond, phosphatidylserine (PS) and its analogues, such as palmitoyl-stearoyl-PS, natural PS from various sources, semi-synthetic PSs, synthetic, natural and artifactual PSs and their isomers.
- PS phosphatidylserine
- phospholipids useful as conjugated moieties in this invention are phosphatidylcholine (PC), phosphatidylinositol (PI), phosphatidic acid and phosphoatidylglycerol (PG), as well as derivatives thereof comprising either phospholipids, lysophospholipids, phosphatidic acid, sphingomyelins, lysosphingomyelins, ceramide, and sphingosine.
- PC phosphatidylcholine
- PI phosphatidylinositol
- PG phosphoatidylglycerol
- the phospholipid is linked to the conjugated monomer or polymer moiety through the nitrogen atom of the phospholipid polar head group, either directly or via a spacer group.
- the phospholipid is linked to the conjugated monomer or polymer moiety through either the nitrogen or one of the oxygen atoms of the polar head group, either directly or via a spacer group.
- the compound for use in the present invention is represented by the structure of the general formula (II):
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein if Y is nothing, the phosphatidylserine is directly linked to X via an amide bond and if Y is a spacer, the spacer is directly linked to X via an amide or an esteric bond and to the phosphatidylserine via an amide bond.
- the compound for use in the present invention is represented by the structure of the general formula (II):
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms;
- X is a glycosaminoglycan; and
- n is a number from 2 to 1000; wherein if Y is nothing, the phosphatidylserine is directly linked to X via an amide bond and if Y is a spacer, the spacer is directly linked to X via an amide or an esteric bond and to the phosphatidylserine via an amide bond.
- the phosphatidylserine may be bonded to Y, or to X if Y is nothing, via the COO ' moiety of the phosphatidylserine.
- R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the phosphatidyl, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (IV):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms;
- X is a glycosaminoglycan; and
- n is a number from 1 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (III):
- R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; [0091] wherein any bond between the phosphatidyl, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (IV):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (IV):
- R 1 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (V):
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (V):
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan
- /i is a number from 2 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (VI):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (VI):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (VII):
- R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, inositol, choline, or glycerol
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- phosphatidylcholine PC
- PI phosphatidylinositol
- PA phosphatidic acid
- Z Z is nothing
- phosphatidylglycerol (PG) conjugates are herein defined as compounds of the general formula (III).
- the compound for use in the present invention is represented by the structure of the general formula (VIII):
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (IX):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (DC):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (IXa):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (IXa):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (IXb):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- DCb general formula
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the phospholipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (X):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the ceramide phosphoryl, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (X):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; [00111] wherein any bond between the ceramide phosphoryl, Z, Y and X is either an amide or an esteric bond.
- R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms;
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein if Y is nothing the sphingosyl is directly linked to X via an amide bond and if Y is a spacer, the spacer is directly linked to X and to the sphingosyl via an amide bond and to X via an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XI):
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms;
- X is a glycosaminoglycan; and
- n is a number from 2 to 1000; wherein if Y is nothing the sphingosyl is directly linked to X via an amide bond and if Y is a spacer, the spacer is directly linked to X and to the sphingosyl via an amide bond and to X via an amide or an esteric bond.
- R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms;
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the ceramide, Z, Y and X is either an amide or an esteric bond.
- XII the compound for use in the present invention is represented by the structure of the general formula (XII):
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, ethanolamine, serine, inositol, choline, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the ceramide, Z, Y and X is either an amide or an esteric bond.
- R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the diglyceryl, Z, Y and X is either an amide or an esteric bond.
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the diglyceryl, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XTV):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and 11 is a number from 1 to 1000; wherein any bond between the glycerolipid, Z, Y and X is either an amide or an esteric bond.
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms;
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the glycerolipid, Z, Y and X is either an amide or an esteric bond.
- R 1 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the glycerolipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XV):
- Ri is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the glycerolipid, Z, Y and X is either an amide or an esteric bond.
- XVI the compound for use in the present invention is represented by the structure of the general formula (XVI):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XVI):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms; X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XVII):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XVII):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XVIH):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol; Y is either nothing or a spacer group ranging in length from 2 to 30 atoms;
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XVIII):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XDC):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms;
- X is a glycosaminoglycan;
- D is a number from 2 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XX):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XXI):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 1 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- the compound for use in the present invention is represented by the structure of the general formula (XXI):
- Ri is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- R 2 is either hydrogen or a linear, saturated, mono-unsaturated, or poly-unsaturated, alkyl chain ranging in length from 2 to 30 carbon atoms;
- Z is either nothing, choline, phosphate, inositol, or glycerol;
- Y is either nothing or a spacer group ranging in length from 2 to 30 atoms
- X is a glycosaminoglycan; and n is a number from 2 to 1000; wherein any bond between the lipid, Z, Y and X is either an amide or an esteric bond.
- X is a glycosaminoglycan.
- the glycosaminoglycan may be, inter alia, hyaluronic acid, heparin, heparan sulfate, chondroitin sulfate, keratin, keratan sulfate, dermatan sulfate or a derivative thereof.
- X is not a glycosaminoglycan.
- X is a polysaccharide, which in one embodiment is a hetero-polysaccharide, and in another embodiment, is a homo-polysaccharide.
- X is a polypyranose.
- the glycosaminoglycan is a polymer of disaccharide units.
- the number of the disaccharide units in the polymer is m.
- m is a number from 2-10,000.
- m is a number from 2-500.
- m is a number from 2-1000.
- m is a number from 50-500.
- m is a number from 2-2000.
- m is a number from 500-2000.
- m is a number from 1000-2000.
- m is a number from 2000-5000. In another embodiment, m is a number from 3000-7000. In another embodiment, m is a number from 5000-10,000.
- a disaccharide unit of a glycosaminoglycan may be bound to one lipid or phospholipid moiety. In another embodiment, each disaccharide unit of the glycosaminoglycan may be bound to zero or one lipid or phospholipid moieties. In another embodiment, the lipid or phospholipid moieties are bound to the -COOH group of the disaccharide unit, hi another embodiment, the bond between the lipid or phospholipid moiety and the disaccharide unit is an amide bond.
- the compound of the present invention comprises a glycosaminoglycan (GAG), and further comprises total phospholipid such that the molar ratio between the phospholipid and the GAG is in the range of between 1.5:1 to 20:1. In another embodiment, the molar ratio between the phospholipid and the GAG is in the range of between 1.5:1 to 10:1. In another embodiment, the molar ratio between the phospholipid and the GAG is in the range of between
- the molar ration between the phospholipid and the GAG is 1.5:1. In another embodiment, the molar ration between the phospholipid and the GAG is 2:1. In another embodiment, the molar ration between the phospholipid and the GAG is 3:1. In another embodiment, the molar ration between the phospholipid and the GAG is 5:1. hi another embodiment, the molar ration between the phospholipid and the GAG is 10:1. In another embodiment, the molar ration between the phospholipid and the GAG is 20: 1.
- the compound of the present invention comprises a glycosaminoglycan (GAG) with a molecular weight in the range of between 30- 100 kD.
- the GAG has a molecular weight in the range of between 30-80 kD.
- the GAG has a molecular weight in the range of between 30-50 kD.
- the GAG has a molecular weight in the range of between 20-80 kD.
- the GAG has a molecular weight in the range of between 20-50 kD.
- the chondroitin sulfate may be, inter alia, chondroitin-6-sulfate, chondroitin-4-sulfate or a derivative thereof.
- Y is nothing.
- suitable divalent groups forming the optional bridging group (which in one embodiment, is referred to as a spacer) Y are straight or branched chain alkylene, e.g.
- related derivatives for use in this invention are phospholipids modified at the Cl or C2 position to contain an amine, ether or alkyl bond instead of an ester bond.
- the alkyl phospholipid derivatives and ether phospholipid derivatives are exemplified herein.
- the sugar rings of the glycosaminoglycan are intact, hi another embodiment, intact refers to closed, hi another embodiment, intact refers to natural. In another embodiment, intact refers to unbroken.
- the structure of the lipid or phospholipid in any compound according to the invention is intact. In another embodiment, the natural structure of the lipid or phospholipids in any compound according to the invention is maintained.
- the compounds for use in the present invention are biodegradable.
- the compound according to the invention is phosphatidylethanolamine bound to aspirin. In one embodiment, the compound according to the invention is phosphatidylethanolamine bound to glutarate.
- the compounds for use are as listed in Table 1 below.
- the compounds for use in the present invention are any one or more of Compounds I-C.
- the invention provides a composition comprising any combination of any of the compounds of the invention or the use of any combination of any of the compounds of the invention.
- the invention provides a composition comprising Compounds XCIX, C, or a combination thereof and uses thereof.
- the invention provides a composition comprising
- the compounds for use in the present invention are Compound XXII, Compound XXIII, Compound XXIV, Compound XXV, Compound XXVI 5 Compound XXVII, Compound XXVIIL Compound XXIX, Compound XXX, Compound LI, or pharmaceutically acceptable salts thereof, in combination with a physiologically acceptable carrier or solvent.
- these polymers when chosen as the conjugated moiety, may vary in molecular weights from 200 to 2,000,000 Daltons.
- the molecular weight of the polymer as referred to herein is from 200 to 1000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 200 to 1000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 1000 to 5000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 5000 to 10,000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 10,000 to 20,000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 10,000 to 50,000 Daltons.
- the molecular weight of the polymer as referred to herein is from 20,000 to 70,000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 50,000 to 100,000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 100,000 to 200,000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 200,000 to 500,000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 200,000 to 1 ,000,000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 500,000 to 1,000,000 Daltons. In another embodiment, the molecular weight of the polymer as referred to herein is from 1,000,000 to 2,000,000 Daltons. Various molecular weight species have been shown to have the desired biological efficacy.
- AIgPE has a molecular weight of approximately 120 kD
- CSAPE has a molecular weight of approximately 100 kD
- HemPE has a molecular weight of approximately 75 kD
- HesDMPE has a molecular weight of approximately 90 kD
- CMPE has a molecular weight of approximately 75 kD, or a combination thereof.
- “approximately” refers to up to 5%
- low molecular weight compounds for use in the present invention are defined hereinabove as the compounds of formula (I)-(XXI) wherein X is a mono- or disaccharide, carboxylated disaccharide, mono- or dicarboxylic acids, a salicylate, salicylic acid, aspirin, lactobionic acid, maltose, an amino acid, glycine, acetic acid, butyric acid, dicarboxylic acid, glutaric acid, succinic acid, fatty acid, dodecanoic acid, didodecanoic acid, bile acid, cholic acid, cholesterylhemmisuccinate, a di- or tripeptide, an oligopeptide, a trisacharide, or a di- or trisaccharide monomer unit of heparin, heparan sulfate, keratin, keratan sulfate, chondroitin, chondroitin, chondroitin, chondroit
- suitable divalent groups forming the optional bridging group Y are straight- or branched -chain alkylene, e.g. of 2 or more, preferably 4 to 18 carbon atoms, — CO — alkylene — CO, — NH — alkylene — NH — , — CO — alkylene — NH — , cycloalkylene, wherein alkylene in each instance, is straight or branched chain and contains 2 or more, preferably 2 to 18 carbon atoms in the chain, — ( — O — CH(CH 3 )CH 2 — ) x — wherein x is an integer of 1 or more.
- related derivatives for use in this invention are phospholipids modified at the Cl or C2 position to contain an ether or alkyl bond instead of an ester bond. These derivatives are exemplified hereinabove by the general formulae (VIII) and (IX).
- X is covalently conjugated to a lipid.
- X is covalently conjugated to a lipid via an amide bond.
- X is covalently conjugated to a lipid via an esteric bond.
- the lipid is phosphatidylethanolamine.
- cell surface GAGs play a key role in protecting cells from diverse damaging agents and processes, such as reactive oxygen species and free radicals, endotoxins, cytokines, invasion promoting enzymes, and agents that induce and/or facilitate degradation of extracellular matrix and basal membrane, cell invasiveness, white cell extravasation and infiltration, chemotaxis, and others.
- cell surface GAGs protect cells from bacterial, viral and parasitic infection, and their stripping exposes the cell to interaction and subsequent internalization of the microorganism. Enrichment of cell surface GAGs would thus assist in protection of the cell from injurious processes.
- PLA2 inhibitors are conjugated to GAGs or GAG- mimicking molecules.
- these compounds for use in the present invention provide wide-range protection from diverse injurious processes, and are effective in amelioration of diseases that requires cell protection from injurious biochemical mediators.
- a GAG-mimicking molecule may be, inter alia, a negatively charged molecule.
- a GAG-mimicking molecule may be, inter alia, a salicylate derivative.
- a GAG-mimicking molecule may be, inter alia, a dicarboxylic acid.
- the invention provides a pharmaceutical composition for treating a subject suffering from an eye disease, including a lipid or phospholipid moiety bonded to a physiologically acceptable monomer, dimer, oligomer, or polymer; and a pharmaceutically acceptable carrier or excipient.
- a pharmaceutical composition for treating a subject suffering from an eye disease including any one of the compounds for use in the present invention or any combination thereof; and a pharmaceutically acceptable carrier or excipient.
- the compounds for use in the present invention include, inter alia, the compounds represented by the structures of the general formulae as described hereinbelow: (A), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (DC), (IXa), (IXb), (X), (XI), (XII), (X ⁇ i), (KW), (XV), (XVI), (XVU), (XVi ⁇ ), (XIX), (XX), (XXI), (XXIII), or any combination thereof.
- lipids such as, but not limited to phosphatidylethanolamine and phosphatidylserine
- additional monomer or polymer moieties is thus a practical route to the production of new drugs for medical purposes, provided that the resultant chemical composition displays the desired range of pharmacological properties.
- the compounds for use in the present invention possess a combination of multiple and potent pharmacological effects in addition to the ability to inhibit the extracellular form of the enzyme phospholipase A2.
- While the pharmacological activity of the compounds for use in the present invention described herein may be due in part to the nature of the lipid moiety, the multiple and diverse combination of pharmacological properties observed for the compounds for use in the present invention emerges from the ability of the compound structure to act essentially as several different drugs in one chemical entity.
- the compounds for use in the present invention may also be used in combination with any device which is applied to an eye surface or applied to the internal regions of the eye.
- a device is a contact lens, while in other embodiments, it is a corneal prosthetic device, prosthetic iris implant, scleral lens prosthetic device, an intra-ocular implant, a scleral buckle, ophthalmic tantalum clip, ophthalmic conformer, artificial eye, absorbable implant, eye sphere implant, extraocular orbital implant, keratoprosthesis, intraocular lens, scleral shell, eye valve implant, or a combination thereof.
- the present invention provides a substrate having a coating on at least a portion of a surface of said substrate, said coating comprising a lipid or phospholipid moiety bound to a physiologically acceptable monomer, dimer, oligomer, or polymer as any of the embodiments describe hereinabove.
- the physiological acceptable monomer, dimer, oligomer, or polymer is a polypyranose.
- the substrate is a contact lens, hi one embodiment, the substrate is an implant. In one embodiment, the substrate is part of a device for ophthalmic or ophthamologic use.
- this invention provides a contact lens solution comprising the compounds of the instant invention.
- Contact lens solutions of the instant invention may comprise, inter alia, rewetting drops, cleaning solutions, washing solutions, storage solutions, packing solutions, saline solution, daily cleaner, multipurpose solution, hydrogen peroxide solution, or a combination thereof. Any solution which may be used for storage, preservation, or cleaning of a contact lens or lenses is considered to be an embodiment of this invention.
- the safety and tolerability of solutions comprising the subject compounds as comfort ingredients, for example, in contact lens packaging solutions is exemplified in Example 6.
- appliances for use with the lenses and/or solutions of this invention may be coated with the compounds for use in the instant invention as described herein, as well.
- contact lens solutions of the instant invention will additionally comprise surfactants, tonicity agents, viscosity builders, anti- microbials, buffering agents, or a combination thereof.
- surfactants may be non-ionic, and in one embodiment may comprise poly(oxyethylene) and poly(oxypropylene), polyethylene glycol esters of fatty acids, e.g. coconut, polysorbate, polyoxyethylene or polyoxypropylene ethers of higher alkanes (C 12 -C 18).
- Tween® 20 polysorbate 20
- Tween® 80 polyoxyethylene (23) lauryl ether (Brij® 35), polyoxyethyene (40) stearate (Myrj® 52), polyoxyethylene (25) propylene glycol stearate (Atlas® G 2612).
- amphoteric, cationic or anionic surfactant may also be present in the contact lens solution.
- Amphoteric surfactants suitable for use in a composition according to the present invention include materials of the type are offered commercially under the trade name "Miranol”. Another useful class of amphoteric surfactants are exemplified by cocoamidopropyl betaine commercially available under the trade name Amphoso CA. Surfactants suitable for use in the invention can be readily ascertained, in view of the foregoing description, from McCutcheon's Detergents and Emulsifiers, North American Edition, McCutcheon
- the pH of some contact lens solutions should, in one embodiment, be maintained within the range of about 6.0 to 8.0, preferably about 6.5 to 7.8.
- Suitable buffers may be added, such as boric acid, sodium borate, potassium citrate, citric acid, sodium bicarbonate, TRIS and various mixed phosphate buffers (including combinations of Na 2 HPO 4 , NaH 2 PO 4 and KH 2 PO 4 ) and mixtures thereof.
- buffers will be used in amounts ranging from about 0.05 to 2.5 percent by weight, and preferably, from 0.1 to 1.5 percent.
- the contact lens solutions of this invention contain a borate buffer, comprising one or more of boric acid, sodium borate, potassium tetraborate, potassium metaborate or mixtures of the same.
- buffer systems such as citrate, phosphate (appropriate mixtures of Na 2 HPO4, NaH 2 PO4, and KH 2 PO4), bicarbonate, tromethamine and other appropriate nitrogen-containing buffers (such as ACES, BES, BICINE, BIS-Tris, BIS-Tris Propane, HEPES, HEPPS, imidazole, MES, MOPS, PIPES, TAPS, TES, Tricine) can be used to ensure a physiologic pH between about pH 6.5 and 8.5.
- the contact lens solutions of the present invention are also adjusted with tonicity agents, to approximate the osmotic pressure of normal lacrimal fluids which is equivalent to a 0.9 percent solution of sodium chloride or 2.5 percent of glycerol solution.
- the solutions are made substantially isotonic with physiological saline used alone or in combination.
- propylene glycol, lactulose, trehalose, sorbitol, mannitol or other osmotic agents may also be added to replace some or all of the sodium chloride.
- Suitable tonicity-adjusting agents include, but are not limited to: sodium and potassium chloride, dextrose, glycerin, calcium and magnesium chloride. These agents are typically used individually in amounts ranging from about 0.01 to 2.5% (w/v) and preferably, from about 0.2 to about
- the tonicity agent will be employed in an amount to provide a final osmotic value of 200 to 400 mOsm/kg, and more preferably between about 250 to about 350 mOsm/kg, and most preferably between about 280 to about 320 mOsm/kg.
- viscosity builders may also be desirable to optionally include water-soluble viscosity builders in the solutions of the present invention. Because of their demulcent effect, viscosity builders have a tendency to further enhance a lens wearer's comfort by means of a film on the lens surface cushioning impact against the eye. Included among the water-soluble viscosity builders are polymers like polyvinylalcohol cellulose-derived polymers, and povidone. In another embodiment, viscosity builders comprise polyethylene glycol, surfactants, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethyl cellulose and similar materials. Such polymers may be used in an amount of from about 0.01 to about 4.0 weight percent or less.
- Sequestering agents such as ethylenedianiinetetraacetic acid (EDTA), phosphonates, citrate, gluconate and tartarate, are also common additives to preservatives, disinfection or cleaning solutions.
- EDTA ethylenedianiinetetraacetic acid
- phosphonates citrate, gluconate and tartarate
- nitrogen non-fluorocarbon
- the contact lens solution of the instant invention further comprises anti-microbial compounds, which in one embodiment, comprise glycosides, alkaloids, phenolics (anthocyanins, quinones, flavonols and flavonoids, etc.), terpenoids (including phytosterols and carotenoids), or a combination thereof.
- anti-microbial compounds comprise glycosides, alkaloids, phenolics (anthocyanins, quinones, flavonols and flavonoids, etc.), terpenoids (including phytosterols and carotenoids), or a combination thereof.
- anti-microbial compounds comprise allicin, aucubin, berberine, bilberry extract, caffeic acid, chlorogenic acid, Echinacea extract, ferulic acid, hydrastine, lipoic acid, naringin, oleuropein, proanthocyanidins, quercetin, rutin, or a combination thereof, which in one embodiment are present in amounts of 10 to 10,000 parts per million.
- saponins can be used as natural plant surface-active or cleaning agents in lens solutions. Specifically, triterpenoid saponins and steriod saponins are particularly effective in contact lens or ophthalmic solutions.
- the solution comprises benzyldimethyl ⁇ 2-[2-(p-l, 1,3,3- tetramethylbutylphenoxy)ethoxy]ethyl ⁇ ammonium chloride (BDT) as an antimicrobial compound.
- a contact lens solution of the instant invention comprises preservatives, which in one embodiment comprise thimerosal, edetate disodium, sorbic acid, polyaminopropyl biguanide, POLYQUAD (polyquartenium-1), EDTA, or a combination thereof.
- a contact lens solution may be a daily cleaner, which in one embodiment comprises cocoamphocarboxyglycinate, sodium lauryl sulfate, hexylene glycol, sodium chloride, sodium, Tween 21, microlens poloxamer 407, potassium chloride, poloxamine, isopropyl alchohol, amphoteric
- contact lens solution may comprise an enzyme, which in one embodiment may be pancreatin, papain, subtilisin, or a combination thereof, which in one embodiment may be for removing protein from the lens.
- a device for use with contact lenses may comprise compounds for use in the instant invention.
- such a device may be a standard device commercially available for the storage, cleaning, disinfection, and/or carriage of contact lenses, which in one embodiment, is characterized by a hollow well.
- a single device may be suitable for storage, cleaning, disinfection, and/or carriage of contact lenses, while in another embodiment, each is a separate device.
- the substrate which in one embodiment is a contact lens, contact lens device, contact lens solution and/or intraocular device, comprising compounds for use in the instant invention suppresses, inhibits, prevents or treats eye-related disorders, including, inter alia, those described hereinabove, in a subject.
- the substrate comprising compounds for use in the instant invention prevents or treats proteinaceous deposits accumulating on the substrate.
- the compounds for use in the instant invention endow the surface of the substrate with the property of being more hydrophilic, which in one embodiment, may increase comfort, decrease eye dryness, or a combination thereof.
- the compounds for use in the instant invention prevent adverse reactions that are directly or indirectly related to the substrate, such as corneal edema, inflammation, or lymphocyte infiltration.
- the substrate comprising compounds for use in the instant invention increases wettability, decreases adhesion, increases biocompatability, provides UV shielding, prevents glare, decreases dryness, grittiness, general discomfort, prevents microbial (in one embodiment, bacterial) infections, or a combination thereof or provides other desirable characteristics and properties to the substrate that are known in the Art.
- the preparation of high molecular weight compounds for use in the methods of the present invention is as described in United States Patent 5,064,817, which is incorporated fully herein by reference, hi one embodiment, these synthetic methods are applicable to the preparation of low molecular weight compounds for use in the present invention as well, i.e. compounds for use in the present invention comprising monomers and dimers as the conjugated moiety, with appropriate modifications in the procedure as would be readily evident to one skilled in the art.
- the preparation of some low molecular weight compounds for use in the present invention may be conducted using methods well known in the art or as described in United States Patent Application 10/952,496, which is incorporated herein by reference in its entirety.
- PE phosphatidyl-ethanolamine
- HA hyaluronic acid
- Cpd Compound
- Cpd XXII dipalmitoyl-PE conjugated to HA
- Cpd XXIII dimyristoyl-phosphatidyl-ethanolamine linked to HA
- Cpd XXIV PE conjugated to heparin
- Cpd XXV PE conjugated to chondroitin sulfate A (CSA)
- Cpd XXVI PE conjugated to carboxymethyl cellulose (CMC)
- Cpd XXVII PE conjugated to Polygeline (haemaccel)
- Cpd XXIX PE conjugated to dextran
- Cpd XXX PE conjugated to aspirin
- Cpd LXXXVIII PE conjugated to glutaryl
- Cpd LI PE conjugated to alginate
- HRECs human retinal endothelial cells
- Isolated bovine retinas are homogenized in ice-cold Eagle's minimal essential medium (MEM) with HEPES by a Teflon-glass homogenizer and microvessels trapped on an 83 mm nylon mesh. Vessels are transferred into 2X MEM containing 500 ⁇ g/ml collagenase, 200 ⁇ g/ml pronase (BDH, Poole, UK) and 200 ⁇ g/ml DNase at 37°C for 20 min. The resultant vessel fragments are trapped on 53 ⁇ m mesh, washed with cold MEM, and centrifiiged at 225x g for 10 min. The pellet is suspended in microvascular endothelial cell basal medium (MECBM) with growth supplement (TCS Works Ltd., Buckingham, UK) at 37 0 C, 5% CO 2 for 3 days. Confluent cells are used between passages 1 and 3.
- MECBM microvascular endothelial cell basal medium
- TCS Works Ltd., Buckingham, UK growth supplement
- VEGF protein concentration is determined from retinal endothelial cell culture-conditioned medium using the Quantikine® Human VEGF Immunoassay ELISA kit (R & D Systems). Retinal endothelial cell culture are treated with either 5.5 or 25 mM glucose and aliquots are taken daily for analysis.
- IGF-I protein concentration is determined from retinal endothelial cell culture-conditioned medium using the Quantikine® Human IGF Immunoassay ELISA kit (R & D Systems). Retinal endothelial cell culture are treated with either 5.5 or 25 mM glucose and aliquots are taken daily for analysis.
- markers may be examined including ICAM-I, VCAM-I, HIF-I, transmembrane reductase (TMR), and EPO; pigment epithelium-derived factor (PEDF) in the eye, markers of oxidative stress including osmotic stress after accumulation of sorbitol, increased cytosolic NADH/NAD ratio, depletion of NADPH and accumulation of fructose with the resulting non- enzymatic production of advanced glycation end products (AGES); and/or ESR, fibrinogen, SDF/1_, RANTES, EpOx, Haptoglobin and ACE in peripheral blood.
- Antibodies are used to probe the GAG portion of the conjugate over a time course compared to unconjugated control, and show greater local persistence.
- GAGs are tagged.
- Diabetes is induced Long-Evans rats via ip streptozotocin (STZ) injections at 70-85mg/kg, for 3 to 5 days.
- STZ streptozotocin
- the rats are given 10% sugar water for 24 hours post-STZ injection.
- Retinal photographs are taken and blood glucose tests are performed to determine baselines for each rat.
- the normal glucose range for a rat is 80-100 mg/dl.
- C57BL/6 mice (SLC, Shizuoka, Japan) are used.
- Postnatal day (P)7 mice with their nursing mothers are maintained for a full 5 days in 80% oxygen to generate the nonvascular retinal area.
- P 12 they are placed in normoxia for an additional 5 days to induce retinal neovascularization.
- Each animal is glucose-tested and photographed with a fundus camera on a weekly basis to record the progression of diabetic retinopathy. Approximately 20-30 minutes prior to starting pictures, one drop of 1% atropine is placed in each eye.
- the rats are anesthetized with sodium pentobarbital, at a dose of 60 mg/kg, to keep them immobile, and then injected ip with 0.1 ml of 25% fluorescein, which is used to visualize the retinal blood vessels when illuminated by blue light, and to determine the relative leakage of blood by the intensity in the background.
- the retinal leakage score is determined by digital analysis of the vascular and extravascular fluorescence.
- Rats treated with PTZ show significantly increased retinal leakage scores compared to vehicle-treated controls. Treatment with 1, 5, and 10 ⁇ M or other concentrations of Compounds XXII, XXIII, or XXV decrease the retinal leakage score of PTZ-treated rats back to the level of controls.
- VEGF vascular endothelial growth factor
- RNA is isolated from the retina using extraction reagent (Isogen; Nippon Gene, Toyama, Japan) and reverse-transcribed with a cDNA synthesis kit (First-Strand; Pharmacia Biotech, Uppsala, Sweden) according to the manufacturer's protocols. PCR is performed with Taq DNA polymerase (Toyobo, Tokyo, Japan) in a thermal controller (MiniCycler; MJ Research, Watertown, MA).
- the primer sequences are as follows: 5'-ATG TGG CAC CAC ACC TTC TAC AAT GAG CTG CG-3 1 (sense) and 5'-CGT CAT ACT CCT GCT TGC TGA TCC ACA TCT GC-3 1 (antisense; 37 bp) for ⁇ -actin, 5'-GTG TCG AGC TTT
- VEGF Rl Human/mouse vascular endothelial growth factor receptor- 1 (VEGF Rl) primers (302 bp; PCR Primer Pair; R&D Systems, Inc., Minneapolis, MN) and human/mouse VEGF R2 primers (569 bp; PCR Primer Pair; R&D Systems, Inc.) are used for VEGFR-I and -2, respectively.
- Venous blood samples are collected from the patients and control subjects. Plasma is harvested by centrifugation, aliquoted and stored at -70 0 C.
- BSA is added(100 ⁇ l/well), and plates are incubated at room temperature for 30 min. Three washes with PBS-Tween are carried out between each of the procedures. Finally, 100 ⁇ l/well of Amerlite signal reagent (Amersham UK) are added to each well and light emission is measured immediately at 420 run in an Amerlite plate reader (Kodak Clinical Diagnostics, Aylesbury, UK).
- PBSTween Serum samples are added in duplicate to the plates (100 ⁇ l/well, diluted 1/2 in PBS-Tween).
- a standard curve is generated using recombinant human VEGF (R & D systems) in a range of 0.1—40 ng/ml on each plate.
- rabbit anti- VEGF antibody (Santa Cruz Biotechnology) is added (100 ⁇ l/well) to the plate at 1/2000 dilution
- Treatment with 1 , 5, and 10 ⁇ M and other concentrations of Compounds XXII, XXm, or XXV dose-dependently decreases the plasma levels of CD 105 and vitreous levels of VEGF in patients with diabetic retinopathy.
- fluorescein angiography, retinal photography, and ultrasound imaging of the eye are used to evaluate progression of the disease.
- ReNu® Rewetting Drops which contains 0.10% poloxamine, 0.50% boric acid, 0.35% sodium borate, 0.40% sodium chloride, 0.10% EDTA, and
- lenses are preconditioned with the solution of the instant invention by soaking the lens in the solution for one hour prior to deposition. After deposition and incubation, the lenses are rinsed with 0.9% saline solution (without sorbic acid).
- BSA solution An in vitro protein mixture consisting of lysozyme, lactoferrin, human serum albumin and mucin in MOPS buffer is used. The pH of the solution is adjusted to 7.2 using 1 N HCl and an osmolality equal to 326 mOsm. After one hour of pre-soaking, the lenses are removed from the formulation and placed in 1.5 ml of the protein mix. The lenses are then incubated in the protein mix at 37°C in a shaking water bath for 48 hours. Protein analysis is done using the colorimetric BCA analytical method (Sigma). The method employs the protein induced reduction of Cu(II) to Cu(I).
- BCA bicinchoninic acid
- the intensity of the complex is directly proportional over the protein concentration range of 5 ⁇ g/ml to 2000 ⁇ g/ml.
- the standard protein solution utilized is BSA with a standard concentration range of 0 to 50 ⁇ g.
- Two mis of a mixture of bicinchoninic acid (BCA) and Cu(II) sulfate is added to each test tube, which are then vortexed. Tubes are then covered and placed in a water bath at 37°C for 15 minutes. After incubation, the purple complex develops. Samples and standards are read in a spectrophotometer at 562 nm. Protein concentration is determined from a standard plot of absorbency vs. concentration ( ⁇ g).
- Lenses are then incubated in the lipid mix at 37°C in a shaking water bath for 24 hours. After incubation, the lenses are removed from the test solution and rinsed with physiological saline solution (without sorbic acid) to remove any residual deposition solution. Lenses are then placed in glass vials for extraction. A three- hour 1:1 CHCl 3 /MeOH extraction is subsequently followed by a three-hour hexane extraction. Extracts are then combined and run on a Hewlett Packard GC. The column utilized is an HP-Ultra 1 with an FED detector and He as the carrier gas. Standard solutions of each of the lipids in the deposition mix are made in 1 :1
- a spherical refraction Prior to lens insertion, a spherical refraction is performed through which high contrast visual acuity with high ambient illumination (HCHI) is measured. Corneal and conjunctival staining and limbal and bulbar injection are assessed with the slitlamp. Each subject is then fitted with a pair of contact lenses of their prescription. Each lens is evaluated for centration and movement, comfort, and deposits/wettability. A spherical over-refraction is then performed. The endpoint of the over-refraction is compared to the refractive endpoint to determine the apparent "on-eye" lens power. LogMAR visual acuity under HCHI testing conditions is measured through the over-refraction.
- HCHI high ambient illumination
- Subjects are evaluated for the effects of the solution comprising lipid- conjugates for comfort, apparent lens Rx power, and sting/burn visual analog score (i.e. lower sting/burn), lens movement/centration, and anterior ocular physiology in the eye treated with lipid-conjugate solutions compared to the eye treated with control solution.
- Cpd LI, Cpd XXV, Cpd XL, Cpd XXVIII and Cpd XXVI were tested for their solubility in an aqueous solution containing Na 2 HPO 4 x7H 2 O, NaH 2 PO 4 and NaCl, pH 7.3, with an osmolality of 250 mOsm/kg.
- PV lenses were tested for lens compatibility and stability. Each lens was soaked in a glass vial containing 3 ml of a solution of one of the following: Cpd
- Each of the compounds in solution was added to MDCK and HCEC cell culture models, with physiological saline or HBSS serving as a control.
- the compounds were individually tested for their toxicity to L929 mouse fibroblasts in an agar diffusion model, in which cells were separated from each compound by a layer of agar. In this test only compounds that can diffuse through the agar and are toxic to the cells are detected.
- the L929 monolayer cultures were incubated with the compounds, and observed for cytotoxicity.
- PV lenses were soaked in solutions of the compounds and tested. In vivo evaluation was assessed in a one-day rabbit ocular irritation experiment. PV lenses were soaked in solutions of the compounds and placed on the corneas of test rabbits.
- Cpds XXV, XL and XXVIII were soluble.
- Cpd XXVI was soluble upon autoclaving the solution.
- Cpd LI was insoluble.
Abstract
Description
Claims
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CA2705785A CA2705785A1 (en) | 2006-11-14 | 2007-11-04 | Use of lipid conjugates in the treatment of diseases or disorders of the eye |
AU2007320736A AU2007320736B2 (en) | 2006-11-14 | 2007-11-14 | Use of lipid conjugates in the treatment of diseases or disorders of the eye |
EP07827380A EP2094281A4 (en) | 2006-11-14 | 2007-11-14 | Use of lipid conjugates in the treatment of diseases or disorders of the eye |
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EP2429531A4 (en) * | 2009-05-11 | 2015-06-03 | Yissum Res Dev Co | Use of lipid conjugates in the treatment of diseases associated with vasculature |
EP2564858A1 (en) * | 2010-04-28 | 2013-03-06 | Nihon Pharmaceuticals Co., Ltd. | Composition for the treatment of aesthenopia |
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US8663716B2 (en) | 2010-04-28 | 2014-03-04 | Nihon Pharmaceutical Co., Ltd. | Composition for treatment of aesthenopia |
EP3305304A4 (en) * | 2015-05-29 | 2019-01-23 | Seikagaku Corporation | Composition including glucosaminoglycan derivative and chemokine receptor activity regulator |
US11253540B2 (en) | 2015-05-29 | 2022-02-22 | Seikagaku Corporation | Composition including glycosaminoglycan derivative and chemokine receptor activity regulator |
WO2020222914A1 (en) * | 2019-04-29 | 2020-11-05 | Bausch & Lomb Incorporated | Glycophospholipid polymeric network and use thereof |
US11673974B2 (en) | 2019-04-29 | 2023-06-13 | Bausch & Lomb Incorporated | Glycophospholipid polymeric network and use thereof |
Also Published As
Publication number | Publication date |
---|---|
EP2094281A2 (en) | 2009-09-02 |
EP2094281A4 (en) | 2012-01-04 |
WO2008059501A3 (en) | 2009-04-23 |
US20150065467A1 (en) | 2015-03-05 |
AU2007320736A1 (en) | 2008-05-22 |
CA2705785A1 (en) | 2008-05-22 |
WO2008059501A8 (en) | 2010-10-07 |
US20080113935A1 (en) | 2008-05-15 |
US8865681B2 (en) | 2014-10-21 |
AU2007320736B2 (en) | 2014-02-20 |
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