WO2007096744A1 - Methodes de traitement de la degenerescence maculaire et de pathologies de l'oeil associees - Google Patents

Methodes de traitement de la degenerescence maculaire et de pathologies de l'oeil associees Download PDF

Info

Publication number
WO2007096744A1
WO2007096744A1 PCT/IB2007/000413 IB2007000413W WO2007096744A1 WO 2007096744 A1 WO2007096744 A1 WO 2007096744A1 IB 2007000413 W IB2007000413 W IB 2007000413W WO 2007096744 A1 WO2007096744 A1 WO 2007096744A1
Authority
WO
WIPO (PCT)
Prior art keywords
unilamellar vesicles
liposomes
administered
pharmaceutical formulation
macular degeneration
Prior art date
Application number
PCT/IB2007/000413
Other languages
English (en)
Inventor
Milton Lethan Pressler
William Sasiela
Original Assignee
Pfizer Products Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Products Inc. filed Critical Pfizer Products Inc.
Publication of WO2007096744A1 publication Critical patent/WO2007096744A1/fr

Links

Classifications

    • 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
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A61K9/0051—Ocular inserts, ocular implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

  • the present invention is directed to the fields of ophthalmology and cell biology of vision. Specifically, the present invention regards the treatment, amelioration or prevention of age-related macular degeneration (ARMD), including nonexudative (Dry ARMD) and exudative (Wet ARMD) forms.
  • ARMD age-related macular degeneration
  • the present invention encompasses novel compositions and methods to treat ARMD and related eye disorders.
  • the method utilizes, or the composition comprises, unilamellar vesicles comprised of phospholipids.
  • Age-related macular degeneration is one of the leading causes of severe visual loss in the developed world (Taylor et al., Br J Ophtalmol 85:261 -266, 2001; VanNewkirk ⁇ tal., Ophtalmol 107:1593- 1600, 2000).
  • Bruch's membrane lies at the critical juncture between the outer retina and its blood supply, the choriocapillaris.
  • RPE retinal pigmented epithelial cells
  • Cholesterol transport may be important in the pathogenesis ofARMD because of lipid efflux from RPE into Bruch's membrane.
  • RPE cells progressively accumulate lipid deposits throughout life; however, unlike vessel wall macrophages, the source of RPE lipid is thought to be retinal photoreceptor outer segments (POS) (Kennedy et al., Eye 9:262-274, 1995). Every day, each RPE cell phagocytoses and degrades more than one thousand POS via lysosomal enzymes. These POS are enriched in phospholipid and contain the photoreactive pigment, rhodopsin. Incompletely digested POS accumulate as lipofuscin in RPE. By age 80, approximately 20% of RPE cell volume is occupied by lipofuscin (Feeney- Bums et al., J invest Ophtalmol Vis Sci 25: 195-200, 1984).
  • Bruch's membrane lipid reveals an age-related accumulation of phospholipid, triglyceride, cholesterol, and cholesterol ester (HoIz et al., 1994, supra; Curcio etal., J Invest Ophtalmol Vis Sd 42:265, 2001 ). The origin of these lipids also is thought to derive principally from POS rather than from the circulation (HoIz etal., 1994, supra; Spaide etal., 1999, supra). POS lipids are hypothesized to efflux from the RPE into Bruch's membrane.
  • AS atherosclerosis
  • Friedman reviews the role of atherosclerosis in the pathogenesis of ARMD. Specifically, the review mentions targeting the angiogenesis pathway for treating the neovascular form of ARMD 1 such as the growth factor VEGF. It is noted that interfering with the upregulation or action of angiogenic agents may prove helpful for choroidal neovascularization, and, in alternative embodiments, statins may be useful for lowering the risk of ARMD.
  • U.S. Patent No. 5,824,685 regards amelioration of proliferative vitreoretinopathy or traction retinal detachment by contacting RPE cells with a retinoic acid receptor selected from ethyl-6- [2- (4, 4- dimethylthiochroman-6- yl) ethynylj nicotinate, 6- [2- (4, 4-dimethylchroman-6-yl) ethynyl] nicotinic acid, and p- [ (E)-2- (5,6, 7,8-tetrahydro-5, 5,8, 8-tetramethyl-2-naphthyl) propenyl] -benzoic acid.
  • a retinoic acid receptor selected from ethyl-6- [2- (4, 4- dimethylthiochroman-6- yl) ethynylj nicotinate, 6- [2- (4, 4-dimethylchroman-6-yl) ethynyl] nicotin
  • WO 01/58494 is directed to treating or preventing an ocular disease, such as age-related macular degeneration, by contacting an ocular cell with an expression vector comprising a nucleic acid sequence encoding an inhibitor of angiogenesis and a neurotrophic agent.
  • an ocular disease such as age-related macular degeneration
  • an expression vector comprising a nucleic acid sequence encoding an inhibitor of angiogenesis and a neurotrophic agent.
  • the inhibitor of angiogenesis and the neurotrophic agent are one and the same, such as pigment epithelium-derived factor (PEDF).
  • PEDF pigment epithelium-derived factor
  • WO 02/13812 regards the use of an insulin-sensitizing agent, preferably peroxisome proliferator- activated receptor y (PPAR y) agonists, for the treatment of an inflammatory disease, such as an ophthalmic disease.
  • PPAR y peroxisome proliferator- activated receptor y
  • WO 00/52479 addresses diagnosing, treating, and preventing drusen-associated disorders (any disorder which involves drusen formation), including ARMD.
  • TNF tumor necrosis factor
  • WO 2004/098506 and WO 2004/0266663 describe the treatment of age-related macular degeneration using regulation of pathogenic mechanisms similar to atherosclerosis.
  • reverse cholesterol transport components such as transporters and HDL fractions, are utilized as diagnostic and therapeutic targets for age-related macular degeneration.
  • Rudolf et al. (Rudolf et al., 2005) describes that LDL receptor deficient mice exhibit an accumulation of lipid particles in Bruch's membrane which is further increased after fat intake.
  • lipid compositions of tissues, cells, membranes, and extracellular regions or structures are characterized by distinctive lipid compositions of tissues, cells, membranes, and extracellular regions or structures.
  • an ARMD characterised by progressive accumulation of cholesterol and other lipids in Bruch's membrane, as discussed above.
  • the other example is atherosclerosis, in which cholesterol (unesterified, esterified, and oxidized forms) and other lipids accumulate in cells and in extracellular spaces of the arterial wall and elsewhere.
  • These lipids have potentially harmful biologic effects, for example, as modulators changing cellular functions, including gene expression, and as deposits narrowing the vessel lumen, obstructing the flow of blood. Removal of these lipids would provide numerous substantial benefits.
  • cells, membranes, tissues, and extracellular structures will benefit in general from compositional alterations that include increasing resistance to oxidation and oxidative damage, such as by increasing the content and types of anti-oxidants, removing oxidized material, and increasing the content of material that is resistant to oxidation.
  • compositional alterations that include increasing resistance to oxidation and oxidative damage, such as by increasing the content and types of anti-oxidants, removing oxidized material, and increasing the content of material that is resistant to oxidation.
  • sphingomyelin and cholesterol which alter cellular functions. These functions can be restored in vitro by removal of these lipids and replacement with phospholipid from liposomes.
  • a major obstacle to performing similar lipid alterations in vivo has been disposition of the lipids mobilized from tissues, cells, extracellular areas, and membranes.
  • Natural (e.g., high-density lipoproteins) and synthetic (e.g., small liposomes) particles that could mobilize peripheral tissue lipids have a substantial disadvantage: they deliver their lipids to the liver in a manner that disturbs hepatic cholesterol homeostasis, resulting in elevations in plasma concentrations of harmful lipoproteins, such as low-density lipoprotein (LDL), a major atherogenic lipoprotein.
  • LDL low-density lipoprotein
  • the invention encompasses a unique approach for the prevention or treatment of age-related macular degeneration or a related disorder in a subject using unilamellar liposomes comprising phospholipids.
  • the present invention provides a pharmaceutical composition comprised of unilamellar vesicles.
  • the present invention provides a pharmaceutical composition comprised of liposomes consisting essentially of phospholipids which are substantially free of sterol, and a pharmaceutically acceptable carrier.
  • the liposome composition is selected from the group consisting of unilamellar liposomes and multilamellar liposomes and the liposomes have an average diameter of about 50 nm to about 200 nm.
  • the liposomes have average diameters larger than about 50 nm, average diameters larger than about 100 nm, and average diameters larger than about 150 nm in different variants. In a specific embodiment, liposomes have mean diameters of about 125 nm.
  • the invention encompasses prevention or treatment of age-related macular degeneration with large unilamellar liposomes containing any suitable phospholipid including but not limited to phosphatidyl choline, phosphatidyl glycerol, palmitoyl-oleoyl phosphatidyl choline, combinations thereof, and derivatives thereof.
  • phospholipid is 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (POPC).
  • the methods of the invention comprise administering to a subject in need thereof a therapeutically effective amount of unilamellar vesicles comprised of phospholipids or a pharmaceutically acceptable salt thereof.
  • unilamellar vesicles comprised of phospholipids that are substantially free of sterol for the treatment of age-related macular degeneration.
  • the therapeutically effective amounts of a liposome composition are in the range of about 10 mg to about 300 mg of phospholipid per kg body weight per dose.
  • the methods for preventing or treating age-related macular degeneration employ the pharmaceutical compositions of the present invention.
  • the compositions are administered to a subject having age-related macular degeneration, often, the compositions will be serially administered over a period of time. Generally, the compositions will be administered parenterally.
  • the methods may be employed therapeutically or prophylactically.
  • compositions and dosage regimens are provided herein, and are believed to encompass safe, effective and non-surgical treatments, without being limited by theory, that rapidly promote cholesterol efflux and mobilization from lipidic plaques in the retina or Bruch's membrane (e.g. drusens), which thereby confer benefit in terms of improvement of visual acuity, prevention of loss of visual acuity, or improvement or prevention of macular degeneration that leads to impaired visual acuity.
  • the mechanism of action encompasses improved blood flow or perfusion of the retina or choroid plexus that directly or indirectly confers improvement in visual acuity, or prevention of loss of visual acuity, or confers amelioration of lesions that promote neovascularization of the retina that reduce visual acuity.
  • a or “an” may mean one or more.
  • the words “a” or “an” when used in conjunction with the word “comprising”, the words “a” or “an” may mean one or more than one.
  • another may mean at least a second or more.
  • age-related macular degeneration refers to macular degeneration, both wet and dry forms, early or late stage, in an individual over the age of about 50. In one specific embodiment, it is associated with destruction and loss of the photoreceptors in the macula region of the retina resulting in decreased central vision and, in advanced cases, legal blindness.
  • Bruch's membrane refers to a five-layered structure separating the choriocapillaris from the retinal pigmented epithelium (RPE).
  • the term "increase lipid efflux” or “increasing lipid efflux” as used herein refers to an increased level and/or rate of lipid efflux, promoting lipid efflux, enhancing lipid efflux, facilitating lipid efflux, upregulating lipid efflux, improving lipid efflux, and/or augmenting lipid efflux.
  • the efflux comprises efflux of phospholipid, triglyceride, cholesterol, and/or cholesterol ester.
  • acula refers to the light-sensing cells or photoreceptors of the central region of the retina.
  • macular degeneration refers to deterioration of the central portion of the retina, the macula.
  • subject refers to an animal such as a mammal, including but not limited to a primate (e.g., a human), a dog, a cat, a rabbit, a rat, a mouse and the like. In specific embodiments, the subject is a human.
  • a primate e.g., a human
  • the subject is a human.
  • terapéuticaally effective amount refers to that amount of an active ingredient sufficient to improve one or more of the symptoms of the condition or disorder being treated as compared to those symptoms that occur without treatment.
  • the improvement may be temporary or permanent.
  • prophylactically effective amount refers to that amount of an active ingredient sufficient to result in the prevention, onset or recurrence of one or more symptoms of the condition or disorder.
  • composition refers to a composition comprising either an active ingredient and a suitable diluent, carrier, vehicle, or excipients suitable for administration to a subject.
  • the pharmaceutical formulation or composition comprises unilamellar liposomes.
  • composition or “pharmaceutically acceptable formulation” refers to a product comprising an active ingredient and a pharmaceutically acceptable carrier, diluent or excipient.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredient of the formulation and not deleterious to the recipient thereof.
  • salts are meant to include salts of active compounds which are prepared with relatively nontoxic acids or bases. Acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable salts include those derived from inorganic acids like hydrochloric, hydrobnomic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobnomic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
  • Suitable bases capable of forming salts with L-NMMA include, for example, inorganic bases such as sodium hydroxide, ammonium hydroxide, potassium hydroxide the like; and organic bases such as mono-, di- and tri-alkyl amines (e.g., triethyl amine, diisopropyl amine, methyl amine, dimethyl amine and the like ) and optionally substituted ethanolamines (e.g., ethanolamine, diethanolamine and the like). It is within the knowledge of those skill in the art to determine which phospholipids could create a pharmaceutically acceptable salt.
  • compositions can contain pharmaceutically acceptable excipients or auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, and tonicity adjusting agents, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride and the like. Injectable pharmaceutical compositions often include an antimicrobial component, especially for multi-dose dosage forms.
  • liposome refers to structures having lipid-containing membranes enclosing aqueous interior.
  • the structures may have one or more lipid membranes, generally the liposomes have only one membrane.
  • Such single layered liposomes are referred to herein as “unilamellar liposomes”.
  • Multilayered liposomes are referred to as “multilamellar liposomes”.
  • drug refers to a synthetic compound suitable for therapeutic use without associated bound carriers, adjuvants, activators or co-factors. It does not include apolipoproteins, lecithin cholesterol acyltransferase or albumin.
  • dose refers to a quantity of a drug or other remedy to be taken or applied all at one time or in fractional amounts within a given period of time.
  • dose regimen refers to a dose schedule.
  • treat refers to alleviating, reducing, abrogating, or otherwise modulating a disease, disorder and/or symptoms thereof, that is a therapeutic effect on an existing condition.
  • prevent refers to barring, or reducing the risk of, a subject from acquiring a disease, disorder and/or symptoms thereof.
  • label refers to a display of written, printed or graphic matter upon the immediate container of an article, for example, the written material displayed on a vial containing a pharmaceutically active agent.
  • labeling refers to all labels and other written, printed or graphic matter upon any article or any of its containers or wrappers or accompanying such article, for example, a package insert, instructional videotapes or instructional DVDs accompanying or associated with a container of a pharmaceutically active agent.
  • the term "/kg” refers to a subject's body weight.
  • the present invention provides methods for treating age-related macular degeneration (ARMD) by administering to a subject in need thereof a therapeutically effective amount of unilamellar vesicles comprised of phospholipids or a pharmaceutically acceptable salt thereof.
  • ARMD age-related macular degeneration
  • the present invention provides methods for treating ARMD by administering to a subject in need thereof a therapeutically effective amount of unilamellar vesicles consisting essentially of phospholids which are substantially free of sterol, and the vesicles are not bound to a drug.
  • Unilamellar vesicles of the present invention have an average diameter of about 50 nm to about 200 nm.
  • liposomes have average diameters larger than 50 nm.
  • liposomes have average diameters larger than 100 nm.
  • liposomes have average diameters larger than 150 nm.
  • liposomes have average diameters of about 125 nm.
  • the methods of the invention include administering an effective amount of "empty liposomes" to treat ARMD.
  • "Empty” is a standard terminology to indicate an absence of an encapsulated drug within a liposome, or that no encapsulated drug is essential for one or more functions of a liposome and that a liposome interior may contain non-drug materials such as water and other inert molecules.
  • the subject can be any mammalian subject that is experiencing ARMD or related condition.
  • the animal is a human.
  • non-human primates, dogs, cats, rodents, horses, cows and the like may be treated by the methods of the present invention.
  • the ARMD can be any ARMD known to those of skill in the art.
  • the ARMD is a nonexudative ARMD (dry form).
  • the ARMD is an exudative ARMD (wet form).
  • the subject is a human.
  • the subject can be of any age suitable for the administration of large unilamellar liposomes according to guidelines known to practitioners of skill in the art.
  • the volume of a cholesterol content in the Bruch's membrane is reduced.
  • the cholesterol content is reduced by at least 10-30%.
  • the cholesterol content is reduced by 30-50%.
  • the cholesterol content is reduced by 50-75%.
  • the volume of a drusen is also reduced.
  • the volume of a drusen is reduced by at least 10-30%.
  • the volume of a drusen is reduced by 30-50%.
  • the volume of a drusen is reduced by 50-75%.
  • the liposomes are in the liquid-crystalline state at 37 0 C, at 35 0 C or at 32 0 C.
  • Liposomes in the liquid-crystalline state typically accept cholesterol more efficiently than liposome in a gel state.
  • liposomes composed of lipids that are liquid-crystalline at 37 0 C are generally in a liquid-crystalline state during the treatment and, therefore, optimize removal of cholesterol from drusens in Bruch's membranes.
  • the present invention provides pharmaceutical compositions comprised of unilamellar vesicles and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition consists essentially of unilamellar liposomes which are substantially free of sterol and are not bound to a drug.
  • unilamellar vesicles of the present invention have an average diameter of about 50 nm to about 200 nm.
  • unilamellar vesicles of the present invention have an average diameter of about 100 nm to about 200 nm.
  • liposomes have average diameters larger than 50 nm.
  • liposomes have average diameters larger than 100 nm.
  • liposomes have average diameters larger than 150 nm.
  • liposomes have average diameters of about 125 nm.
  • compositions comprise pharmaceutically acceptable excipients as required to approximate physiological conditions, such as pH adjusting agents, buffering agents, and tonicity adjusting agents (e.g., sodium acetate, sodium lactate, sodium chloride, potassium chloride, and calcium chloride). They may also comprise osmotically active cryoprotectants like mannitol or sucrose. Antibacterial agents (e.g., phenol, benzalkonium chloride or benzethonium chloride) can be added to maintain sterility of a product, especially to pharmaceutical formulations intended for multi-dose parenteral use. Suspending, stabilizing and/or dispersing agents can also be used in the compositions of the invention.
  • pH adjusting agents e.g., buffering agents, and tonicity adjusting agents
  • tonicity adjusting agents e.g., sodium acetate, sodium lactate, sodium chloride, potassium chloride, and calcium chloride.
  • osmotically active cryoprotectants like mannitol or sucrose.
  • the pharmaceutical formulation can be in a variety of forms suitable for any route of administration which include, but are not limited to parenteral, intraocular, subcutaneous, oral, transdermal, transmucosal and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for parenteral administration.
  • Parenteral administration refers to any route of administration that is not through the alimentary canal, including, but not limited to, injectable administration ⁇ i.e., intravenous, intraarterial, intramuscular, intradermal, intraocular, and the like as described herein) (see generally, Remington's Pharmaceutical Sciences, 18 th Edition, Gennaro et al., eds., Mack Printing Company, Easton, Pennsylvania, 1990).
  • the pharmaceutical formulation of the present invention can be in a form suitable for ocular route of administration, which includes, but are not limited to an intraocular (intracamera!) injection, a subconjunctival, sub-Tenon's, retrobulbar, intravital injection and a topical application.
  • the pharmaceutical formulation is injected directly into the eye or the space surrounding the orbit of the eye.
  • the injectable pharmaceutical formulation can be a pharmaceutically appropriate formulation for administration directly into the eye including aqueous and vitreous humors.
  • Injectable pharmaceutical formulations can be sterile suspensions, solutions or emulsions in aqueous or oily vehicles.
  • the formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multidose containers, and can comprise added preservatives.
  • Buffers suitable for parenteral pharmaceutical formulations are phosphate, citrate and acetate, and may contain stabilizers or cryopreservatives (e.g., sucrose, mannitol).
  • Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms of the invention.
  • the pharmaceutical formulations can be formulated for a single, one-time use or can be formulated in multiple doses.
  • the pharmaceutical formulation can be lyophilized in sterile bottles or in sterile pre-filled syringes or sterile pre-filled bags which can be frozen or refrigerated.
  • the present invention provides compositions and methods for the treatment of ARMD (age-related macular degeneration), its various forms (e.g., wet, dry; early, late) or related conditions by administering a pharmaceutical composition comprised of unilamellar liposomes.
  • ARMD age-related macular degeneration
  • the pharmaceutical composition of the invention consists essentially of unilamellar liposomes which are substantially free of sterol and are not bound to a drug, and a pharmaceutically acceptable carrier.
  • unilamellar vesicles of the present invention have an average diameter of about 50 nm to about 200 nm.
  • multilamellar liposomes may be employed in the compositions of the present invention, either exclusively or in addition to unilamellar liposomes.
  • the liposomes have an average diameter of about 50 nm to about 200 nm, typically about 100 nm to about 200 nm.
  • liposomes may or may not be in the form of a pharmaceutical composition.
  • Liposomes utilized by the pharmaceutical compositions of the present invention may be obtained by any method known to those skilled in the art, such as described in, e.g., U.S. Patent Nos.4,186,183, 4,217,344, 4,261,975, 4,485,054, 4,774,085, 4,946,787, 6,139,871, US published application US 2005/0260256 published November 24, 2005, PCT publication No. WO91 /17424, Deamer and Bangham (1976), Fraley et Qi., 1979, Hope ⁇ tal., 1985, Mayer et al., 1986, and Williams ⁇ tal., 1988, each of which is incorporated herein by reference. Suitable methods include, but not limited to, sonication, extrusion, high pressure/homogenization, microfluidization, detergent dialysis, calcium-induced fusion of small liposome vesicles and ether-infused methods.
  • the liposomes are most conveniently generated by sonication and extrusion procedures. Sonication is generally performed with a tip sonifier, such as a Branson tip sonifier, in an ice bath. Typically, the suspension is subjected to several sonication cycles. Extrusion may be carried our by biomembrane extruders, such as the Lipex Biomembrane Extruder. Defined pore size in the extrusion filters may generate unilamellar liposome vesicles of specific sizes. Liposomes may also be formed by extrusion through an asymmetric ceramic filter, such as a Ceraflow Microfilter, commercially available from the Norton Company, Worcester, MA.
  • asymmetric ceramic filter such as a Ceraflow Microfilter, commercially available from the Norton Company, Worcester, MA.
  • the size of the liposomal vesicles may be determined by quasi-electric light scattering (QELS) as described in Bloomfield, Ann Rev Biophys Bioeng, 10:421-450 (1981), incorporated herein by reference. Average liposome diameter may be reduced by sonication of formed liposomes. Intermittent sonication cycles may be alternated with QELS assessment to guide efficient liposome synthesis.
  • QELS quasi-electric light scattering
  • a chloroform solution of a lipid is vortexed and the solvent is removed under a steady stream of nitrogen.
  • the sample is dried under a high vacuum.
  • the resulting dry lipid film is rehydrated in 150 mM NaCI and 20 mM [4-(2-hydroethyl)]-piperazine-ethanesulfonic acid (Hepes, pH 7.4).
  • the lipid can be any suitable lipid known to those of skill in the art.
  • Non-phosphorus containing lipids can be used, including stearylamine, dodecylamine, acetyl palmitate, (1 ,3)-D-mannosyl- (1,3)diglyceride, aminophenylglycoside, 3-cholesteryl- 6'-(glycosylthio)hexyl ether glycolipids, N-(2,3-di(9-(Z)- octadecenyloxy))-prop-1-yl-N,N,N-trimethylammonium chloride and fatty acid amides.
  • lipids suitable for use in the liposomes of the present invention are well known to those skilled in the art and cited in a variety of sources, e.g., McCutcheon's Detergents and Emulsifiers and McCutcheon's Functional Materials. Allured Publishing Co., Ridgewood, N.J., both of which are incorporated herein by reference.
  • the lipid is a phospholipid.
  • the phospholipid can be obtained from any source known to those of skill in the art.
  • the phospholipid can be obtained from commercial sources, natural sources or by synthetic or semi-synthetic means known to those of skill in the art (see, e.g., Mel'nichuk etal., UkrBiokhim Zh 59(6):75-7 (1987); Mel'nichuk etal., UkrBiokhim Zh 59(5):66-70 (1987); Ramesh etal, J. Am. Oil Chem. Soc.
  • the phospholipid can be any phospholipid known to those of skill in the art.
  • the phospholipid can be a small alkyl chain phospholipid, phosphatidylcholine, egg phosphatidylcholine, soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, soy phosphatidylglycerol, egg phosphatidylglycerol, distearoylphosphatidylglycerol, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dilaurylphosphatidylcholine,
  • the liposomes of the present invention are composed of one phospholipid.
  • liposomes are composed of more than one phospholipid.
  • the liposomes be composed of lipids that are liquid-crystalline at 37 0 C, at 35 0 C and at 32 0 C. Liposomes in the liquid-crystalline state typically accept cholesterol more efficiently than liposome in a gel state. As patients usually have a core temperature of about 37 0 C, liposomes composed of lipids that are liquid-crystalline at 37 0 C are generally in a liquid-crystalline state during the treatment and, therefore, optimize removal of cholesterol from drusens in Bruch's membranes.
  • compositions of the present invention also comprise a pharmaceutically acceptable earner.
  • Many pharmaceutically acceptable carriers may be employed in the compositions of the present invention. Suitable carriers include, but are not limited to, glucose, trehalose, sucrose, sterile water, buffered water, 0.4% saline, and 0.3% glycine and glycoproteins for enhanced stability, such as albumin, lipoprotein, globulin, etc.
  • the pharmaceutically acceptable buffer includes, but is not limited to, citrate, acetate, phosphate, tris(hydroxymethyl)-aminomethane or THAM (tromethamine).
  • compositions can contain pharmaceutically acceptable excipients or auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, and tonicity adjusting agents, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride and the like.
  • Injectable pharmaceutical compositions often include an antimicrobial component, especially for multi-dose dosage forms.
  • compositions may be sterilized by conventional, well-known sterilization techniques.
  • the resulting aqueous solution may be packaged for further use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration.
  • the concentration of liposomes in the carrier may vary. In one embodiment, the liposomes' concentration is about 20-300 mg/ml. In another embodiment, it is about 50-200 mg/ml. In yet another embodiment, the concentration is about 200 mg/ml. Persons of skill in the art may vary these concentrations to optimize treatment with different liposomal components or for particular patients.
  • compositions of the present invention can be in a variety of forms suitable for any route of administration which include, but are not limited to parenteral, intraocular, subcutaneous, oral, transdermal, transmucosal and rectal administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for parental administration.
  • Parenteral administration refers to any route of administration that is not through the alimentary canal, including, but not limited to, injectable administration (i.e., intravenous, intraarterial, intramuscular, intradermal, intraocular, and the like as described herein) (see generally, Remington's Pharmaceutical Sciences, 18 th Edition, Gennaro etal., eds., Mack Printing Company, Easton, Pennsylvania, 1990).
  • injectable administration i.e., intravenous, intraarterial, intramuscular, intradermal, intraocular, and the like as described herein
  • Remington's Pharmaceutical Sciences 18 th Edition, Gennaro etal., eds., Mack Printing Company, Easton, Pennsylvania, 1990.
  • the pharmaceutical formulation of the present invention can be in a form suitable for an ocular route of administration, which includes, but is not limited to an intravitreal, intraocular (intracameral), subconjunctival, sub-Tenon's, retrobulbar injection and a topical application.
  • the pharmaceutical formulation is administered as an intravitreal injection.
  • the injectable pharmaceutical formulation of the present invention is ophthalmically acceptable, i.e., it is appropriate for administration directly into the eye including aqueous and vitreous humors.
  • Injectable pharmaceutical formulations can be sterile suspensions, solutions or emulsions in aqueous or oily vehicles.
  • the formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multidose containers, and can comprise added preservatives.
  • the buffers for parenteral pharmaceutical formulations are phosphate, citrate and acetate, and may contain stabilizers or cryopreservatives (e.g., sucrose, mannitol, trehalose).
  • Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorporated into the parenteral dosage forms of the invention.
  • the doses of liposomes may vary depending on the clinical condition of a patient receiving the treatment and the route of administration.
  • the intravenous dose is about 10-300 mg of liposomes/kg body weight.
  • the intravenous dose is about 25- 200 mg of liposomes/kg body weight.
  • the intravenous dose is about 50-150 mg of liposomes/kg body weight.
  • the intravenous dose is about 100-150 mg of liposomes/kg body weight.
  • an average 70 kg person is treated with about 4-8 g of intravenous liposomes per treatment.
  • the dose is greatly reduced because of the limited volume of the orbit and its structures.
  • the intraocular dose is about 0.4-8 mg of liposomes/kg of body weight. In another embodiment, the intraocular dose is about 0.5-4 mg of liposomes/kg of body weight. In yet another embodiment, the intraocular dose is about 1-2 mg of liposomes/kg of body weight.
  • the dose is ussually constant over the course of treatment, also it may vary according to clinical outcome of a patient.
  • the pharmaceutical formulations can be formulated for a single, one-time use or can be formulated in multiple doses.
  • the components of the combination therapy can be in the same or different pharmaceutical formulations and can be administered simultaneously or sequentially.
  • the pharmaceutical formulation can be lyophilized in sterile bottles or in sterile pre-filled syringes or sterile pre-filled bags which can be frozen or refrigerated.
  • the formulation can also be lyophilized and reconstituted with a suitable vehicle.
  • composition consisting essentially of unilamellar vesicles of
  • ETC-588 1-palmitoyl-2-oleoyl-s ⁇ -glycero-3-phosphocholine
  • ETC-588 is suitable for treatment of age-related macular degeneration or related conditions.
  • the pharmaceutical formulation consists essentially of liposomes, consisting of POPC, having an average diameter of about 100 nm or a mean diameter of 125 ⁇ 30 nm, suspended in a phosphate-buffered saline and stored at 2-8 0 C.
  • the pharmaceutical formulation comprises a buffer in an amount sufficient to make a pharmaceutically suitable formulation of ETC-588.
  • the pharmaceutical formulation comprises a phosphate buffer.
  • the phosphate concentration is about 10 mM to about 30 mM.
  • the phosphate concentration is about 15 mM to about 25 mM.
  • the phosphate concentration is about 20 mM.
  • the pharmaceutical formulation comprises a saline in an amount sufficient to make a pharmaceutically suitable formulation of ETC-588.
  • the pharmaceutical formulation comprises sodium chloride.
  • the sodium chloride concentration is about 80 mM to about 200 mM.
  • sodium chloride concentration is about 110 mM to about 150 mM.
  • sodium chloride concentration is about 130 mM.
  • an appropriate buffer is added to adjust the pH of the pharmaceutical formulation to a range suitable for administration to a subject.
  • the pharmaceutical formulation has a pH of about 6.8 to about 7.8.
  • the pharmaceutical formulation has a pH of about 7.0 to about 7.8.
  • the pharmaceutical formulation has a pH of about 7.2 to about 7.6.
  • the pharmaceutical formulation has a pH of about 7.4.
  • the pharmaceutical formulations can be provided in a powder form or lyophilized form for reconstitution before use with a suitable vehicle, including but not limited to sterile pyrogen free water, phosphate buffered saline, saline or dextrose.
  • a suitable vehicle including but not limited to sterile pyrogen free water, phosphate buffered saline, saline or dextrose.
  • the ETC-588 can be lyophilized.
  • the pharmaceutical formulations can be supplied in unit dosage forms and reconstituted prior to use.
  • Targeting of ocular tissues may be accomplished in any one of a variety of ways. Injection into the aqueous or vitreous humor of the eye is one means. Directly injecting the
  • ETC-588 into the proximity of the RPE or Bruch's membrane provides targeting of the complex with some forms ofARMD.
  • the complex is administered via intra-ocular sustained delivery (such as Vitrasert® or Envision® by Bausch and Lomb).
  • the compound is delivered by posterior suborbital injection.
  • the pharmaceutical formulation of the ETC-588 is a unit dose package.
  • a unit dose package provides delivery of a single dose of a drug to a subject.
  • the compositions and methods of the invention provide a unit dose package of a pharmaceutical formulation comprising, for example, 8 g of liposomes per package.
  • 8 g of liposomes is an amount that administers 100 mg of liposomes/kg body weight to a 70 kg subject.
  • the unit can be, for example, a sterile single use vial, a sterile pre-filled syringe, a sterile pre-filled bag (i.e., piggybacks) and the like.
  • the pharmaceutical formulation is a unit-of-use package.
  • a unit-of-use package is a convenient, prescription size, patient ready unit labeled for direct distribution by health care providers.
  • a unit-of-use package contains a pharmaceutical formulation in an amount necessary for a typical treatment interval and duration for a given indication.
  • the compositions and methods of the invention provide for a unit-of-use package of a pharmaceutical formulation comprising the ETC-588 in an amount sufficient to treat an average sized adult male or female with, for example, 75 mg of liposomes/kg body weight once weekly for 5 weeks.
  • a unit-of-use package may comprise five doses of the ETC-588 (available in a vial or pre-filled syringes).
  • the unit-of-use package comprises a pharmaceutical formulation comprising the ETC-588 in an amount sufficient to treat an average sized adult male or female with a dose of 75 mg of liposomes/kg, 100 mg of liposomes/kg or 150 mg of liposomes/kg body weight once weekly for 5 weeks. It will be apparent to those of skill in the art that the doses described herein are based on the subject's body weight.
  • the pharmaceutical formulations comprising the ETC-588 must be of a suitable pH, osmolality, tonicity, purity and sterility to allow safe administration to a subject. 4.3.3 Use of ETC-588 for Treating Age-Related Macular Degeneration (ARMD)
  • ETC-588 encompassed by the invention are described herein.
  • Doses useful for treatment of age-related macular degeneration include intravenous doses up to about 300 mg of liposomes/kg of body weight administered intravenously to a subject in need thereof.
  • the compositions and methods comprise intravenous administration of the ETC-588 at a dose of about 10 mg of liposomes to about 300 mg of liposomes/kg of a subject's body weight.
  • the compositions and methods comprise intravenous administration of ETC-588 at a dose of about 25 mg of liposomes/kg to about 200 mg of liposomes/kg body weight.
  • compositions and methods comprise intravenous administration of ETC-588 at a dose of about 50 mg of liposomes/kg to about 150 mg of liposomes/kg body weight. In certain embodiments, the compositions and methods comprise intravenous administration of ETC-588 at a dose of about 100 mg of liposomes/kg to about 150 mg of liposomes/kg body weight. In other embodiments, the composition and methods comprise an intra-ocular administration of ETC-588 at a dose of about 0.5 mg of liposomes/kg to about 4 mg of liposomes/kg body weight.
  • ETC-588 can vary with the route of administration, height, weight, age, severity of illness of the subject, the presence of concomitant medical conditions and the like.
  • an elderly subject with compromised renal or liver function can be treated with an intravenous dose of the ETC-588 that is at the lower range of about 12.5 mg of liposomes/kg body weight dose as part of the therapy.
  • a subject with severe cardiovascular disease or related disorders that is obese with good renal and liver function can be treated with an intravenous dose of the ETC-588 that is, for example, at the upper range of about 150 mg of liposomes/kg body weight dose (e.g., 150 mg of liposomes/kg body weight, 145 mg of liposomes/kg body weight, 140 mg of liposomes/kg body weight and the like) as part of the therapy.
  • these doses achieve a range of circulating concentrations that include the effective dose with an acceptable risk-to-benefit profile.
  • the dose of ETC-588 can vary over the duration of treatment.
  • a subject can be treated with the dose of 150 mg of liposomes/kg body weight of the ETC-588, intravenously once weekly for 3 weeks and then treated with the dose of 50 mg of liposomes/kg body weight of the ETC-588 once every four months or once per year for the lifetime of the subject.
  • Such intermittent doses can be administered to maintain a reduced size and number of drusens in Bruch's membrane. Intermittent doses during the lifetime of the subject to maintain a reduced volume of lipids in the drusens are within the scope of the present invention.
  • a single high dose (e.g., 150 mg of liposomes/kg body weight or 145 mg of liposomes/kg body weight) of the ETC-588 is administered intravenously to the subject.
  • one or more high doses of the ETC-588 are administered to the subject followed by one or more of the same or lower doses of the ETC-588 (e.g., 12.5, 25, 50, 75, 100 or 150 mg of liposomes/kg body weight).
  • the opposite regimen may be used comprising administration of one or more low doses of the ETC-588 (e.g., about 12.5, 25, 50 mg of liposomes/kg body weight ) followed by one or more of the same or higher doses of the ETC-588 (e.g., about 12.5, 25, 50, 75, 100 or 150 mg of liposomes/kg body weight).
  • the high dose is preferably delivered first.
  • the ETC-588 is administered as an intravenous infusion.
  • the compositions and methods comprise administration as a intravenous push infusion.
  • intravenous push infusion it is preferred that the ETC-588 is administered intravenously over a short time period, such as up to 5 minutes, for example, 2-5 minutes.
  • administration of the ETC-588 comprises a continuous intravenous infusion.
  • continuous intravenous infusion it is preferred that the ETC-588 is administered continuously over a period of time, for example, about 1 hour to 3 hours, preferably, about 30 minutes to 120 minutes.
  • Continuous intravenous infusions can be administered with the aid of an infusion pump or device.
  • administration of the ETC-588 can be a combination of continuous intravenous infusions and intravenous push infusions ("bolus doses"). The bolus doses can be administered before, after or during the continuous infusion.
  • compositions and methods provide for intravenous infusion of the ETC-588.
  • Any suitable blood vessel can be used for infusion, including peripheral vessels, such as the vessels in the antecubital fossa of the arm or a central line into the major veins of the chest.
  • the pharmaceutical formulation is infused into the cephalic or median cubital vessel at the antecubital fossa in the arm of a subject.
  • the infusion may be administered in a hospital or the outpatient section of the hospital, Surgeons' center, emergency room or another urgent care center, infusion center, ophthalmologist's or doctor's office, or with the assistance of a health-care provider in the home.
  • the methods for the treatment of age-related macular degeneration or related conditions comprise administering the ETC-588 about every week, about every other week, about every 4, 5, 6, 7, 8 to 10 or 11 to 14 days to a subject in need thereof.
  • the ETC- 588 can be administered about every 7 days.
  • administration of the ETC-588 can be a one-time administration every six months or every year. In certain embodiments, administration can continue for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7-12 weeks, about 13-24 weeks or about 25-52 weeks.
  • administration of the ETC-588 is about every 7 days for about 5 weeks.
  • administration can be intermittent after, for example, about 5 weeks.
  • a subject can be treated once a week for about 5 weeks and then treated about 3 to about 4 times over the following year.
  • the pharmaceutical formulations described herein can be administered to the subject intermittently to maintain a reduced size and number of drusens in Bruch's membrane.
  • the ETC-588 in a dose of about 50 mg of liposomes/kg body weight can be administered about every 10 days for about 7 weeks and then administered, for example, about 26 weeks later or about 52 weeks later.
  • the invention provides novel compositions and methods to treat age-related macular degeneration or related disorders or forms (wet, dry, early, late).
  • compositions and methods of the present invention are to treat age- related macular degeneration or related disorders in subjects with signs or symptoms thereof.
  • Age-related macular degeneration is a clinical diagnosis based upon the presence of visual disturbance and characteristic findings on dilated eye examination.
  • ARMD is a clinical diagnosis based upon the presence of visual disturbance and characteristic findings on dilated eye examination.
  • drusens are visible on dilated eye examination.
  • round or oval patches of geographic atrophy of the retina may be evident as areas of depigmentation, increased pigmentation may be seen with RPE pigmentary mottling.
  • patients with wet type of ARMD 1 dilated examination may reveal subretinal fluid, hemorrhage, and lipid exudates.
  • neovascularization appears as a grayish discoloration in the macular area.
  • age-related macular degeneration including epidemiology, etiology/risk factors, clinical presentation, diagnosis, treatment and prevention is included in Jorge G. Arroyo, "Age- related macular degeneration-l and II," UpToDate (on-line service) (last modified September 19, 2005), which is hereby incorporated herein by reference.
  • compositions and methods of the invention provide for treating age-related macular degeneration or related disorders in subjects at risk for developing ARMD.
  • age-related macular degeneration or related disorders A number of possible risk factors have been identified, of which age and smoking are the only factors that appear to definitively increase risk. Additional risk factors are set forth in Jorge G. Arroyo, "Age-related macular degeneration-l and II," UpToDate (on-line service), as referenced above.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Ophthalmology & Optometry (AREA)
  • Dermatology (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des vésicules unilamellaires constituées de phospholipides destinés à empêcher et à traiter la dégénérescence maculaire liée à l'âge et les pathologies associées. Les compositions et méthodes selon l'invention constituent une nouvelle approche du traitement de la dégénérescence maculaire liée à l'âge et des pathologies associées. L'invention concerne également des compositions pharmaceutiques destinées à cette utilisation.
PCT/IB2007/000413 2006-02-21 2007-02-09 Methodes de traitement de la degenerescence maculaire et de pathologies de l'oeil associees WO2007096744A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US77552006P 2006-02-21 2006-02-21
US60/775,520 2006-02-21

Publications (1)

Publication Number Publication Date
WO2007096744A1 true WO2007096744A1 (fr) 2007-08-30

Family

ID=38226652

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/000413 WO2007096744A1 (fr) 2006-02-21 2007-02-09 Methodes de traitement de la degenerescence maculaire et de pathologies de l'oeil associees

Country Status (4)

Country Link
JP (1) JP2007224032A (fr)
AR (1) AR059581A1 (fr)
TW (1) TW200744670A (fr)
WO (1) WO2007096744A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017184081A1 (fr) * 2016-04-19 2017-10-26 Nanyang Technological University Formulations formant un dépôt sous-conjonctival pour l'administration de médicament au niveau de l'œil

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5514098B2 (ja) * 2008-02-29 2014-06-04 公益財団法人名古屋産業科学研究所 後眼部到達用リポソーム及び後眼部疾患用医薬組成物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018028A1 (fr) * 2001-08-22 2003-03-06 Eidgenoessische Technische Hochschule Zuerich Compositions renfermant des phospholipides charges negativement et servant a traiter et/ou a prevenir la degenerescence maculaire et methode de fabrication associee
US20050260260A1 (en) * 2004-05-19 2005-11-24 Edward Kisak Liposome compositions for the delivery of macromolecules
WO2007038549A1 (fr) * 2005-09-26 2007-04-05 Vasogen Ireland Limited Traitement d'inflammations et d'anomalies vasculaires de l'oeil

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003018028A1 (fr) * 2001-08-22 2003-03-06 Eidgenoessische Technische Hochschule Zuerich Compositions renfermant des phospholipides charges negativement et servant a traiter et/ou a prevenir la degenerescence maculaire et methode de fabrication associee
US20050260260A1 (en) * 2004-05-19 2005-11-24 Edward Kisak Liposome compositions for the delivery of macromolecules
WO2007038549A1 (fr) * 2005-09-26 2007-04-05 Vasogen Ireland Limited Traitement d'inflammations et d'anomalies vasculaires de l'oeil

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ISHIDA B Y ET AL: "High density lipoprotein mediated lipid efflux from retinal pigment epithelial cells in culture", BRITISH JOURNAL OF OPHTHALMOLOGY 2006 UNITED KINGDOM, vol. 90, no. 5, 2006, pages 616 - 620, XP002442509, ISSN: 0007-1161 *
SHABAN H ET AL: "A2E AND BLUE LIGHT IN THE RETINA: THE PARADIGM OF AGE-RELATED MACULAR DEGENERATION", BIOLOGICAL CHEMISTRY, vol. 383, no. 3/4, March 2002 (2002-03-01), pages 537 - 545, XP001106922, ISSN: 1431-6730 *
SHABAN H ET AL: "PHOSPHATIDYLGLYCEROL POTENTLY PROTECTS HUMAN RETINAL PIGMENT EPITHELIAL CELLS AGAINST APOPTOSIS INDUCED BY A2E, A COMPOUND SUSPECTED TO CAUSE AGE-RELATED MACULA DEGENERATION", EXPERIMENTAL EYE RESEARCH, ACADEMIC PRESS LTD., LONDON, GB, vol. 75, no. 1, July 2002 (2002-07-01), pages 99 - 108, XP001105977, ISSN: 0014-4835 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017184081A1 (fr) * 2016-04-19 2017-10-26 Nanyang Technological University Formulations formant un dépôt sous-conjonctival pour l'administration de médicament au niveau de l'œil

Also Published As

Publication number Publication date
TW200744670A (en) 2007-12-16
AR059581A1 (es) 2008-04-16
JP2007224032A (ja) 2007-09-06

Similar Documents

Publication Publication Date Title
US20070254832A1 (en) Methods for the treatment of macular degeneration and related eye conditions
US10736846B2 (en) Methods of treating arthritis
US20080213351A1 (en) Compositions and methods for dosing liposomes of certain sizes to treat or prevent disease
US11957731B2 (en) Reconstituted HDL formulation
US20070197442A1 (en) Methods for the Treatment of Macular Degeneration and Related Eye Conditions
WO2007096744A1 (fr) Methodes de traitement de la degenerescence maculaire et de pathologies de l'oeil associees
ES2325360T3 (es) Tratamiento de trastornos oftalmicos usando urea y derivados de urea.
TWI786328B (zh) 緩釋眼用藥物組合物及其用途
ES2719275T3 (es) Formulación de lipoproteína de alta densidad reconstituida
TW202220668A (zh) 用於疼痛控制之關節內皮質類固醇的藥學組成物
US20170128542A1 (en) Non-aqueous glucagon formulations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07705628

Country of ref document: EP

Kind code of ref document: A1