WO1999003503A1 - The use of angiostatic steroids in photodynamic therapy - Google Patents

The use of angiostatic steroids in photodynamic therapy Download PDF

Info

Publication number
WO1999003503A1
WO1999003503A1 PCT/US1998/012711 US9812711W WO9903503A1 WO 1999003503 A1 WO1999003503 A1 WO 1999003503A1 US 9812711 W US9812711 W US 9812711W WO 9903503 A1 WO9903503 A1 WO 9903503A1
Authority
WO
WIPO (PCT)
Prior art keywords
neovascularization
angiostatic
steroids
diol
pregnadien
Prior art date
Application number
PCT/US1998/012711
Other languages
French (fr)
Inventor
Abbot F. Clark
Original Assignee
Alcon Laboratories, 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 Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to EP98931367A priority Critical patent/EP1003553B1/en
Priority to AU81515/98A priority patent/AU734195B2/en
Priority to AT98931367T priority patent/ATE274356T1/en
Priority to JP2000502798A priority patent/JP2001510170A/en
Priority to DE69825906T priority patent/DE69825906T2/en
Priority to BR9811012-8A priority patent/BR9811012A/en
Priority to CA002296558A priority patent/CA2296558A1/en
Priority to US09/445,237 priority patent/US6297228B1/en
Publication of WO1999003503A1 publication Critical patent/WO1999003503A1/en
Priority to HK00107465A priority patent/HK1028952A1/en

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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0027—Azides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

Definitions

  • This invention relates to the use of angiostatic steroids in photodynamic therapy (PDT).
  • Steroids functioning to inhibit angiogenesis in the presence of heparin or specific heparin fragments are disclosed in Crum, et al., A New Class of Steroids Inhibits Angiogenesis In The Presence of Heparin or Heparin Fragment, Science, 230:375-378, December 20, 1985.
  • the authors refer to such steroids as "angiostatic" steroids. Included in the new class of steroids found to be angiostatic are cortisol, cortexolone, and several dihydro and tetrahydro derivatives.
  • a group of tetrahydrosteroids useful in inhibiting angiogenesis is disclosed in U.S. Patent No. 4,975,537, issued to Aristoff, et al.
  • the compounds are disclosed for use in treating head trauma, spinal trauma, septic or traumatic shock, stroke, and hemorrhage shock.
  • the patent discusses the utility of these compounds in embryo implantation and in the treatment of cancer, arthritis, and arteriosclerosis.
  • the compounds are not disclosed for ophthalmic use.
  • Some of the tetrahydrosteroids disclosed in Aristoff, et al. are disclosed in U.S. Patent No. 4,771,042 in combination with heparin or a heparin fragment for inhibiting angiogenesis in a warm blooded animal. The patent does not disclose the combination for ophthalmic use.
  • compositions of hydrocortisone, "tetrahydrocortisol-S,” and U-72,745G, each in combination with a beta cyclodextrin have been shown to inhibit corneal neovascularization.
  • panretinal photocoagulation is the current medical practice for the treatment of diabetic retinopathy and is effective in inhibiting diabetic retinal neovascularization, this procedure destroys healthy peripheral retinal tissue. This destruction of healthy tissue decreases the retinal metabolic demand and thereby reduces retinal ischemia driven neovascularization.
  • a recent new laser procedure is being tested for the inhibition of ocular neovascularization.
  • Photodynamic therapy is a procedure in which a photoactivatable dye is given systemically followed by laser activation of the dye in the eye at the site of new blood vessel formation (Asrani & Zeimer, Br J Ophthalmol, 79(8):776-770, August, 1995; Asrani et al, Invest Ophthalmol. Vis Sci, 38(13);2702-2710, December, 1997; Husain et al, Ophthalmology, 104(8):242-1250, August, 1997; Lin et al, Curr Eye Res, 13(7):513-522, July, 1994.)
  • the photoactivated drug generates free oxygen radicals which seal the newly formed blood vessels.
  • the subject matter of the present invention involves combining the PDT induced regression of ocular neovascular tissue with agents, such as angiostatic steroids, which inhibit new blood vessel formation.
  • This invention is directed to methods for treating ocular neovascular diseases by combining the use of PDT with particular angiostatic steroids.
  • Figure 1 Compares the ability of angiostatic steroids to inhibit neovascularization in the rabbit cornea.
  • angiogenesis The development of blood vessels for the purpose of sustaining vital tissue is known as angiogenesis or neovascularization.
  • Agents which inhibit neovascularization are known by a variety of terms such as angiostatic, angiolytic, or angiotropic agents.
  • angiostatic agent means compounds which can be used to inhibit neovascularization.
  • Neovascularization of tissues in the front of the eye i.e. the cornea, iris, and the trabecular meshwork
  • other conditions including conditions in the back of the eye, for example, retinal, subretinal, macular, and optical nerve head neovascularization
  • the angiostatic agents are useful in preventing and treating ocular neovascularization, including providing for the regression of neovascularization.
  • the angiostatic agents of this invention are steroids available from Steraloids, Inc., Wilton, N.H. and have the following structures and names: ,9(11 )-Pregnadien-17a,21 -diol- 4,9(11 )-Pregnadien-17a,21 3,20-dion ⁇ -21 -acetate diol-3,20-dione
  • TFS Tetrahydrocortexolone
  • THF Tetrahydrocortisol
  • the above structures include all pharmaceutically acceptable salts of the angiostatic steroids.
  • the preferred angiostatic steroids are 4,9(1 l)-pregnadi en- 17 ,21-diol-3,20-dione and 4,9(1 l)-pregnadien-17 ⁇ ,21-diol-3,20-dione-21 -acetate (anecortave acetate).
  • the angiostatic steroids in combination with PDT are useful in preventing and treating any ocular neovascularization, including, but not limited to: retinal diseases (diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, age related macular degeneration (ARMD) due to subretinal neovascularization); rubeosis ulceris; inflammatory diseases; chronic uveitis; neoplasms (retinoblastoma, pseudoglioma); Fuchs' heterochromic iridocyclitis; neovascular glaucoma; corneal neovascularization (inflammatory, transplantation, developmental hypoplasia of the iris); neovascularization resulting following a combined vitrectomy and lensectomy; vascular diseases (retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia); neovascularization of the optic nerve;
  • neovascularization The initiation of new blood vessel formation may arise quite differently in various tissues or as a result of different diseases. Many substances have been found to induce neovascularization, see, Folkman, et al., Angiogenic Factors, Science, Volume 235, pp. 442-447 (1987). However, it is believed, that once initiated, the process of neovascularization is similar in all tissues and regardless of the associated disease, Furcht, Critical Factors Controlling Angiogenesis: Cell Products, Cell Matrix, and Growth Factors, Laboratory Investigation, Volume 55, No. 5, pp. 505-509 (1986).
  • angiostatic steroids there are a variety of theories regarding the mechanism of action of angiostatic steroids.
  • angiostatic steroid induced inhibition of neovascularization may occur due to, dissolution of the capillary basement membrane, Ingber, et al., Supra; inhibition of vascular endothelial cell proliferation, Cariou, et al., Inhibition of Human Endothelial Cell Proliferation by Heparin and Steroids, Cell Biology International Reports, Vol. 12, No. 12, pp.
  • angiostatic agents work by inhibiting one or more steps in the process of neovascularization. Therefore, the angiostatic steroids of this invention are useful in the treatment and prevention of neovascularization associated with a variety of diseases and surgical complications.
  • the angiostatic steroids of the present invention may be incorporated in various formulations for delivery to the eye.
  • topical formulations can be used and can include ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride, and water to form aqueous sterile ophthalmic solutions and suspensions.
  • an angiostatic steroid is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin, or white petrolatum.
  • Sterile ophthalmic gel formulations comprising the angiostatic steroids of the present invention can be prepared by suspending an angiostatic steroid in a hydrophilic base prepared from a combination of, for example, Carbopol (a carboxy vinyl polymer available the BF Goodrich Company) according to published formulations for analogous ophthalmic preparations. Preservatives and antimicrobial agents may also be incorporated in such gel formulations. Ocular injection (intravitreal, subtenons, subconjunctival, periocular, retrobulbar) as well as intraocular slow release devices and implants may be used, particularly for delivery to the back of the eye. Systemic formulations, for example, orally ingested tablets and formulations for intraocular injection are also contemplated.
  • a hydrophilic base prepared from a combination of, for example, Carbopol (a carboxy vinyl polymer available the BF Goodrich Company) according to published formulations for analogous ophthalmic preparations. Preservatives and antimicrobial agents may also be incorporated
  • Topical ophthalmic aqueous solutions, suspensions, ointments, and gels are the preferred dosage forms for the treatment of neovascularization in the front of the eye (the cornea, iris, trabecular meshwork); or neovascularization of the back of the eye if the angiostatic agent can be formulated such that it can be delivered topically and the agent is able to penetrate the tissues in the front of the eye.
  • the angiostatic steroid will normally be contained in these and other formulations in an amount from about 0.01 to about 15.0 weight/percent.
  • Preferable concentrations range from about 0.1 to about 7.5 weight/percent.
  • these formulations are delivered to the surface of the eye one to six times a day, depending on the routine discretion of the skilled clinician.
  • Systemic administration for example, in the form of tablets is useful for the treatment of neovascularization particularly of the back of the eye, for example, the retina.
  • Tablets containing 10-100 mg of angiostatic agent can be taken 2-3 times per day depending on the discretion of the skilled clinician.
  • the compounds no matter how delivered, can be administered prior to, during, and/or after PDT. It is preferred to administer the compounds both before and after surgury to slow or prevent the reoccurrence of neovascularization.
  • Example 1 Topical Ocular Formulation Ingredient Amount (wt.%)
  • the formulation is prepared by first placing a portion of the purified water into a beaker and heating to 90°C.
  • the hydroxypropylmethylcellulose (HPMC) is then added to the heated water and mixed by means of vigorous vortex stirring until all of the HPMC is dispersed.
  • the resulting mixture is then allowed to cool while undergoing mixing in order to hydrate the HPMC.
  • the resulting solution is then sterilized by means of autoclaving in a vessel having a liquid inlet and a hydrophobic, sterile air vent filter.
  • the sodium chloride and the edetate disodium are then added to a second portion of the purified water and dissolved.
  • the benzalkonium chloride is then added to the solution, and the pH of the solution is adjusted to 7.4 with 0.1M NaOH/HCl.
  • the solution is then sterilized by means of filtration.
  • the 4,9(1 l)-Pregnadien-17 ⁇ ,21-diol-3,20-dione-21 -acetate is sterilized by either dry heat or ethylene oxide. If ethylene oxide sterilization is selected, aeration for at least 72 hours at 50°C is necessary.
  • the sterilized 4,9(1 l)-Pregnadien-17 ⁇ ,21-diol-3,20-dione-21 -acetate is weighed aseptically and placed into a pressurized ballmill container.
  • the tyloxapol, in sterilized aqueous solution form, is then added to the ballmill container.
  • Sterilized glass balls are then added to the container and the contents of the container are milled aseptically at 225 rpm for 16 hours, or until all particles are in the range of approximately 5 microns.
  • the micronized drug suspension formed by means of the preceding step is then poured into the HPMC solution with mixing.
  • the ballmill container and balls contained therein are then rinsed with a portion of the solution containing the sodium chloride, the edetate disodium and benzalkonium chloride.
  • the rinse is then added aseptically to the HPMC solution.
  • the final volume of the solution is then adjusted with purified water and, if necessary, the pH of the solution is adjusted to pH 7.4 with NaOH/HCl.
  • the formulation will be given topically, in a therapeutically effective amount.
  • the phrase "therapeutically effective amount” means an amount which is sufficient to substantially prevent or reverse any ocular neovascularization.
  • the dosage regimen used will depend on the nature of the neovascularization, as well as various other factors such as the patient's age, sex, weight, and medical history.
  • Topical Ocular Formulation Ingredient Amount (wt.%)
  • anecortave acetate with inactive ingredients such as starch, lactose and magnesium stearate can be formulated according to procedures known to those skilled in the art of tablet formulation.
  • the corneal pocket system of BenEzra (Am. J. Ophthalmol 86:455-461, 1978) was used to induce corneal neovascularization in the rabbit.
  • a small Elvax pellet containing 0.5 ⁇ g of lipopolysaccharide (LPS) was inserted into the middle of the corneal stroma and positioned 2.5 mm from the limbus.

Abstract

Methods for treating ocular neovascularization using photodynamic therapy in combination with an angiostatic steroid are disclosed.

Description

THE USE OF ANGIOSTATIC STEROIDS IN PHOTODYNAMIC THERAPY
Field of the Invention:
This invention relates to the use of angiostatic steroids in photodynamic therapy (PDT).
Description of the Related Art:
Steroids functioning to inhibit angiogenesis in the presence of heparin or specific heparin fragments are disclosed in Crum, et al., A New Class of Steroids Inhibits Angiogenesis In The Presence of Heparin or Heparin Fragment, Science, 230:375-378, December 20, 1985. The authors refer to such steroids as "angiostatic" steroids. Included in the new class of steroids found to be angiostatic are cortisol, cortexolone, and several dihydro and tetrahydro derivatives. In a follow up study directed to testing a hypothesis as to the mechanism by which the steroids inhibit angiogenesis, it was shown that heparin/angiostatic steroid compositions caused dissolution of the basement membrane scaffolding to which anchorage dependent endothelia are attached resulting in capillary involution; see, Ingber, et al. A Possible Mechanism for Inhibition of Angiogenesis by Angiostatic Steroids: Induction of Capillary Basement Membrane Dissolution, Endocrinology 119:768-775, 1986.
A group of tetrahydrosteroids useful in inhibiting angiogenesis is disclosed in U.S. Patent No. 4,975,537, issued to Aristoff, et al. The compounds are disclosed for use in treating head trauma, spinal trauma, septic or traumatic shock, stroke, and hemorrhage shock. In addition, the patent discusses the utility of these compounds in embryo implantation and in the treatment of cancer, arthritis, and arteriosclerosis. The compounds are not disclosed for ophthalmic use. Some of the tetrahydrosteroids disclosed in Aristoff, et al. are disclosed in U.S. Patent No. 4,771,042 in combination with heparin or a heparin fragment for inhibiting angiogenesis in a warm blooded animal. The patent does not disclose the combination for ophthalmic use.
Compositions of hydrocortisone, "tetrahydrocortisol-S," and U-72,745G, each in combination with a beta cyclodextrin have been shown to inhibit corneal neovascularization. Li, et al., Angiostatic Steroids Potentiated by Sulphated Cyclodextrin Inhibit Corneal Neovascularization, Investigative Ophthalmology and Visual Science, 32(l l):2898-2905, October, 1991. The steroids alone reduce neovascularization somewhat but are not effective alone in providing for regression of neovascularization.
There are currently no effective therapies for the treatment of ocular neovascular diseases which do not include the destruction of healthy viable tissue. Although panretinal photocoagulation is the current medical practice for the treatment of diabetic retinopathy and is effective in inhibiting diabetic retinal neovascularization, this procedure destroys healthy peripheral retinal tissue. This destruction of healthy tissue decreases the retinal metabolic demand and thereby reduces retinal ischemia driven neovascularization. A recent new laser procedure is being tested for the inhibition of ocular neovascularization. Photodynamic therapy (PDT) is a procedure in which a photoactivatable dye is given systemically followed by laser activation of the dye in the eye at the site of new blood vessel formation (Asrani & Zeimer, Br J Ophthalmol, 79(8):776-770, August, 1995; Asrani et al, Invest Ophthalmol. Vis Sci, 38(13);2702-2710, December, 1997; Husain et al, Ophthalmology, 104(8):242-1250, August, 1997; Lin et al, Curr Eye Res, 13(7):513-522, July, 1994.) The photoactivated drug generates free oxygen radicals which seal the newly formed blood vessels. This procedure has been used in patients with the exudative form of macular degeneration and many patients show regression of their subretinal neovascular membranes. Unfortunately, it appears that the PDT induced inhibition of neovascularization is transient lasting only 6-12 weeks (Gragoudas et al, Investigative Ophthalmology & Visual Science, 38(4):S17; March 15, 1997; Sickenberg et al, Investigative Ophthalmology & Visual Science, 38(4):S92, March 15, 1997; Thomas et al, Investigative Ophthalmology & Visual Science, 39(4):S242, March 15, 1998.) The subject matter of the present invention involves combining the PDT induced regression of ocular neovascular tissue with agents, such as angiostatic steroids, which inhibit new blood vessel formation.
Summary of the Invention
This invention is directed to methods for treating ocular neovascular diseases by combining the use of PDT with particular angiostatic steroids.
Brief Description of the Drawing
Figure 1 - Compares the ability of angiostatic steroids to inhibit neovascularization in the rabbit cornea.
Detailed Description Of The Preferred Embodiments
The development of blood vessels for the purpose of sustaining vital tissue is known as angiogenesis or neovascularization. Agents which inhibit neovascularization are known by a variety of terms such as angiostatic, angiolytic, or angiotropic agents. For purposes of this specification, the term "angiostatic agent" means compounds which can be used to inhibit neovascularization.
Ocular neovascularization has not been successfully treated in the past.
Neovascularization of tissues in the front of the eye (i.e. the cornea, iris, and the trabecular meshwork) and other conditions, including conditions in the back of the eye, for example, retinal, subretinal, macular, and optical nerve head neovascularization, can be prevented and treated by administration of the steroids of this invention. The angiostatic agents are useful in preventing and treating ocular neovascularization, including providing for the regression of neovascularization.
The angiostatic agents of this invention are steroids available from Steraloids, Inc., Wilton, N.H. and have the following structures and names:
Figure imgf000006_0001
,9(11 )-Pregnadien-17a,21 -diol- 4,9(11 )-Pregnadien-17a,21 3,20-dionβ-21 -acetate diol-3,20-dione
Figure imgf000006_0002
11 -Epicortisol 17alpha-Hydroxy progesterone
Figure imgf000006_0003
Tetrahydrocortexolone (THS) Tetrahydrocortisol (THF) The above structures include all pharmaceutically acceptable salts of the angiostatic steroids.
The preferred angiostatic steroids are 4,9(1 l)-pregnadi en- 17 ,21-diol-3,20-dione and 4,9(1 l)-pregnadien-17α,21-diol-3,20-dione-21 -acetate (anecortave acetate).
The angiostatic steroids in combination with PDT are useful in preventing and treating any ocular neovascularization, including, but not limited to: retinal diseases (diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, age related macular degeneration (ARMD) due to subretinal neovascularization); rubeosis iritis; inflammatory diseases; chronic uveitis; neoplasms (retinoblastoma, pseudoglioma); Fuchs' heterochromic iridocyclitis; neovascular glaucoma; corneal neovascularization (inflammatory, transplantation, developmental hypoplasia of the iris); neovascularization resulting following a combined vitrectomy and lensectomy; vascular diseases (retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia); neovascularization of the optic nerve; and neovascularization due to penetration of the eye or contusive ocular injury. In particular, this therapy is useful in the treatment of exudative ARMD and diabetic retinopathy.
The initiation of new blood vessel formation may arise quite differently in various tissues or as a result of different diseases. Many substances have been found to induce neovascularization, see, Folkman, et al., Angiogenic Factors, Science, Volume 235, pp. 442-447 (1987). However, it is believed, that once initiated, the process of neovascularization is similar in all tissues and regardless of the associated disease, Furcht, Critical Factors Controlling Angiogenesis: Cell Products, Cell Matrix, and Growth Factors, Laboratory Investigation, Volume 55, No. 5, pp. 505-509 (1986).
There are a variety of theories regarding the mechanism of action of angiostatic steroids. For example, angiostatic steroid induced inhibition of neovascularization may occur due to, dissolution of the capillary basement membrane, Ingber, et al., Supra; inhibition of vascular endothelial cell proliferation, Cariou, et al., Inhibition of Human Endothelial Cell Proliferation by Heparin and Steroids, Cell Biology International Reports, Vol. 12, No. 12, pp. 1037-1047 (December, 1988); effect on vascular endothelial cell laminin expression, Tokida, et al., Production of Two Variant Laminin Forms by Endothelial Cells and Shift of Their Relative Levels by Angiostatic Steroids, The Journal of Biological Chemistry, Vol. 264, No. 30, pp. 18123-18129 (October 25, 1990); inhibition of vascular cell collagen synthesis, Maragoudakis, et al., Antiangiogenic Action of Heparin Plus Cortisone is Associated with Decreased Collagenous Protein Synthesis in the Chick Chorioallantoic Membrane System, The Journal of Pharmacology and Experimental Therapeutics, Vol. 251, No. 2, pp. 679-682 (1989); and inhibition of vascular endothelial cell plasminogen activator activity, Ashino-Fuse, et al., Medroxyprogesterone Acetate, An Anti-Cancer and Anti-Angiogenic Steroid, Inhibits the Plasminogen Activator in Bovine Endothelial Cells, Int. J. Cancer, 44, pp. 859-864 (1989).
There are many theories associated with the cause of neovascularization, and there may be different inducers depending on the disease or surgery involved, BenEzra, Neovasculogenic Ability of Prostaglandins, Growth Factors, and Synthetic Chemoattractants, American Journal of Ophthalmology, Volume 86, No. 4, pp. 455-461, (October, 1978). Regardless of the cause or the associated disease or surgery, it is believed that angiostatic agents work by inhibiting one or more steps in the process of neovascularization. Therefore, the angiostatic steroids of this invention are useful in the treatment and prevention of neovascularization associated with a variety of diseases and surgical complications.
The angiostatic steroids of the present invention may be incorporated in various formulations for delivery to the eye. For example, topical formulations can be used and can include ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride, and water to form aqueous sterile ophthalmic solutions and suspensions. In order to prepare sterile ophthalmic ointment formulations, an angiostatic steroid is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations comprising the angiostatic steroids of the present invention can be prepared by suspending an angiostatic steroid in a hydrophilic base prepared from a combination of, for example, Carbopol (a carboxy vinyl polymer available the BF Goodrich Company) according to published formulations for analogous ophthalmic preparations. Preservatives and antimicrobial agents may also be incorporated in such gel formulations. Ocular injection (intravitreal, subtenons, subconjunctival, periocular, retrobulbar) as well as intraocular slow release devices and implants may be used, particularly for delivery to the back of the eye. Systemic formulations, for example, orally ingested tablets and formulations for intraocular injection are also contemplated.
The specific type of formulation selected will depend on various factors, such as the angiostatic steroid or its salt being used, the dosage frequency, and the location of the neovascularization being treated. Topical ophthalmic aqueous solutions, suspensions, ointments, and gels are the preferred dosage forms for the treatment of neovascularization in the front of the eye (the cornea, iris, trabecular meshwork); or neovascularization of the back of the eye if the angiostatic agent can be formulated such that it can be delivered topically and the agent is able to penetrate the tissues in the front of the eye. The angiostatic steroid will normally be contained in these and other formulations in an amount from about 0.01 to about 15.0 weight/percent. Preferable concentrations range from about 0.1 to about 7.5 weight/percent. Thus, for topical administration, these formulations are delivered to the surface of the eye one to six times a day, depending on the routine discretion of the skilled clinician. Systemic administration, for example, in the form of tablets is useful for the treatment of neovascularization particularly of the back of the eye, for example, the retina. Tablets containing 10-100 mg of angiostatic agent can be taken 2-3 times per day depending on the discretion of the skilled clinician.
The compounds, no matter how delivered, can be administered prior to, during, and/or after PDT. It is preferred to administer the compounds both before and after surgury to slow or prevent the reoccurrence of neovascularization.
The following examples illustrate formulations of the present invention, but are in no way limiting. Example 1 Topical Ocular Formulation Ingredient Amount (wt.%)
Anecortave Acetate 1.0
Tyloxapol 0.01 to 0.05 HPMC 0.5
B enzalkonium Chloride 0.01
Sodium Chloride 0.8
Edetate Disodium 0.01
NaOH/HCl q.s. pH 7.4
Purified Water q.s. 100 mL
The formulation is prepared by first placing a portion of the purified water into a beaker and heating to 90°C. The hydroxypropylmethylcellulose (HPMC) is then added to the heated water and mixed by means of vigorous vortex stirring until all of the HPMC is dispersed. The resulting mixture is then allowed to cool while undergoing mixing in order to hydrate the HPMC. The resulting solution is then sterilized by means of autoclaving in a vessel having a liquid inlet and a hydrophobic, sterile air vent filter.
The sodium chloride and the edetate disodium are then added to a second portion of the purified water and dissolved. The benzalkonium chloride is then added to the solution, and the pH of the solution is adjusted to 7.4 with 0.1M NaOH/HCl. The solution is then sterilized by means of filtration.
The 4,9(1 l)-Pregnadien-17α,21-diol-3,20-dione-21 -acetate is sterilized by either dry heat or ethylene oxide. If ethylene oxide sterilization is selected, aeration for at least 72 hours at 50°C is necessary. The sterilized 4,9(1 l)-Pregnadien-17α,21-diol-3,20-dione-21 -acetate is weighed aseptically and placed into a pressurized ballmill container. The tyloxapol, in sterilized aqueous solution form, is then added to the ballmill container. Sterilized glass balls are then added to the container and the contents of the container are milled aseptically at 225 rpm for 16 hours, or until all particles are in the range of approximately 5 microns.
Under aseptic conditions, the micronized drug suspension formed by means of the preceding step is then poured into the HPMC solution with mixing. The ballmill container and balls contained therein are then rinsed with a portion of the solution containing the sodium chloride, the edetate disodium and benzalkonium chloride. The rinse is then added aseptically to the HPMC solution. The final volume of the solution is then adjusted with purified water and, if necessary, the pH of the solution is adjusted to pH 7.4 with NaOH/HCl. The formulation will be given topically, in a therapeutically effective amount. In this instance, the phrase "therapeutically effective amount" means an amount which is sufficient to substantially prevent or reverse any ocular neovascularization. The dosage regimen used will depend on the nature of the neovascularization, as well as various other factors such as the patient's age, sex, weight, and medical history.
Example 2
Topical Ocular Formulation Ingredient Amount (wt.%)
Anecortave Acetate 1.0
Mannitol 2.40
Sodium Chloride 0.40
Carbopol 974P 0.50
Polysorbate 80 0.05
Edetate Disodium 0.01
Benzalkonium Chloride 0.01 + 5% XS
Sodium Hydroxide adjust pH to 7.2
Purified Water qs to l00% Example 3
Tablet: 5-100 mg anecortave acetate with inactive ingredients such as starch, lactose and magnesium stearate can be formulated according to procedures known to those skilled in the art of tablet formulation.
Example 4
Formulation for Sterile Intraocular Injection each mL contains:
4,9(1 l)-Pregnadien-17α,21-diol-3,20-dione 10-100 mg Sodium Chloride 7.14 mg
Potassium Chloride 0.38 mg
Calcium chloride dihydrate 0.154 mg
Magnesium chloride hexahydrate 0.2 mg
Dried sodium phosphate 0.42 mg Sodium bicarbonate 2.1 mg
Dextrose 0.92 mg Hydrochloric acid or sodium hydroxide to adjust pH to approximately 7.2 Water for injection
Example 5 Sterile Injection Formulation List of Components mg/ml
Anecortave Acetate 0.1-150 (0.0 for vehicle)
Monobasic Sodium Phosphate, Monohydrate 0.1-5
Diabasic Sodium Phosphate, Anhydrous 0.1-5
Tyloxapol 0.0-10
Sodium Chloride 0.1-10
Hydrochloric Acid and/or Sodium Hydroxide Adjust pH 7.0 - 7.8
Water for Injection q.s.
Example 6
Sterile Injection Formulation
List of Compounds mg/ml
Anecortave Acetate 60
Monobasic Sodium Phosphate, Monohydrate 0.45
Dibasic Sodium Phosphate, Anhydrous 2.0
Tyloxapol 4.0
Sodium Chloride 7.0
Hydrochloric Acid and/or
Sodium Hydroxide Adjust pH 7.4 ± 0.2
Water for Injection q.s Example 7
Inhibition of angiogenesis in the rabbit corneal neovascularization model:
The corneal pocket system of BenEzra (Am. J. Ophthalmol 86:455-461, 1978) was used to induce corneal neovascularization in the rabbit. A small Elvax pellet containing 0.5 μg of lipopolysaccharide (LPS) was inserted into the middle of the corneal stroma and positioned 2.5 mm from the limbus. An additional Elvax pellet with or without 50μg of angiostatic steroid was placed next to the
LPS implant. The eyes were examined daily and the area of neovascularization calculated. Results after 8 days of LPS implantation are shown in Figure 1. THF - tetrahydrocortisol; A = 4,9(1 l)-Pregnadien-17α,21-diol-3,20-dione-21- acetate; B = 4,9(1 l)-Pregnadien-17α,21-diol-3,20-dione. As can be seen, A & B totally inhibited corneal neovascularization, whereas THF partially inhibited the neovascular response.

Claims

I Claim:
1. A method for preventing and treating ocular neovascularization, which comprises the use of PDT in combination with a compound selected from the group consisting of:
4,9(1 l)-Pregnadien-17╬▒,21-diol-3,20-dione-21 -acetate, 4,9(1 l)-Pregnadien-17╬▒,21-diol-3, 20- dione, 11-Epicortisol, 17alpha-Hydroxyprogesterone, Tetrahydrocortexolone (THS), and Tetrahydrocortisol (THF).
2. The method of Claim 1 wherein the angiostatic steroid is 4,9(11)-Pregnadien-17╬▒,21- diol-3 ,20-dione-21 -acetate.
3. The method of Claim 1 wherein the angiostatic steroid is 4,9(11)-Pregnadien-17╬▒,21- diol-3,20-dione.
4. The method of Claim 1 wherein the angiostatic steroid is administered at a concentration of about 0.01 to 15.0 weight percent.
5. The method of Claim 4 wherein the angiostatic steroid is administered at a concentration of about 0.1 - 7.5 weight percent.
PCT/US1998/012711 1991-11-22 1998-06-18 The use of angiostatic steroids in photodynamic therapy WO1999003503A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
EP98931367A EP1003553B1 (en) 1997-07-16 1998-06-18 The use of angiostatic steroids in photodynamic therapy
AU81515/98A AU734195B2 (en) 1997-07-16 1998-06-18 The use of angiostatic steroids in photodynamic therapy
AT98931367T ATE274356T1 (en) 1997-07-16 1998-06-18 USE OF ANGIOSTATIC STEROIDS IN PHOTODYNAMIC THERAPY
JP2000502798A JP2001510170A (en) 1997-07-16 1998-06-18 Methods and uses of anti-angiogenic steroids in photodynamic therapy
DE69825906T DE69825906T2 (en) 1997-07-16 1998-06-18 USE OF ANGIOSTATIC STEROIDS IN PHOTODYNAMIC THERAPY
BR9811012-8A BR9811012A (en) 1997-07-16 1998-06-18 "use of a compound".
CA002296558A CA2296558A1 (en) 1997-07-16 1998-06-18 The use of angiostatic steroids in photodynamic therapy of ocular neovascularization
US09/445,237 US6297228B1 (en) 1991-11-22 1998-06-18 Use of angiostatic steroids in photodynamic therapy
HK00107465A HK1028952A1 (en) 1997-07-16 2000-11-22 The use of angiostatic steroids in photodynamic therapy.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/895,184 US5770592A (en) 1991-11-22 1997-07-16 Prevention and treatment of ocular neovascularization using angiostatic steroids
US08/895,184 1997-07-16

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/456,432 Continuation US6372723B1 (en) 1997-06-18 1999-12-08 Compositions and methods for preventing restenosis following revascularization procedures

Publications (1)

Publication Number Publication Date
WO1999003503A1 true WO1999003503A1 (en) 1999-01-28

Family

ID=25404127

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/012711 WO1999003503A1 (en) 1991-11-22 1998-06-18 The use of angiostatic steroids in photodynamic therapy

Country Status (13)

Country Link
US (2) US5770592A (en)
EP (1) EP1003553B1 (en)
JP (1) JP2001510170A (en)
AT (1) ATE274356T1 (en)
AU (1) AU734195B2 (en)
BR (1) BR9811012A (en)
CA (1) CA2296558A1 (en)
DE (1) DE69825906T2 (en)
DK (1) DK1003553T3 (en)
ES (1) ES2224412T3 (en)
HK (1) HK1028952A1 (en)
PT (1) PT1003553E (en)
WO (1) WO1999003503A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001058240A2 (en) * 2000-02-10 2001-08-16 Massachusetts Eye And Ear Infirmary Photodynamic therapy for treating conditions of the eye
US6602274B1 (en) 1999-01-15 2003-08-05 Light Sciences Corporation Targeted transcutaneous cancer therapy
EP1539182A1 (en) * 2002-08-05 2005-06-15 Alcon, Inc. Use of anecortave acetate for the protection of visual acuity in patients with age related macular degeneration
EP1570859A2 (en) * 2000-03-24 2005-09-07 Novartis AG Improved treatment of neovascularization
WO2005102297A2 (en) * 2004-04-23 2005-11-03 Alcon, Inc. Angiostatic agents for controlling choroidal neovascularisation after ocular surgery of trauma
EP2278978A2 (en) * 2008-05-28 2011-02-02 Validus Biopharma, Inc. Non-hormonal steroid modulators of nf-kb for treatment of disease
US8158669B2 (en) 2000-03-24 2012-04-17 Qlt, Inc. Method for treating neovascularization
US9198921B2 (en) 2010-04-05 2015-12-01 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US10799514B2 (en) 2015-06-29 2020-10-13 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kappa beta for treatment of disease
US11382922B2 (en) 2019-03-07 2022-07-12 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions

Families Citing this family (84)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002534139A (en) * 1999-01-05 2002-10-15 マサチューセッツ・アイ・アンド・イア・インファーマリー Transscleral sustained release drug targeted delivery to retina and choroid
JP2002534218A (en) 1999-01-15 2002-10-15 ライト サイエンシーズ コーポレイション Non-invasive vascular therapy
DE60001629T2 (en) * 1999-01-15 2003-12-18 Light Sciences Corp THERAPEUTIC COMPOSITIONS FOR BONE METABOLISM DISORDERS OR BONE METASTASES CONTAINING A PHOTOSENSITIZER AND A BISPHOSPHONATE
US7943162B2 (en) * 1999-10-21 2011-05-17 Alcon, Inc. Drug delivery device
US6416777B1 (en) 1999-10-21 2002-07-09 Alcon Universal Ltd. Ophthalmic drug delivery device
US6413245B1 (en) 1999-10-21 2002-07-02 Alcon Universal Ltd. Sub-tenon drug delivery
DE60016271T2 (en) 1999-10-21 2005-12-01 Alcon Inc. drug delivery
US7678836B2 (en) * 1999-11-04 2010-03-16 Fxs Ventures, Llc Method for rendering a contact lens wettable
US9603741B2 (en) 2000-05-19 2017-03-28 Michael S. Berlin Delivery system and method of use for the eye
CA2446143C (en) * 2000-05-19 2010-01-19 Michael S. Berlin Delivery system and method of use for the eye
US8679089B2 (en) 2001-05-21 2014-03-25 Michael S. Berlin Glaucoma surgery methods and systems
US7563255B2 (en) 2001-05-03 2009-07-21 Massachusetts Eye And Ear Infirmary Implantable drug delivery device and use thereof
WO2003009774A2 (en) 2001-07-23 2003-02-06 Alcon, Inc. Ophthalmic drug delivery device
JP4249611B2 (en) * 2001-07-23 2009-04-02 アルコン，インコーポレイティド Ophthalmic drug delivery device
AU2002331916B2 (en) * 2001-10-03 2008-07-24 Merck Sharp & Dohme Corp. Androstane 17-beta-carboxamides as androgen receptor modulators
EA006746B1 (en) * 2001-11-09 2006-04-28 Айтек Фармасьютикалз Methods for treating ocular neovascular diseases
US6723750B2 (en) 2002-03-15 2004-04-20 Allergan, Inc. Photodynamic therapy for pre-melanomas
AU2003217531A1 (en) * 2002-05-02 2003-11-17 Massachusetts Eye And Ear Infirmary Ocular drug delivery systems and use thereof
WO2004011460A2 (en) 2002-07-24 2004-02-05 Qlt, Inc. Pyrazolylbenzothiazole derivatives and their use as therapeutic agents
US6828356B2 (en) * 2002-07-29 2004-12-07 Ast Products, Inc. Preparation of ophthalmic compositions
AU2003259301A1 (en) * 2002-07-29 2004-02-16 Ast Products, Inc. Ophtalmic compositions
US6806364B2 (en) * 2002-07-29 2004-10-19 Ast Products, Inc. Ophthalmic compositions
DE10238310A1 (en) * 2002-08-21 2004-03-04 Erich Jaeger Gmbh electrode assembly
US7288106B2 (en) * 2002-10-03 2007-10-30 Light Sciences Oncology, Inc. System and method for excitation of photoreactive compounds in eye tissue
US20060167435A1 (en) * 2003-02-18 2006-07-27 Adamis Anthony P Transscleral drug delivery device and related methods
JP2006518382A (en) * 2003-02-20 2006-08-10 アルコン，インコーポレイテッド Use of steroids to treat people suffering from eye disorders
WO2004073608A2 (en) * 2003-02-20 2004-09-02 Alcon, Inc. Formulations of glucocorticoids to treat pathologic ocular angiogenesis
US20070043006A1 (en) * 2003-06-13 2007-02-22 Bingaman David P Formulations of non-steroidal anti-inflammatory agents to treat pathologic ocular angiogenesis
AU2004249256A1 (en) * 2003-06-20 2004-12-29 Alcon, Inc. Treatment of AMD with combination of ingredients
JP2007526019A (en) * 2003-07-10 2007-09-13 アルコン，インコーポレイティド Ophthalmic drug delivery device
AU2004274026A1 (en) * 2003-09-18 2005-03-31 Macusight, Inc. Transscleral delivery
BRPI0414699A (en) * 2003-09-23 2006-11-28 Alcon Inc anecortave acetate and triamcinolone acetonide formulations for injection
WO2005072744A1 (en) * 2004-02-02 2005-08-11 Yuichi Kaji Vitreous-visualizing agents
EP1720874A4 (en) * 2004-02-24 2010-03-03 Bioaxone Therapeutique Inc 4-substituted piperidine derivatives
US20160106717A1 (en) 2004-09-24 2016-04-21 Gen Pharma Holdings LLC Cai-based systems and methods for the localized treatment of uveitis
EP1802373B1 (en) 2004-09-24 2011-07-06 RFE Pharma LLC Carboxy-amido-triazoles for the localized teatment of ocular diseases
US20060107555A1 (en) * 2004-11-09 2006-05-25 Curtis Marc D Universal snow plow adapter
US8663639B2 (en) * 2005-02-09 2014-03-04 Santen Pharmaceutical Co., Ltd. Formulations for treating ocular diseases and conditions
ES2564194T3 (en) * 2005-02-09 2016-03-18 Santen Pharmaceutical Co., Ltd. Liquid formulations for the treatment of diseases or ailments
AU2006250914B2 (en) 2005-05-25 2012-03-01 Chemisches Institut Schaefer Ag Biocompatible polymers and co-polymers comprising amino acids in the side chain
EP2462959B1 (en) * 2005-07-12 2016-06-22 Ampio Pharmaceuticals, Inc. Methods and products for treatment of diseases
CA2616537A1 (en) 2005-07-27 2007-02-01 University Of Florida Research Foundation, Inc. Small compounds that correct protein misfolding and uses thereof
US7261529B2 (en) * 2005-09-07 2007-08-28 Southwest Research Institute Apparatus for preparing biodegradable microparticle formulations containing pharmaceutically active agents
TWI541253B (en) 2005-09-07 2016-07-11 艾默根佛蒙特有限公司 Human monoclonal antibodies to activin receptor-like kinase-1
US9693967B2 (en) * 2005-09-07 2017-07-04 Southwest Research Institute Biodegradable microparticle pharmaceutical formulations exhibiting improved released rates
US7758778B2 (en) * 2005-09-07 2010-07-20 Southwest Research Institute Methods for preparing biodegradable microparticle formulations containing pharmaceutically active agents
US20080125406A1 (en) * 2005-10-14 2008-05-29 Robin Alan L Method for Treating Primary and Secondary Forms of Glaucoma
US20070197491A1 (en) * 2005-10-14 2007-08-23 Alcon, Inc. Method for treating primary and secondary forms of glaucoma
US20070134244A1 (en) * 2005-10-14 2007-06-14 Alcon, Inc. Combination treatment for pathologic ocular angiogenesis
EP1956906A4 (en) 2005-11-09 2009-12-30 Combinatorx Inc Methods, compositions, and kits for the treatment of medical conditions
AU2006320535B2 (en) 2005-11-29 2010-09-23 Glaxosmithkline Llc Treatment method
KR20140093764A (en) 2006-02-09 2014-07-28 산텐 세이야꾸 가부시키가이샤 Stable formulations, and methods of their preparation and use
DK2001466T3 (en) 2006-03-23 2016-02-29 Santen Pharmaceutical Co Ltd LOW-DOSAGE RAPAMYCINE FOR TREATMENT OF VASCULAR PERMEABILITY-RELATED DISEASES
US20080265343A1 (en) * 2007-04-26 2008-10-30 International Business Machines Corporation Field effect transistor with inverted t shaped gate electrode and methods for fabrication thereof
US20170360609A9 (en) 2007-09-24 2017-12-21 Ivantis, Inc. Methods and devices for increasing aqueous humor outflow
US20090181933A1 (en) * 2008-01-11 2009-07-16 Bingaman David P Use of steroids to treat persons suffering from ocular disorders
AU2009221859B2 (en) 2008-03-05 2013-04-18 Alcon Inc. Methods and apparatus for treating glaucoma
US8632511B2 (en) 2009-05-06 2014-01-21 Alcon Research, Ltd. Multiple thermal sensors in a multiple processor environment for temperature control in a drug delivery device
IN2012DN00352A (en) 2009-06-16 2015-08-21 Bikam Pharmaceuticals Inc
MX2011013984A (en) * 2009-06-22 2012-06-01 Dmi Acquisition Corp Methods and products for treatment of diseases.
PL2326332T3 (en) * 2009-06-22 2013-05-31 Ampio Pharmaceuticals Inc Method for treatment of diseases
AU2010271274B2 (en) 2009-07-09 2015-05-21 Alcon Inc. Single operator device for delivering an ocular implant
CN102481404B (en) 2009-07-09 2014-03-05 伊万提斯公司 Ocular implants
US20120232102A1 (en) 2009-09-30 2012-09-13 Chun-Fang Xu Methods Of Administration And Treatment
US8177747B2 (en) 2009-12-22 2012-05-15 Alcon Research, Ltd. Method and apparatus for drug delivery
US20120283557A1 (en) 2011-05-05 2012-11-08 Berlin Michael S Methods and Apparatuses for the Treatment of Glaucoma using visible and infrared ultrashort laser pulses
US8657776B2 (en) 2011-06-14 2014-02-25 Ivantis, Inc. Ocular implants for delivery into the eye
CN103917093B (en) 2011-06-14 2017-08-11 比卡姆药品公司 Opsin binding partner, composition and application method
EP2768307B1 (en) 2011-10-19 2020-03-18 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use
CA2862807A1 (en) 2011-11-30 2013-06-06 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use
CA2862746A1 (en) 2011-12-01 2013-06-06 Bikam Pharmaceuticals, Inc. Opsin-binding ligands, compositions and methods of use
US8663150B2 (en) 2011-12-19 2014-03-04 Ivantis, Inc. Delivering ocular implants into the eye
US9358156B2 (en) 2012-04-18 2016-06-07 Invantis, Inc. Ocular implants for delivery into an anterior chamber of the eye
US10617558B2 (en) 2012-11-28 2020-04-14 Ivantis, Inc. Apparatus for delivering ocular implants into an anterior chamber of the eye
US9351979B2 (en) 2012-12-19 2016-05-31 Ampio Pharmaceuticals, Inc. Methods of treatment of diseases
WO2016011056A1 (en) 2014-07-14 2016-01-21 Ivantis, Inc. Ocular implant delivery system and method
US10857157B2 (en) 2015-01-26 2020-12-08 BioAxone BioSciences, Inc. Treatment of cerebral cavernous malformations and cerebral aneurysms with rho kinase inhibitors
US10106525B2 (en) 2015-01-26 2018-10-23 BioAxone BioSciences, Inc. Rho kinase inhibitor BA-1049 (R) and active metabolites thereof
US10149856B2 (en) 2015-01-26 2018-12-11 BioAxone BioSciences, Inc. Treatment of cerebral cavernous malformations and cerebral aneurysms with rho kinase inhibitors
CN108135470B (en) 2015-08-14 2021-03-09 伊万提斯公司 Ocular implant with pressure sensor and delivery system
WO2017106517A1 (en) 2015-12-15 2017-06-22 Ivantis, Inc. Ocular implant and delivery system
US11198680B2 (en) 2016-12-21 2021-12-14 BioAxone BioSciences, Inc. Rho kinase inhibitor BA-1049 (R) and active metabolites thereof
WO2019014322A1 (en) 2017-07-11 2019-01-17 BioAxone BioSciences, Inc. Kinase inhibitors for treatment of disease
EP4274529A1 (en) 2021-01-11 2023-11-15 Alcon Inc. Systems and methods for viscoelastic delivery

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991019731A1 (en) * 1990-06-11 1991-12-26 The Upjohn Company Steroids which inhibit angiogenesis
US5371078A (en) * 1988-10-31 1994-12-06 Alcon Laboratories, Inc. Angiostatic steroids and methods and compositions for controlling ocular hypertension
WO1995024930A1 (en) * 1994-03-14 1995-09-21 Massachusetts Eye & Ear Infirmary Use of green porphyrins in ocular diagnosis and therapy

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4975537A (en) * 1985-10-23 1990-12-04 The Upjohn Company Δ9(11) -angiostatic steroids
US4771042A (en) * 1985-11-25 1988-09-13 The Upjohn Company Inhibition of angiogenesis involving the coadministration of steroids with heparin or heparin fragments
US4876250A (en) * 1988-10-31 1989-10-24 Alcon Laboratories, Inc. Methods for controlling ocular hypertension with angiostatic steroids

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5371078A (en) * 1988-10-31 1994-12-06 Alcon Laboratories, Inc. Angiostatic steroids and methods and compositions for controlling ocular hypertension
WO1991019731A1 (en) * 1990-06-11 1991-12-26 The Upjohn Company Steroids which inhibit angiogenesis
WO1995024930A1 (en) * 1994-03-14 1995-09-21 Massachusetts Eye & Ear Infirmary Use of green porphyrins in ocular diagnosis and therapy

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ABBOT F. CLARK: "AL-3789: a novel ophtalmic angiostatic steroid", EXPERT. OPIN. INVEST. DRUGS., vol. 6, no. 12, December 1997 (1997-12-01), pages 1867 - 1877, XP002082568 *
ANDERSON C. ET AL.: "Phtalocyanine Photodynamic Therapy: Disparate effects of Pharmacologic Inhibitors on Cutaneous Photosensitivity and on Tumor Regression", PHOTOCHEMISTRY AND PHOTOBIOLOGY, vol. 65, no. 5, May 1997 (1997-05-01), pages 895 - 901, XP002082567 *
COWLED P.A. ET AL.: "Potentiation of Photodynamic Therapy with Haematoporphyrin Derivatives by Glucocorticoids", CANCER LETTERS, vol. 29, 1985, pages 107 - 114, XP002081606 *
DATABASE DISSERTATION ABSTRACTS University Microfilms International; 1996, DEFALLER JOSEPH MICHAEL: "Mechanism of action and clinical efficay of AL-3789, an angiostatic steroid", XP002082569 *
MILLER J W ET AL: "PHOTODYNAMIC THERAPY OF EXPERIMENTAL CHOROIDAL NEOVASCULARIZATION USING LIPOPROTEIN-DELIVERED BENZOPORPHYRIN", ARCHIVES OF OPHTHALMOLOGY, vol. 113, no. 6, June 1995 (1995-06-01), pages 810 - 818, XP000672344 *
VERINDER S. NIRANKARI: "Laser Photocoagulation for Corneal Stromal Vascularization", TRANS. AM. OPHTALMOL. SOC., vol. 90, 1992, pages 565 - 669, XP002082566 *

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6602274B1 (en) 1999-01-15 2003-08-05 Light Sciences Corporation Targeted transcutaneous cancer therapy
US7125542B2 (en) 2000-02-10 2006-10-24 Massachusetts Eye And Ear Infirmary Methods and compositions for treating conditions of the eye
WO2001058240A3 (en) * 2000-02-10 2002-04-11 Massachusetts Eye & Ear Infirm Photodynamic therapy for treating conditions of the eye
JP2003530146A (en) * 2000-02-10 2003-10-14 マサチューセッツ・アイ・アンド・イア・インファーマリー Photodynamic therapy to treat eye conditions
JP2013082746A (en) * 2000-02-10 2013-05-09 Massachusetts Eye & Ear Infirmary Photodynamic therapy for treating condition of eye
JP2010065057A (en) * 2000-02-10 2010-03-25 Massachusetts Eye & Ear Infirmary Photodynamic therapy for treating condition of eye
WO2001058240A2 (en) * 2000-02-10 2001-08-16 Massachusetts Eye And Ear Infirmary Photodynamic therapy for treating conditions of the eye
EP1570859A3 (en) * 2000-03-24 2008-04-02 Novartis AG Improved treatment of neovascularization
EP1570859A2 (en) * 2000-03-24 2005-09-07 Novartis AG Improved treatment of neovascularization
US8862224B2 (en) 2000-03-24 2014-10-14 Valeant Pharmceuticals International, Inc. Method for treating neovascularization
US8158669B2 (en) 2000-03-24 2012-04-17 Qlt, Inc. Method for treating neovascularization
EP1539182A4 (en) * 2002-08-05 2010-01-20 Alcon Inc Use of anecortave acetate for the protection of visual acuity in patients with age related macular degeneration
EP1539182A1 (en) * 2002-08-05 2005-06-15 Alcon, Inc. Use of anecortave acetate for the protection of visual acuity in patients with age related macular degeneration
WO2005102297A3 (en) * 2004-04-23 2006-01-05 Alcon Inc Angiostatic agents for controlling choroidal neovascularisation after ocular surgery of trauma
WO2005102297A2 (en) * 2004-04-23 2005-11-03 Alcon, Inc. Angiostatic agents for controlling choroidal neovascularisation after ocular surgery of trauma
EP2444092A1 (en) * 2008-05-28 2012-04-25 Validus Biopharma, Inc. Non-hormonal steroid modulators of nf-kb for treatment of disease
US9649320B2 (en) 2008-05-28 2017-05-16 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US8334279B2 (en) 2008-05-28 2012-12-18 Validus Genetics Non-hormonal steroid modulators of NF-κB for treatment of disease
EP2278978A4 (en) * 2008-05-28 2011-06-15 Validus Biopharma Inc Non-hormonal steroid modulators of nf-kb for treatment of disease
CN102076344B (en) * 2008-05-28 2013-11-13 瓦利杜斯生物医药有限公司 Non-hormonal steroid modulators of nf-kb for treatment of disease
US8673887B2 (en) 2008-05-28 2014-03-18 Reveragen Biopharma, Inc Non-hormonal steroid modulators of NF-kB for treatment of disease
CN103739647A (en) * 2008-05-28 2014-04-23 雷沃根生物医药有限公司 Non-hormonal steroid modulators of nf-kb for treatment of disease
EP2278978A2 (en) * 2008-05-28 2011-02-02 Validus Biopharma, Inc. Non-hormonal steroid modulators of nf-kb for treatment of disease
AU2009260471B2 (en) * 2008-05-28 2014-12-11 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-KB for treatment of disease
US11833159B2 (en) 2008-05-28 2023-12-05 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kB for treatment of disease
US9434758B2 (en) 2008-05-28 2016-09-06 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US8207151B2 (en) 2008-05-28 2012-06-26 Validus Biopharma Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
CN103739647B (en) * 2008-05-28 2017-06-09 雷沃根生物医药有限公司 Non- steroid conditioning agent for treating the NF κ B of disease
US10857161B2 (en) 2008-05-28 2020-12-08 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kB for treatment of disease
US10206933B2 (en) 2008-05-28 2019-02-19 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kB for treatment of disease
US10000525B2 (en) 2010-04-05 2018-06-19 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US9198921B2 (en) 2010-04-05 2015-12-01 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κB for treatment of disease
US10799514B2 (en) 2015-06-29 2020-10-13 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-kappa beta for treatment of disease
US11690853B2 (en) 2015-06-29 2023-07-04 Reveragen Biopharma, Inc. Non-hormonal steroid modulators of NF-κβ for treatment of disease
US11382922B2 (en) 2019-03-07 2022-07-12 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions
US11471471B2 (en) 2019-03-07 2022-10-18 Reveragen Biopharma, Inc. Aqueous oral pharmaceutical suspension compositions

Also Published As

Publication number Publication date
ES2224412T3 (en) 2005-03-01
AU734195B2 (en) 2001-06-07
PT1003553E (en) 2004-10-29
DE69825906T2 (en) 2005-09-01
DK1003553T3 (en) 2004-09-20
HK1028952A1 (en) 2001-03-16
JP2001510170A (en) 2001-07-31
US5770592A (en) 1998-06-23
DE69825906D1 (en) 2004-09-30
US6297228B1 (en) 2001-10-02
ATE274356T1 (en) 2004-09-15
CA2296558A1 (en) 1999-01-28
AU8151598A (en) 1999-02-10
EP1003553A1 (en) 2000-05-31
EP1003553B1 (en) 2004-08-25
BR9811012A (en) 2000-10-17

Similar Documents

Publication Publication Date Title
EP1003553B1 (en) The use of angiostatic steroids in photodynamic therapy
US5679666A (en) Prevention and treatment of ocular neovascularization by treatment with angiostatic steroids
EP0614463B1 (en) Angiostatic steroids
US6011023A (en) Angiostatic steroids
WO2005074942A1 (en) Slow release steroid composition
JPH0725679B2 (en) Intraocular pressure control agent
JP2007056041A (en) Glucocorticoid prescription for treating neovascularization in morbid eye
US5929111A (en) A-seco steroids effective at treating ophthalmic pathological neovascularization and controlling intraocular pressure
CA2064478C (en) Ophthalmic composition
US5358943A (en) Use of tetrahydrocortisol to prevent elevations in intraocular pressure caused by corticosteroids
MXPA99011140A (en) The use of angiostatic steroids in photodynamic therapy
US20080234245A1 (en) Angiostatic Agents for Controlling Choroidal Neovascularisation After Ocular Surgery or Trauma
WO1997041867A1 (en) Use of steroid compounds to prevent non-cancerous tissue growth
CN1239161C (en) Method for treating dry eye disorders

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BR CA JP MX US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1998931367

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: PA/a/1999/011140

Country of ref document: MX

Ref document number: 09445237

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 81515/98

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2296558

Country of ref document: CA

Kind code of ref document: A

Country of ref document: CA

WWP Wipo information: published in national office

Ref document number: 1998931367

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 81515/98

Country of ref document: AU

WWG Wipo information: grant in national office

Ref document number: 1998931367

Country of ref document: EP