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WO2005051357A1 - Agents antiangiogenes - Google Patents

Agents antiangiogenes Download PDF

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Publication number
WO2005051357A1
WO2005051357A1 PCT/US2004/038971 US2004038971W WO2005051357A1 WO 2005051357 A1 WO2005051357 A1 WO 2005051357A1 US 2004038971 W US2004038971 W US 2004038971W WO 2005051357 A1 WO2005051357 A1 WO 2005051357A1
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WIPO (PCT)
Prior art keywords
methoxyestradiol
solid powder
angiogenesis
disease
cosolvent
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Inventor
Albert W. Brzeczko
Nestor M. Vargas
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Casi Pharmaceuticals Inc
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Entremed Inc
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    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to treating disease states characterized by abnormal cell mitosis and to treating disease states characterized by abnormal angiogenesis and to treating disease states characterized by a combination of these events. More particularly, the present invention relates to an improved form of 2-methoxyestradiol (2ME 2 ), and analogs thereof, and their effect in treating various disease states; especially, diseases characterized by abnormal cell mitosis and/or abnormal angiogenesis. A method of making the improved form of 2ME 2 , and analogs thereof, is also disclosed.
  • Angiogenesis is the generation of new blood vessels into a tissue or organ. Under normal physiological conditions, humans and animals undergo angiogenesis only in very specific, restricted situations. For example, angiogenesis is normally observed in wound healing, fetal and embryonal development, and formation of the corpus luteum, endometrium and placenta. Angiogenesis is controlled through a highly regulated system of angiogenic stimulators and inhibitors. The control of angiogenesis has been found to be altered in certain disease states and, in many cases, pathological damage associated with the diseases is related to uncontrolled angiogenesis. Both controlled and uncontrolled angiogenesis are thought to proceed in a similar manner.
  • Endothelial cells and pericytes surrounded by a basement membrane, form capillary blood vessels.
  • Angiogenesis begins with the erosion of the basement membrane by enzymes released by endothelial cells and leukocytes. Endothelial cells, lining the lumen of blood vessels, then protrude through the basement membrane. Angiogenic stimulants induce the endothelial cells to migrate through the eroded basement membrane. The migrating cells form a "sprout" off the parent blood vessel where the endothelial cells undergo mitosis and proliferate. The endothelial sprouts merge with each other to form capillary loops, creating a new blood vessel.
  • Persistent, unregulated angiogenesis occurs in many disease states, tumor metastases, and abnormal growth by endothelial cells.
  • the diverse pathological disease states in which unregulated angiogenesis is present have been grouped together as angiogenic-dependent or angiogenic-associated diseases.
  • a disease mediated by angiogenesis is ocular neovascular disease. This disease is characterized by invasion of new blood vessels into the structures of the eye, such as the retina or cornea. It is the most common cause of blindness and is involved in approximately twenty eye diseases.
  • age-related macular degeneration the associated visual problems are caused by an ingrowth of choroidal capillaries through defects in Bruch's membrane with proliferation of fibrovascular tissue beneath the retinal pigment epithelium.
  • Angiogenic damage is also associated with diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, and retrolental f ⁇ broplasia.
  • Other diseases associated with corneal neovascularization include, but are not limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, and pterygium keratitis sicca.
  • Other diseases associated with undesirable angiogenesis include Sj ⁇ gren's syndrome, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infection, Herpes zoster infections, protozoan infections, Kaposi's sarcoma, Mooren's ulcer, Terrien's marginal degeneration, marginal keratolysis, rheumatoid arthritis, systemic lupus, polyarteritis, trauma, Wegener's sarcoidosis, scleritis, Stevens- Johnson's disease, pemphigoid, and radial keratotomy.
  • Diseases associated with retinal/choroidal neovascularization include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoidosis, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, Mycobacteria infections, lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Behcet's disease, infections causing retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargardt's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications.
  • Eye-related diseases include, but are not limited to, diseases associated with rubeosis (neovascularization of the angle) and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue, including all forms of prolific vitreoretinopathy.
  • Another angiogenesis associated disease is rheumatoid arthritis.
  • the blood vessels in the synovial lining of the joints undergo angiogenesis.
  • the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction.
  • Angiogenesis may also play a role in osteoarthritis.
  • the activation of the chondrocytes by angiogenic-related factors contributes to the destruction of the joint. At a later stage, the angiogenic factors promote new bone growth.
  • Chronic inflammation may also involve pathological angiogenesis.
  • diseases as ulcerative colitis and Crohn's disease show histological changes with the ingrowth of new blood vessels and the inflamed tissues.
  • Bartonelosis a bacterial infection found in South America, can result in a chronic stage that is characterized by proliferation of vascular endothelial cells.
  • Another pathological role associated with angiogenesis is found in atherosclerosis. The plaques formed within the lumen of blood vessels have been shown to have angiogenic stimulatory activity. The hypothesis that tumor growth is angiogenesis-dependent was first proposed in 1971. (Folkman, New Eng. J. Med., 285:1182-86 (1971)).
  • Tumor 'take' has occurred, every increase in tumor cell population must be preceded by an increase in new capillaries converging on the tumor.”
  • Tumor 'take' is currently understood to indicate a prevascular phase of tumor growth in which a population of tumor cells occupying a few cubic millimeters volume, and not exceeding a few million cells, can survive on existing host microvessels. Expansion of tumor volume beyond this phase requires the induction of new capillary blood vessels. For example, pulmonary micrometastases in the early prevascular phase in mice would be undetectable except by high power microscopy on histological sections.
  • Examples of the indirect evidence which support this concept include: (1) The growth rate of tumors implanted in subcutaneous transparent chambers in mice is slow and linear before neovascularization, and rapid and nearly exponential after neovascularization. (Algire, et al, J. Nat. Cancer Inst, 6:73-85 (1945)). (2) Tumors grown in isolated perfused organs where blood vessels do not proliferate are limited to 1-2 mm 3 but expand rapidly to >1000 times this volume when they are transplanted to mice and become neovascularized. (Folkman, et al, Annals of Surgery, 164:491-502 (1966)). (3) Tumor growth in the avascular cornea proceeds slowly and at a linear rate, but switches to exponential growth after neovascularization.
  • Tumors suspended in the aqueous fluid of the anterior chamber of a rabbit eye remain viable, avascular, and limited in size to ⁇ 1 mm . Once they are implanted on the iris vascular bed, they become neovascularized and grow rapidly, reaching 16,000 times their original volume within 2 weeks. (Gimbrone, Jr., et al, J. Exp. Med., 136:261-76).
  • Tumors are generally avascular up to 1 mm in diameter, but are neovascularized beyond that diameter. (Lien, et al, Surgery, 68:334-40 (1970)). (7) In transgenic mice that develop carcinomas in the beta cells of the pancreatic islets, pre-vascular hyperplastic islets are limited in size to ⁇ 1 mm.
  • VEGF vascular endothelial growth factor
  • Anti-bFGF monoclonal antibody causes 70% inhibition of growth of a mouse tumor which is dependent upon secretion of bFGF as its only mediator of angiogenesis. The antibody does not inhibit growth of the tumor cells in vitro. (Hori, et al, Cancer Res., 51:6180-84 (1991)).
  • Intraperitoneal injection of bFGF enhances growth of a primary tumor and its metastases by stimulating growth of capillary endothelial cells in the tumor.
  • the tumor cells themselves lack receptors for bFGF, and bFGF is not a mitogen for the tumor cells in vitro. (Gross, et al, Proc. Am. Assoc. Cancer Res., 31:79 (1990)).
  • a specific angiogenesis inhibitor (AGM-1470) inhibits tumor growth and metastases in vivo, but is much less active in inhibiting tumor cell proliferation in vitro. It inhibits vascular endothelial cell proliferation half- maximally at 4 logs lower concentration than it inhibits tumor cell proliferation. (Ingber, et al, Nature, 48:555-57 (1990)). There is also indirect clinical evidence that tumor growth is angiogenesis dependent. (12) Human retinoblastomas that are metastatic to the vitreous develop into avascular spheroids that are restricted to less than 1 mm 3 despite the fact that they are viable and incorporate H-thymidine (when removed from an enucleated eye and analyzed in vitro).
  • angiogenesis has been associated with a number of different types of cancer, including solid tumors and blood-borne tumors. Solid tumors with which angiogenesis has been associated include, but are not limited to, rhabdomyosarcomas, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma.
  • Angiogenesis is also associated with blood-borne tumors, such as leukemias, any of various acute or chronic neoplastic diseases of the bone marrow in which unrestrained proliferation of white blood cells occurs, usually accompanied by anemia, impaired blood clotting, and enlargement of the lymph nodes, liver and spleen. It is believed that angiogenesis plays a role in the abnormalities in the bone marrow that give rise to leukemia tumors and multiple myeloma diseases.
  • One of the most frequent angiogenic diseases of childhood is the hemangioma.
  • a hemangioma is a tumor composed of newly formed blood vessels. In most cases the tumors are benign and regress without intervention.
  • hemangiomas In more severe cases, the tumors progress to large cavernous and infiltrative forms and create clinical complications. Systemic forms of hemangiomas, hemangiomatoses, have a high mortality rate. Therapy-resistant hemangiomas exist that cannot be treated with therapeutics currently in use. Angiogenesis is also responsible for damage found in heredity diseases such as Osier- Weber-Rendu disease, or heredity hemorrhagic telangiectasia. This is an inherited disease characterized by multiple small angiomas, tumors of blood or lymph vessels. The angiomas are found in the skin and mucous membranes, often accompanied by epitaxis (nose bleeds) or gastrointestinal bleeding and sometimes with pulmonary or hepatitic arteriovenous fistula.
  • Angiogenesis is also involved in normal physiological processes, such as reproduction and wound healing. Angiogenesis is an important step in ovulation and also in implantation of the blastula after fertilization. Prevention of angiogenesis could be used to induce amenorrhea, to block ovulation, or to prevent implantation by the blastula. In wound healing, excessive repair or fibroplasia can be a detrimental side effect of surgical procedures and may be caused or exacerbated by angiogenesis. Adhesions are a frequent complication of surgery and lead to problems such as small bowel obstruction. Several compounds have been used to inhibit angiogenesis. Taylor, et al.
  • Interferon alpha or human interferon beta have been shown to inhibit tumor-induced angiogenesis in mouse dermis stimulated by human neoplastic cells. Interferon beta is also a potent inhibitor of angiogenesis induced by allogeneic spleen cells. (Sidky, et al, Cancer Res., 47:5155-61(1987)). Human recombinant interferon (alpha/A) was reported to be successfully used in the treatment of pulmonary hemangiomatosis, an angiogenesis-ind ⁇ ced disease. (White, et al, New Eng. J. Med., 320:1197-1200 (1989)).
  • agents that have been used to inhibit angiogenesis include ascorbic acid ethers and related compounds. (Japanese Kokai Tokkyo Koho No.58-13 (1978)). Sulfated polysaccharide DS 4152 also inhibits angiogenesis. (Japanese Kokai Tokkyo Koho No. 63-119500). Additional anti-angiogenic compounds include Angiostatin® (U.S. Patent Nos. 5,639,725; 5,792,845; 5,885,795; 5,733,876; 5,776,704; 5,837,682; 5,861,372, and 5,854,221) and Endostatin (U.S. Patent No. 5,854,205).
  • Angiostatin® U.S. Patent Nos. 5,639,725; 5,792,845; 5,885,795; 5,733,876; 5,776,704; 5,837,682; 5,861,372, and 5,854,221
  • Endostatin U.S. Patent No.
  • Thalidomide is a hypnosedative that has been successfully used to treat a number of diseases, such as rheumatoid arthritis (Gutierrez-Rodriguez, Arthritis Rheum., 27 (10):1118-21 (1984); Gutierrez-Rodriguez, et al, J. Rheumatol., 16(2): 158-63 (1989)), Behcet's disease (Handley, et al, Br. J.
  • 2-methoxyestradiol When administered orally, it exhibits anti-tumor and anti-proliferative activity with little toxicity.
  • 2-methoxyestradiol does not engage the estrogen receptor for its anti-proliferative activity and is not estrogenic over a wide range of concentrations, as assayed by estrogen dependant MCF-7 cell proliferation.
  • 2-Methoxyestradiol is known to inhibit cell mitosis and angiogenesis and to treat various diseases associated therewith. See U.S. Pat. No. 5,504,074.
  • 2-methoxyestradiol is produced in a crystalline form and has a relatively low solubility in water or aqueous solutions.
  • the present invention relates to a form of 2-methoxyestradiol, and analogs thereof, that has greater bioavailable when administered orally and/or has greater solubility in water or aqueous solutions.
  • the novel form of 2ME 2 , and analogs thereof, is in an amorphous, non-crystalline form.
  • the method by which the more bioavailable form of estradiol derivatives, especially 2-methoxyestradiol, and analogs thereof, is prepared is as follows. An estradiol derivative and at least one water-soluble polymer or copolymer are dissolved in a solvent or cosolvent system.
  • This solution is then spray dried to form a solid powder having an amorphous, non-crystalline form and having improved solubility in water or aqueous solutions.
  • the novel form of 2-methoxyestradiol, and analogs thereof, is useful in treating diseases associated with undesirable cell mitosis and/or undesirable angiogenesis.
  • a mammalian disease characterized by undesirable cell mitosis includes but is not limited to excessive or abnormal stimulation of endothelial cells (e.g., atherosclerosis), solid tumors and tumor metastasis, benign tumors, for example, hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas, vascular malfunctions, abnormal wound healing, inflammatory and immune disorders, Bechet's disease, gout or gouty arthritis, abnormal angiogenesis accompanying: rheumatoid arthritis, skin diseases, such as psoriasis, diabetic retinopathy and other ocular angiogenic diseases such as retinopathy of prematurity (retrolental fibroplasic), macular degeneration, corneal graft rejection, neovascular glaucoma and Osier Weber syndrome (Osier- Weber-Rendu disease).
  • endothelial cells e.g., atherosclerosis
  • compositions described above can be used to block ovulation and implantation of a blastula or to block menstruation (induce amenorrhea).
  • the novel form of 2-methoxyestradiol, and analogs thereof is especially useful in treating cancer. Accordingly, it is an object of the present invention to provide a novel form of 2-methoxyestradiol, and analogs thereof, that have greater bioavailable when administered orally. Another object of the present invention is to provide a novel form of 2- methoxyestradiol, and analogs thereof, that have greater solubility in water or aqueous solutions.
  • a further object of the present invention is to provide a novel form of 2- methoxyestradiol, and analogs thereof, that are more effective in treating diseases associated with cell mitosis and/or angiogenesis.
  • Yet another object of the present invention is to provide a novel form of 2- methoxyestradiol, and analogs thereof, that are more effective at treating cancer, especially solid tumors and metastatic tumors.
  • This novel form of 2- methoxyestradiol, and analogs thereof is in an amorphous, non-crystalline form.
  • This novel form of 2-methoxyestradiol, and analogs thereof also exhibits anti- mitotic, anti-angiogenic and/or anti-tumor properties.
  • the novel form of 2- methoxyestradiol, and analogs thereof is prepared by dissolving 2ME 2 , or analogs thereof, and at least one water-soluble polymer or copolymer in a cosolvent system.
  • the solution is then spray dried to form a solid powder having an amorphous, non-crystalline form.
  • Water-soluble polymers or copolymers useful in the present invention include, but are not limited to polyvinylpyrrolidone.
  • the polyvinylpyrrolidone can generally have a weight average molecular weight of approximately 15,000 to 90,000. Other water-soluble polymers or copolymers that are used in spray drying processes may also be used.
  • the ratio of the amount of 2ME 2 to water- soluble polymer is approximately 3 : 1 to 1 :3 ; preferably, 1:1.
  • the cosolvent system comprises any solvent or combination of two or more solvents that will dissolve both 2-methoxyestradiol and the water-soluble polymer(s) or copolymer(s).
  • Useful solvents include, but are not limited to water, acetone, ethyl alcohol, and N-methyl-2-pyrrolidone ("NMP").
  • NMP N-methyl-2-pyrrolidone
  • a preferred solvent system is a mixture of acetone and ethyl alcohol.
  • the cosolvents may be heated and agitation may also be provided so that the 2ME 2 , or analogs thereof, and water-soluble polymer(s) or copolymer(s) are completely dissolved in the cosolvents. Heating of the cosolvents should be relatively mild so as to avoid excessive evaporation of the cosolvents.
  • the solution of 2-methoxyestradiol and water-soluble polymer(s) or copolymer(s) may include additives that will improve the bioavailability of the novel form of 2-methoxyestradiol.
  • additives include surfactants including, but not limited to, tocopheryl polyethylene glycol succinate ("TPGS").
  • Surfactants are also added to the solution of the present invention to enhance wetting, dispersion, dissolution, stability and/or solubilization of the novel form of 2-methoxyestradiol.
  • the amount of additive used is that amount that is effective to render the novel form of 2-methoxyestradiol more bioavailable and/or to enhance wetting, dispersion, dissolution, stability and/or solubilization.
  • amounts of surfactant that can be used to enhance bioavailability and/or to enhance wetting, dispersion, dissolution, and/or solubilization are approximately 1% to 25% by weight; preferably, approximately 4% to 15% by weight.
  • Spray drying of the solution is carried out in a conventional two-fluid nozzle spray drier, such as Niro SD Micro 1 " 1 spray dryer available from Niro Inc., Columbia, Maryland.
  • the spray drier is adjusted to have a gas inlet temperature of approximately 105°- 135° C. and a gas outlet temperature of approximately 70°-90° C.
  • the spray drying produces a solid powder that is collected at the bottom of the spray drier.
  • the temperatures listed herein are specific to the Niro SD Micro* 111 spray dryer. Those skilled in the art will understand that different temperatures may be used for commercial scale equipment or equipment from other manufacturers.
  • the solid powder is transferred from the spray drier to a fluid bed drier, such as the Niro MP l 1 TM fluid bed.
  • the solid powder is dried in the fluid bed drier to remove additional amounts of the cosolvent system not removed from the solid powder during processing in the spray drier.
  • the fluid bed drier is adjusted to have an air inlet temperature of approximately 50°-90° C.
  • the powder is dried in the fluid bed drier for a period of time sufficient to remove substantially all of the cosolvents from the powder; i.e., not more than 1% by weight cosolvents in the final product. Generally speaking, drying in the fluid bed drier takes approximately 10 minutes to 1 hour.
  • the temperatures and times listed herein are specific to the Niro MP l ta fluid bed. Those skilled in the art will understand that different temperatures and times may be used for commercial scale equipment or equipment from other manufacturers.
  • the invention relates to a form of estradiol derivatives, especially 2- methoxyestradiol, that is more bioavailable and/or has greater water or aqueous solubility.
  • 2-Methoxyestradiol has the formula:
  • the more bioavailable form of 2ME 2 is prepared by first dissolving polyvinyl pyrrolidone (PVP) in ethyl alcohol. Acetone is added to the mixture. Then, 2ME 2 is added to the mixture of PVP, ethyl alcohol and acetone. The mixture is then heated to a temperature of 35°-40° C along with constant agitation. After the 2ME 2 is completely dissolved, the mixture is permitted to cool down to a temperature of 25°-30° C.
  • PVP polyvinyl pyrrolidone
  • the mixture is then spray dried in a Niro SD Micro*" 1 spray dryer having a gas inlet temperature of 105°- 135° C. and a gas outlet temperature of 70°-90° C.
  • Powder is collected from the spray drier and is then placed in a Niro MP l ta fluid bed drier.
  • the fluid bed drier has a product retention screen of 100 mesh and an exhaust filter bag having pores of 3-20 microns.
  • the fluid bed drier has an air inlet temperature of 50°-90° C.
  • the powder is dried for 20 minutes. The dried powder is then collected from the fluid bed drier.
  • the powder is in an amorphous, non-crystalline form and has greater bioavailability when administered orally and/or has greater solubility in water or aqueous solutions than 2-methoxyestradiol in its conventional crystalline form.
  • the increased bioavailability of the present invention is dramatically demonstrated by the following data.
  • the current clinical form of 2- methoxyestradiol being tested by EntreMed, Inc.; the prior art crystalline form of 2-methoxyestradiol, has a typical Cmax (nM) at 60 mg/km of 4.32.
  • the amorphous form of 2-methoxyetsradiol in accordance with the present invention has a Cmax (nM) at 60 mg/km of 1195.47.
  • Tables II, III and IV below show the composition of 16 different spray dryable formulas in accordance with the present invention.
  • the invention can be used to treat any disease characterized by abnormal cell mitosis.
  • diseases include, but are not limited to: abnormal stimulation of endothelial cells (e.g., atherosclerosis), solid tumors and tumor metastasis, benign tumors, for example, hemangiomas, acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas, vascular malfunctions, abnormal wound healing, inflammatory and immune disorders, Bechet's disease, gout or gouty arthritis, abnormal angiogenesis accompanying: rheumatoid arthritis, skin diseases, such as psoriasis, diabetic retinopathy, and other ocular angiogenic diseases such as retinopathy of prematurity (retrolental fibroplasic), macular degeneration, corneal graft rejection, neuroscular glaucoma, liver diseases and Oster Webber syndrome (Osier- Weber Rendu disease).
  • endothelial cells e.g.
  • Such diseases include, but are not limited to, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma and retrolental fibroplasias, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear, atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, Sjogren's, acne rosacea, phylectenulosis, syphilis, Mycobacteria infections, lipid degeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections, protozoan infections, Kaposi's sarcoma, Mooren's ulcer, Temen's marginal degeneration, marginal keratolysis, trauma, rheumatoid arthritis, systemic lup
  • Diseases associated with retinal/choroidal neovascularization can be treated according to the present invention.
  • diseases include, but are not limited to, diabetic retinopathy, macular degeneration, sickle cell anemia, sarcoid, syphilis, pseudoxanthoma elasticum, Paget's disease, vein occlusion, artery occlusion, carotid obstructive disease, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus erythematosis, retinopathy of prematurity, Eales' disease, Bechet's disease, infections causing a retinitis or choroiditis, presumed ocular histoplasmosis, Best's disease, myopia, optic pits, Stargart's disease, pars planitis, chronic retinal detachment, hyperviscosity syndromes, toxoplasmosis, trauma and post-laser complications.
  • diseases include, but are not limited to, diseases associated with rubeosis (neovasculariation of the angle) and diseases caused by the abnormal proliferation of fibrovascular or fibrous tissue including all forms of proliferative vitreoretinopathy, whether or not associated with diabetes.
  • Another disease that can be treated according to the present invention is rheumatoid arthritis. It is believed that the blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to forming new vascular networks, the endothelial cells release factors and reactive oxygen species that lead to pannus growth and cartilage destruction. The factors involved in angiogenesis may actively contribute to, and help maintain, the chronically inflamed state of rheumatoid arthritis.
  • diseases that can be treated according to the present invention are hemangiomas, Osler-Weber-Rendu disease, or hereditary hemorrhagic telangiectasia, solid or blood borne tumors and acquired immune deficiency syndrome.
  • the invention can be used to treat a variety of post-menopausal symptoms, osteoporosis, cardiovascular disease, Alzheimer's disease, to reduce the incidence of strokes, and as an alternative to prior estrogen replacement therapies.
  • the compounds of the present invention can work by estrogenic and non-estrogenic biochemical pathways.
  • the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.
  • one or more pharmacological agents of value in treating one or more disease conditions referred to hereinabove.
  • a person skilled in the art will be able by reference to standard texts, such as Remington's Pharmaceutical Sciences 17th edition, to determine how the formulations are to be made and how these may be administered.
  • the pharmaceutical composition may be used for the prophylaxis or treatment of conditions associated with angiogenesis or accelerated cell division or inflammation.
  • a method of prophylaxis or treatment of a condition associated with angiogenesis or accelerated or increased amounts of cell division hypertrophic growth or inflammation including administering to a patient in need of such prophylaxis or treatment an effective amount of a conjugated prodrug according to the present invention, as described above.
  • prophylaxis or treatment of said condition includes amelioration of said condition.
  • an effective amount is meant a therapeutically or prophylactically effective amount.
  • Such amounts can be readily determined by an appropriately skilled person, taking into account the condition to be treated, the route of administration and other relevant factors. Such a person will readily be able to determine a suitable dose, mode and frequency of administration.
  • compositions described above can be provided as physiologically acceptable formulations using known techniques, and these formulations can be administered by standard routes.
  • the combinations may be administered by the topical, oral, rectal or parenteral (e.g., intravenous, subcutaneous or intramuscular) route.
  • the combinations may be incorporated into biodegradable polymers allowing for sustained release, the polymers being implanted in the vicinity of where delivery is desired, for example, at the site of a tumor or within or near the eye.
  • the dosage of the composition will depend on the condition being treated, the particular derivative used, and other clinical factors such as weight and condition of the patient and the route of administration of the compound. However, for oral administration to humans, a dosage of 0.01 to 100 mg/kg/day, preferably 0.01-20 mg/kg/day, is generally sufficient.
  • the formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intraocular, intratracheal, and epidural) and inhalation administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques.
  • Such techniques include the step of bringing into association the active ingredient and a pharmaceutical canier(s) or excipient(s).
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid earners or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion, etc.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Molded tablets may be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide a slow or controlled release of the active ingredient therein.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
  • Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered in a pharmaceutical acceptable carrier.
  • a preferred topical delivery system is a transdermal patch containing the ingredient to be administered.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for nasal administration include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing, in addition to the active ingredient, ingredients such as carriers as are known in the art to be appropriate.
  • Formulation suitable for inhalation may be presented as mists, dusts, powders or spray formulations containing, in addition to the active ingredient, ingredients such as carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) conditions requiring only the addition of the sterile liquid canier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tables of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered ingredient.
  • formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un 2-méthoxyestradiol amélioré et ses analogues sous forme amorphe non cristalline. Cette nouvelle forme de 2-méthoxyestradiol et ses analogues, possèdent des caractéristiques améliorées de biodisponibilité quand on l'administre par voie orale et/ou de solubilité améliorée dans de l'eau ou dans des solutions aqueuses. L'invention concerne également une méthode de préparation de ce 2-méthoxyestradiol amélioré et de ses analogues.
PCT/US2004/038971 2003-11-19 2004-11-19 Agents antiangiogenes Ceased WO2005051357A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US52411003P 2003-11-19 2003-11-19
US60/524,110 2003-11-19

Publications (1)

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WO2005051357A1 true WO2005051357A1 (fr) 2005-06-09

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PCT/US2004/038971 Ceased WO2005051357A1 (fr) 2003-11-19 2004-11-19 Agents antiangiogenes

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WO (1) WO2005051357A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1795185A3 (fr) * 2005-12-07 2007-06-27 Cordis Corporation Formulations nano- et/ou microparticulaires pour le traitement local basé sur injection de maladies vasculaires
GB2451360B (en) * 2006-03-09 2011-10-05 Jonathan V Wright Hormone replacement formulation
TWI419695B (zh) * 2011-11-29 2013-12-21 Chi Mei Foundation Hospital Use 2-methoxy estradiol to treat sepsis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5504074A (en) * 1993-08-06 1996-04-02 Children's Medical Center Corporation Estrogenic compounds as anti-angiogenic agents

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5504074A (en) * 1993-08-06 1996-04-02 Children's Medical Center Corporation Estrogenic compounds as anti-angiogenic agents

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1795185A3 (fr) * 2005-12-07 2007-06-27 Cordis Corporation Formulations nano- et/ou microparticulaires pour le traitement local basé sur injection de maladies vasculaires
GB2451360B (en) * 2006-03-09 2011-10-05 Jonathan V Wright Hormone replacement formulation
TWI419695B (zh) * 2011-11-29 2013-12-21 Chi Mei Foundation Hospital Use 2-methoxy estradiol to treat sepsis

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