WO2010132498A1 - Vascular disrupting agents for treatment of polypoidal choroidal vasculopathy - Google Patents

Vascular disrupting agents for treatment of polypoidal choroidal vasculopathy Download PDF

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WO2010132498A1
WO2010132498A1 PCT/US2010/034442 US2010034442W WO2010132498A1 WO 2010132498 A1 WO2010132498 A1 WO 2010132498A1 US 2010034442 W US2010034442 W US 2010034442W WO 2010132498 A1 WO2010132498 A1 WO 2010132498A1
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vascular disrupting
disrupting agent
administered
independently
membered
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PCT/US2010/034442
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French (fr)
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Patricia Walicke
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Oxigene, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Fosbretabulin (combretastatin A4 phosphate [CA4P]) is a novel vascular disrupting agent (VDA) that targets abnormal vasculature in oncology and in preclinical models of ophthalmologic disorders.
  • VDA vascular disrupting agent
  • CA4P is a synthetic phosphorylated pro-drug of combretastatin A- 4 (CA4), a naturally occurring derivative of the South African willow tree, Combretum caffrum, which reversibly binds tubulin at the colchicine-binding site to inhibit microtubule assembly.
  • VDAs Vascular Disrupting Agents
  • VDAs are a separate class of anti-vascular chemotherapeutics.
  • anti-angiogenic drugs which disrupt the new microvessel formation
  • VDAs selectively target the abnormal vasculature, both new and established, causing extensive shutdown of blood flow through the abnormal vasculature.
  • a single dose of a VDA can cause a rapid and selective shutdown of tumor vasculature within a period of minutes to hours, leading eventually to tumor necrosis by induction of hypoxia and nutrient depletion.
  • This vascular-mediated cytotoxic mechanism of VDA action is quite divorced from that of anti-angiogenic agents, which inhibit the formation of new vascularization rather than interfering with the existing vasculature.
  • VDAs tubulin-binding VDAs selectively destabilize the microtubule cytoskeleton of newly formed endothelial cells, causing a profound alteration in the shape of the cell which ultimately leads to occlusion of the blood vessel and shutdown of blood flow (Kanthou et al., Blood 99(6):2060-9 (2002); Cooney et al., Curr Oncol Rep. 7(2):90-5 (2005); Chaplin et al., Curr Opin Investig Drugs 7(6):522-8(2006)).
  • combretastatins A particularly promising subclass of VDAs is the class of combretastatins. Derived from the South African tree Combretum caffrum, combretastatins such as combretastatin A- 4 (CA4), were initially identified in the 1980's as potent inhibitors of tubulin polymerization. CA4 and other combretastatins (e.g. combretastatin A-1 (CA1 )) have been shown to bind a site at or near the colchicine binding site on tubulin with high affinity. In vitro studies clearly demonstrated that combretastatins are potent cytotoxic agents against a diverse spectrum of tumor cell types in culture.
  • CA4 combretastatin A-1
  • each of R 1 , R 2 and R 3 independently of the others, is selected from the group consisting of hydrogen, d- 6 alkoxy, and halogen, wherein at least two of R 1 , R 2 and R 3 are non-hydrogen;
  • R 4 is selected from the group consisting of R 5 , R 6 , R 5 substituted with one or more of the same or different R 7 or R 6 , -OR 7 substituted with one or more of the same or R 7 or R 6 , -B(OR 7 ) 2 , -B(NR 8 R 8 ) 2 , -(CH 2 ) m -R 6 , -(CHR 7 ) m -R 6 , -O-(CH 2 ) m -R 6 , -S-(CH 2 ) m -R 6 , -0-CHR 7 R 6 , -O-CR 7 (R 6 ) 2 , -O-(CHR 7 ) m -R 6 , -O- (CH 2 ) m -CH[(CH 2 ) m R 6 ]R 6 ,
  • each R 7 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 4-11 cycloalkylalkyl, C 5-10 aryl, C 6-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-1 1 membered heterocyclylalkyl, 5-10 membered heteroaryl, 6-16 membered heteroarylalkyl, phosphate, phosphate ester, phosphonate, phosphorodiamidate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, cyclic phosphorodiamidate, and phosphonamidate; each R 8 is independently R 7 or, alternatively, two R 8 are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered heterocyclyl or heteroaryl which may optional
  • the combretastatin agent is a phosphate prodrug of a combretastatin agent.
  • An exemplary phosphate prodrug is a compound of the Formula II:
  • OR 1 , OR 2 , OR 3 and OR 4 are each, independently, OH, -0 " QH + or -O " M + , wherein M + is a monovalent or divalent metal cation and Q is, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH + ; or b) an organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation, QH + .
  • R a is H or OP(O)(OR 3 )OR 4
  • R 1 , R 2 , R 3 and R 4 are each, independently, an aliphatic organic amine, alkali metals, transition metals, heteroarylene, heterocyclyl, nucleoside, nucleotide, alkaloid, amino sugar, amino nitrile, or nitrogenous antibiotic.
  • R 1 , R 2 , R 3 and R 4 are each, independently, Na, tromethamine, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)- ethylamine, choline, or hydrabamine.
  • to "prevent" PCV by administration of a vascular disrupting agent means that detectable physical characteristics or symptoms of PCV do not develop following administration of the vascular disrupting agent.
  • a volume of a liquid formulation described herein is administered to the vitreous of a subject's eye, including but not limiting a human subject's eye that is less than about 500 ⁇ l, less than about 400 ⁇ l, less than about 300 ⁇ l, less than about 200 ⁇ l, less than about 100 ⁇ l, less than about 90 ⁇ l, less than about 80 ⁇ l, less than about 70 ⁇ l, less than about 60 ⁇ l, less than about 50 ⁇ l, less than about 40 ⁇ l, less than about 30 ⁇ l, less than about 20 ⁇ l, less than about 10 ⁇ l, less than about 5 ⁇ l, less than about 3 ⁇ l, or less than about 1 ⁇ l.
  • a volume of a liquid formulation described herein is subconjunctival ⁇ administered to a subject's eye, including but not limited to a human subject's eye that is 40 ⁇ l. In some embodiments, a volume of a liquid formulation described herein is subconjunctival ⁇ administered to a subject's eye, including but not limited to a human subject's eye that is any of between about 10 ⁇ l and about 50 ⁇ l, between about 15 ⁇ l and about 45 ⁇ l, between about 20 ⁇ l and about 40 ⁇ l, or between about 25 ⁇ l and about 35 ⁇ l.
  • a total amount of vascular disrupting agent administered subconjunctival ⁇ is about 880 ⁇ g.
  • a liquid formulation containing an amount of vascular disrupting agent of 220 ⁇ g is subconjunctival ⁇ administered to a human subject by administering about 10 ⁇ l of a liquid formulation described herein.
  • a liquid formulation containing an amount of vascular disrupting agent of 440 ⁇ g is subconjunctival ⁇ administered to a human subject by administering about 20 ⁇ l of a liquid formulation described herein.
  • a liquid formulation containing an amount of vascular disrupting agent of 660 ⁇ g is subconjunctival ⁇ administered to a human subject by administering about 30 ⁇ l of a liquid formulation described herein. In some embodiments, a liquid formulation containing an amount of vascular disrupting agent of 880 ⁇ g is subconjunctival ⁇ administered to a human subject by administering about 40 ⁇ l of a liquid formulation described herein.
  • a volume of a liquid formulation described herein is subtenonally administered to a subject's eye, including but not limited to a human subject's eye that is less than about 200 ⁇ l. In some embodiments, a volume of a liquid formulation described herein is subtenonally administered to a subject's eye, including but not limited to a human subject's eye that is less than about 100 ⁇ l.
  • the vascular disrupting agent may be a combretastatin compound. In some embodiments, the vascular disrupting agent may be combretastatin A-4 or an analog, prodrug or derivative thereof. In some implementations, the vascular disrupting agent is combretastatin A-4 phosphate.
  • a liquid formulation that comprises a vascular disrupting agent and a component that may be considered either a solvent or a solubilizing agent or surfactant will be considered a solvent if it is playing the role of a solvent; if the component is not playing the role of the solvent, the component may be considered a solubilizing agent or surfactant.
  • the solubilizing agent is a surfactant or combination of surfactants.
  • surfactants are possible.
  • Combinations of surfactants, including combinations of various types of surfactants, may also be used. For instance, surfactants which are nonionic, anionic (i.e. soaps, sulfonates), cationic (i.e. CTAB), zwitterionic, polymeric or amphoteric may be used.
  • Liquid formulations may optionally further comprise stabilizers, excipients, gelling agents, adjuvants, antioxidants, and/or other components as described herein.
  • the vascular disrupting agent in the liquid formulation comprises between about 0.001 to about 1.00% of the total weight of the composition. In some embodiments the vascular disrupting agent in the liquid formulation comprises any of about 0.07%, about 0.08%, 0.09%, 0.17%, 1.38%, 1.47%, 2%, 4%, 4.84%, or 5% of the total weight of the composition. In some embodiments, the vascular disrupting agent may be a combretastatin compound. In some embodiments, the vascular disrupting agent may be CA4 or an analog, prodrug or derivative thereof. In some embodiments, the vascular disrupting agent is CA4P.
  • the liquid formulations described herein have a viscosity of between 40% and 120% centipoise. In some embodiments the liquid formulations described herein have a viscosity of between 60% and 80% centipoise.
  • kits comprising one or more unit dose forms as described herein.
  • the kit comprises one or more of packaging and instructions for use to treat one or more diseases or conditions.
  • the kit comprises a diluent which is not in physical contact with the formulation or pharmaceutical formulation.
  • the kit comprises any of one or more unit dose forms described herein in one or more sealed vessels.
  • the kit comprises any of one or more sterile unit dose forms.
  • Figure 1 illustrates the change in the number of PCV lesions in a patient receiving a single infusion of 45 mg/m 2 combretastatin A4 phosphate as compared to a patient receiving the placebo.
  • Figure 2 illustrates the percent change in the number of PCV lesions in the placebo patient and the patient receiving 45 mg/m 2 combretastatin A4 phosphate.
  • the patient receiving combretastatin A4 phosphate demonstrated a decrease in the number of lesion, whereas the placebo patient experienced an overall increase in the number of lesions.
  • treatment with CA4P is anticipated to decrease or completely eliminate PCV lesions in the affected eye.
  • Figure 3 illustrates the area of branching vascular network as measured by ICGA for the patient receiving 45 mg/m 2 combretastatin and the patient receiving placebo.
  • the branching network area of the patient receiving combretastatin remained relatively stable while the branching network expanded in the patient receiving placebo.
  • the total lesion area for the patient receiving combretastatin remained relatively stable or increased only slightly, while the total lesion area increased substantially over the three month course of the trial (see Figure 4). Additional expected beneficial effects include stabilization or amelioration of visual acuity.
  • Treatment with CA4P is anticipated to decrease or completely eliminate PCV lesions in the affected eye. Additional expected beneficial effects include a decrease in area of branching vascular network, and stabilization or amelioration of visual acuity.

Abstract

The present disclosure provides methods of treating polypoidal choroidal vasculopathy comprising administering a therapeutically effective amount of a vascular disrupting agent to a subject suffering from polypoidal choroidal vasculopathy. In certain implementations the vascular disrupting agent is a combretastatin, more preferably combretastatin A-4, or a derivative, prodrug or analog thereof. The vascular disrupting agent can be administered systemically, e.g. intravenously, or non-systemically, e.g. topically, to an eye of the subject. The present disclosure also provides the use of a vascular disrupting agent for the manufacture of a medicament for the treatment or prevention of polypoidal choroidal vasculopathy.

Description

VASCULAR DISRUPTING AGENTS FOR TREATMENT OF POLYPOIDAL
CHOROIDAL VASCULOPATHY
I. CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. provisional patent application no. 61/176,943, filed 1 1 May 2009, incorporated herein by reference.
II. BACKGROUND
Polypoidal choroidal vasculopathy (PCV) is a primary abnormality of the choroidal circulation, characterized by an inner choroidal vascular network of vessels ending in polyp- like dilations. The choroidal vascularization of PCV is considered distinct from that of the more common age-related macular degeneration (AMD) because (i) PCV is associated with an earlier onset, (ii) the polypoidal lesions and branching vascular network of PCV are observed inside the Bruch's membrane, wherein vascularization associated with AMD is typically located under the Bruch's membrane; (iii) PCV is characterized by large serosanguinous retinopathy, orange polyp-like structures and multiple lesions throughout the posterior pole, all of which are typically not seen in AMD. Up to 13% of all atypical cases of AMD, when re-examined with indocyanine green angiography, have been found to be a PCV. Ciardella, et al. Sur Ophthalmol 49:25-37 (2004).
The current standard treatment for PCV is photodynamic therapy (PDT). PDT has been demonstrated to result in recurrent hemorrhage and result vision loss in a significant portion of the population. Hirami, et al. Retina 27:335-41 (2007). the risk of massive bleeding post-therapy has led investigators to consider less traumatic medical interventions, particularly anti-VEGF therapies. The results to date with anti-VEGF therapies have been mixed. While one study demonstrated that intravitreal bevacizumab injection causes temporary exudation decrease, the choroidal vascular abnormalities remained detectable by indocyanine green angiography (ICGA) in 10 of 11 eyes. Gomi, et al. British Journal of Ophthalmology 92:70-73 (2008). While bevacizumab can stabilize vision and reduce exudative retinal detachment, PDT is still necessary to treat the polypoidal lesions. Lai, et al. British Journal of Ophthalmology 92:661-666 (2008).
In contrast to anti-angiogenic drugs, such as anti-VEGF therapies, which disrupt the new microvessel formation, Vascular Disrupting Agents ("VDAs") selectively target the abnormal vasculature, both new and established, causing extensive shutdown of blood flow through the abnormal vasculature. A single dose of a VDA can cause a rapid and selective shutdown of abnormal vasculature within a period of minutes to hours. This vascular- mediated cytotoxic mechanism of VDA action is quite divorced from that of anti-angiogenic agents, which inhibit the formation of new vascularization rather than interfering with the existing vasculature.
Fosbretabulin (combretastatin A4 phosphate [CA4P]) is a novel vascular disrupting agent (VDA) that targets abnormal vasculature in oncology and in preclinical models of ophthalmologic disorders. CA4P is a synthetic phosphorylated pro-drug of combretastatin A- 4 (CA4), a naturally occurring derivative of the South African willow tree, Combretum caffrum, which reversibly binds tubulin at the colchicine-binding site to inhibit microtubule assembly. Without being limited by theory, it appears that CA4P and CA4 act on pathologic neovasculature by disrupting microtubule assembly leading to the collapse of the nascent endothelial cell cytoskeleton (mature endothelial cell shape is maintained by the secondary scaffolding protein actin). These newly formed or abnormal endothelial cells then change shape from flat and elongated to rounded or spherical. This endothelial cell shape alteration causes vascular occlusion in immature and abnormal blood vessels, but has no effect on normal mature blood vessels. Selectivity depends on the differentiated state as much as on the age of the endothelial call.
The sensitivity of abnormal and immature vasculature to CA4P provides the basis for its use in diseases outside of oncology where abnormal neovascularization significantly contributes to pathophysiology. In preclinical models of pathologic ophthalmologic neovascularization, CA4P targets vessels with anomalous structure, resulting in an acute occlusion and reduction in blood flow. Aberrant vessels induced by overexpression of VEGF or by exposure to elevated oxygen were disrupted by dose levels of 3 - 4 mg/kg CA4P compared to 75 mg/kg required for normal immature vessels induced by burn injury. These observations suggest that the potential for different dose responses in different indications, depending on the underlying vascular structure.
Nambu and colleagues (Investigative Ophthalmology & Visual Science 44:3650-5 (2003)) evaluated the capacity of CA4P to inhibit vascular growth in two murine models of ocular neovascularization. Transgenic mice with an overexpression of vascular endothelial growth factor (rho/VEGF mice) were administered daily IP injections of vehicle, 2.2 (6.6 mg/m2), or 4.0 (12 mg/m2) mg/kg CA4P between postnatal day 7 (P7) and postnatal day 21 (P21 ). At P21 , the mice were euthanized and histopathology and fluorescein angiography were used to quantitate choroidal neovascularization (CNV). At P21 , mice treated with vehicle or 2.2 mg/kg of CA4P showed numerous neovascular lesions. In contrast, mice treated with 4.0 mg/kg of CA4P showed a significant reduction in the number of neovascular lesions and the total area of neovascularization per retina when compared to vehicle treated mice.
Grigg and colleagues {Am J. Pathology 160(3): 1097-103 (March 2002)) investigated the efficacy of CA4P in preventing retinal neovascularization in a mouse model of retinopathy of prematurity (ROP). Seven-day old mice were placed into a 75% oxygen atmosphere for five consecutive days to induce retinopathy. On postnatal day 12 (P12), hyperoxic mice (5 per group) were administered 5 daily intraperitoneal injections of 0.78, 1.56, 3.125, 6.25, or 12 mg/kg CA4P (2.34, 4.68, 9.375, 18.75, or 36 mg/m2). Additional untreated mice were kept under both 75% oxygen atmosphere and normal oxygen atmosphere (21 % oxygen) and served as controls. At P17, the mice were euthanized and eyes enucleated for histopathology. To quantify retinopathy, nuclei penetrating the inner limiting membrane were counted in representative sections. Histological analysis of retinas from the untreated hyperoxic mice revealed a substantial amount of neovascular growth. The aberrant vessels penetrated the vitreous in a manner that closely resembled retinopathy of prematurity. Retinas of normal mice had no cellular protrusions beyond the inner limiting membrane. Administration of 6.25 and 12 mg/kg CA4P exhibited lethal toxicity in hyperoxic pup mice. Doses of 3.125 mg/kg CA4P or lower caused a dose-dependent inhibition of neovascularization with no apparent side effects. Quantitative analysis revealed a 34, 50, and 84% decrease in nuclei penetrating the inner limiting membrane in mice treated with 0.78, 1.56, 3.125 mg/kg CA4P respectively, when compared to the untreated hyperoxic controls. In addition, further histological and immunohistological analyses indicated that CA4P did not affect the development of normal retinal vasculature.
III. SUMMARY OF THE INVENTION
One aspect of the present disclosure provides methods of treating polypoidal choroidal vasculopathy comprising administering a therapeutically effective amount of a vascular disrupting agent to a subject suffering from polypoidal choroidal vasculopathy. In certain implementations the vascular disrupting agent is a combretastatin, more preferably combretastatin A-4, or a derivative, prodrug or analog thereof. In a certain implementation, the vascular disrupting agent is combretastatin A-4 phosphate (CA4P) or a pharmaceutically acceptable salt thereof. The vascular disrupting agent can be administered systemically, e.g. intravenously, or non-systemically, e.g. topically, to an eye of the subject.
The present disclosure also provides the use of a vascular disrupting agent for the manufacture of a medicament for the treatment or prevention of polypoidal choroidal vasculopathy. IV. DETAILED DESCRIPTION
Fosbretabulin is a novel vascular disrupting agent that targets abnormal vasculature in oncology and in preclinical models of ophthalmologic disorders. CA4P is a synthetic phosphorylated pro-drug of CA4, a naturally occurring derivative of the South African willow tree, Combretum caffrum, which reversibly binds tubulin at the colchicine-binding site to inhibit microtubule assembly. CA4P and CA4 disrupt microtubule assembly leading to the collapse of the nascent endothelial cell cytoskeleton (mature endothelial cell shape is maintained by the secondary scaffolding protein actin). These newly formed or abnormal endothelial cells then change shape from flat and elongated to rounded or spherical. This endothelial cell shape alteration causes vascular occlusion in immature and abnormal blood vessels, but has no effect on normal mature blood vessels. Selectivity depends on the differentiated state as much as on the age of the endothelial call. For example, in tumor vasculature, mature endothelial cells are structurally abnormal and lack an actin cytoskeleton, rending them sensitive to fosbretabulin.
Thirty-two subjects have been enrolled in three ophthalmology studies, one Phase 1 study, one Phase 2 study, and one compassionate use study. Eight subjects were enrolled in the first Phase I dose escalation study in subjects with neovascular age related macular degeneration (AMD), performed by Dr. Quan Dong Nguyen at the Wilmer Eye Institute, Johns Hopkins University. There were no severe or serious drug related adverse events (AEs); the most common adverse events were transient hypertension and QTc prolongation. The compassionate use study enrolled one subject with choroidal neovascularization due to pathologic myopic macular degeneration (MMD). The subject experienced objective improvement in visual acuity, and led to the third study which enrolled 23 subjects with MMD. All subjects in the myopic macular degeneration study showed stabilization of visual function. The most commonly observed AEs were headache, hypoesthesia, nausea, tachycardia, choroidal neovascularization (CNY), and transient hypertension. There were no drug related SAEs.
A. Vascular disrupting agents
Most generally, any vascular disrupting agent currently known or yet to be discovered that is useful in treating, preventing, inhibiting, delaying the onset of, or causing the regression of the polypoidal choroidal vasculopathy may be used in the compositions, liquid formulations, and methods described herein.
Vascular Disrupting Agents ("VDAs") are a separate class of anti-vascular chemotherapeutics. In contrast to anti-angiogenic drugs which disrupt the new microvessel formation, VDAs selectively target the abnormal vasculature, both new and established, causing extensive shutdown of blood flow through the abnormal vasculature. A single dose of a VDA can cause a rapid and selective shutdown of tumor vasculature within a period of minutes to hours, leading eventually to tumor necrosis by induction of hypoxia and nutrient depletion. This vascular-mediated cytotoxic mechanism of VDA action is quite divorced from that of anti-angiogenic agents, which inhibit the formation of new vascularization rather than interfering with the existing vasculature. Other agents have been known to disrupt tumor vasculature, but differ in that they also manifest substantial normal tissue toxicity at their maximum tolerated dose. In contrast, genuine VDAs retain their vascular shutdown activity at a fraction of their maximum tolerated dose. It is thought that tubulin-binding VDAs selectively destabilize the microtubule cytoskeleton of newly formed endothelial cells, causing a profound alteration in the shape of the cell which ultimately leads to occlusion of the blood vessel and shutdown of blood flow (Kanthou et al., Blood 99(6):2060-9 (2002); Cooney et al., Curr Oncol Rep. 7(2):90-5 (2005); Chaplin et al., Curr Opin Investig Drugs 7(6):522-8(2006)).
A particularly promising subclass of VDAs is the class of combretastatins. Derived from the South African tree Combretum caffrum, combretastatins such as combretastatin A- 4 (CA4), were initially identified in the 1980's as potent inhibitors of tubulin polymerization. CA4 and other combretastatins (e.g. combretastatin A-1 (CA1 )) have been shown to bind a site at or near the colchicine binding site on tubulin with high affinity. In vitro studies clearly demonstrated that combretastatins are potent cytotoxic agents against a diverse spectrum of tumor cell types in culture. CA4P and CA1 P, respective phosphate prodrugs of CA4 and CA1 , were subsequently developed to combat problems with aqueous insolubility (see US Patent Nos. 4,996,237; 5,409,953; and 5,569,786, each of which is incorporated herein by reference). CA1 P and CA4P have also been shown to cause a rapid and acute shutdown of the blood flow to tumor tissue that is separate and distinct from the anti-proliferative effects of the agents on tumor cells themselves. A number of studies have shown that combretastatins cause extensive shut-down of blood flow within tumor microvasculature, leading to secondary tumor cell death (Dark et al., Cancer Res. 57: 1829-34, (1997); Chaplin et al., Anticancer Res. 19: 189-96, (1999); Hill et al., Anticancer Res. 22(3):1453-8 (2002); Holwell et al., Anticancer Res. 22(2A):707-11 , (2002). Blood flow to normal tissues is generally far less affected by CA4P and CA1 P than blood flow to tumors (Tozer et al., Cancer Res. 59: 1626-34 (1999)).
In particular embodiments, a combretastatin derivative is a compound of Formula I:
Figure imgf000007_0001
(I) wherein each of R1, R2 and R3, independently of the others, is selected from the group consisting of hydrogen, d-6 alkoxy, and halogen, wherein at least two of R1, R2 and R3 are non-hydrogen;
R4 is selected from the group consisting of R5, R6, R5 substituted with one or more of the same or different R7 or R6, -OR7 substituted with one or more of the same or R7 or R6, -B(OR7)2, -B(NR8R8)2, -(CH2)m-R6, -(CHR7)m-R6, -O-(CH2)m-R6, -S-(CH2)m-R6, -0-CHR7R6, -O-CR7(R6)2, -O-(CHR7)m-R6, -O- (CH2)m-CH[(CH2)mR6]R6,
-S-(CH R7)m-R6, -C(O)N H-(CH2)m-R6, -C(O)N H-(CH R7)m-R6, -0-(CH2VC(O)NH-(CH2VR6, -S-(CH2VC(O)NH-(CH2),,,^6, -0-(CH R7)m-C(O)N H-(CH R7)m-R6, -S-(CH R7)m-C(O)N H-(CH R7)m-R6, -N H-(CH2VR6, -NH-(CHR7)m-R6, -NH[(CH2)mR6], -N[(CH2)mR6]2, -NH-C(O)-NH-(CH2VR6, -NH-C(O)-(CH2VCHR6R6 and -NH-(CH2)m-C(O)-NH-(CH2)m-R6; each R5 is independently selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C4-11 cycloalkylalkyl, C5-10 aryl, C6-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-1 1 membered heterocyclylalkyl, 5-10 membered heteroaryl, 6-16 membered heteroarylalkyl, phosphate, phosphate ester, phosphonate, phosphorodiamidate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, cyclic phosphorodiamidate, and phosphonamidate each R6 is a suitable group independently selected from the group consisting of =0, -OR7, C1-3 haloalkyloxy, -OCF3, =S, -SR7, =NR7, =NOR7, -NR8R8, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)R7, -S(O)2R7, -S(O)2OR7,
-S(O)NR8R8, -S(O)2NR8R8, -OS(O)R7, -OS(O)2R7, -OS(O)2OR7, -OS(O)2NR8R8, -C(O)R7, -C(O)OR7, -C(O)NR8R8, -C(NH)NR8R8, -C(NR7)NR8R8, -C(NOH)R7, -C(NOH)NR8R8, -OC(O)R7, -OC(O)OR7, -OC(O)NR8R8, -OC(NH)NR8R8, -OC(N R7)N R8R8, -[NHC(O)JnR7, -[N R7C(O )]nR7, -[NHC(O)JnOR7, -[N R7C(O)JnO R7, -[NHC(O)JnNR8R8, -[NR7C(O)JnNR8R8, -[NHC(NH)JnNR8R8 and
-[N R7C(N R7)]nN R8R8; each R7 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C4-11 cycloalkylalkyl, C5-10 aryl, C6-16 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-1 1 membered heterocyclylalkyl, 5-10 membered heteroaryl, 6-16 membered heteroarylalkyl, phosphate, phosphate ester, phosphonate, phosphorodiamidate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, cyclic phosphorodiamidate, and phosphonamidate; each R8 is independently R7 or, alternatively, two R8 are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered heterocyclyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R7 or suitable R6 groups; each m independently is an integer from 1 to 3; each n independently is an integer from 0 to 3; p is an integer from 1 to 5, and wherein two adjacent R4 groups and their intervening atoms can be bonded to form a 5-8 membered ring fused to the central phenyl group.
In a particular embodiment, the combretastatin agent is a phosphate prodrug of a combretastatin agent. An exemplary phosphate prodrug is a compound of the Formula II:
Figure imgf000008_0001
wherein
Ra is H or OP(O)(OR3)OR4; and
OR1, OR2, OR3 and OR4 are each, independently, OH, -0" QH+ or -O" M+, wherein M+ is a monovalent or divalent metal cation and Q is, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH+; or b) an organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation, QH+. In one embodiment of Formula II, Ra is H, one of OR1 and OR2 is hydroxyl, and the other is -0" QH+ where Q is tris(hydroxymethyl)amino methane ("TRIS" or "tromethamine").
In another embodiment of Formula II, Ra is H or OP(O)(OR3)OR4, and R1, R2, R3 and R4 are each, independently, an aliphatic organic amine, alkali metals, transition metals, heteroarylene, heterocyclyl, nucleoside, nucleotide, alkaloid, amino sugar, amino nitrile, or nitrogenous antibiotic.
In another embodiment of Formula II, R1, R2, R3 and R4 are each, independently, Na, tromethamine, histidine, ethanolamine, diethanolamine, ethylenediamine, diethylamine, triethanolamine, glucamine, N-methylglucamine, ethylenediamine, 2-(4-imidazolyl)- ethylamine, choline, or hydrabamine.
In another embodiment, Formula Il is represented by a compound of Formula III:
Figure imgf000009_0001
(III) wherein
OR1, OR2, OR3 and OR4 are each, independently, OH, -0" QH+ or -O" M+, wherein M+ is a monovalent or divalent metal cation, and Q is, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH+; or b) an organic containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation, QH+.
In one embodiment of Formula III, at least one of OR1, OR2, OR3 and OR4 is hydroxyl, and at least one of OR1, OR2, OR3 and OR4 is -0" QH+, where Q is tromethamine.
In one exemplary embodiment, a combretastatin derivative is the amine or serinamide derivative of CA4, e.g. AVE8032 (Aventis Pharma, France). In another exemplary embodiment, a combretastatin derivative is ZD6126 (AstraZeneca, UK).
Exemplary combretastatin salts contemplated for use in the methods described herein are discussed in detail in WO 99/35150; WO 01/81355; US Patent Nos. 6,670,344; 6,538,038; 5,569,786; 5,561 ,122; 5,409,953; 4,996,237 which are incorporated herein by reference in their entirety.
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As used herein, the following definitions shall apply unless otherwise indicated.
"Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n- propyl (CH3CH2CH2-), isopropyl ((CHa)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CHs)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
Alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like.
"Aryl" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic provided that the point of attachment is through an atom of the aromatic aryl group. For example, 1 , 2, 3, 4- tetrahydronaphthalen-5-yl, 9H-fluoren-2-yl, and the like. Preferred aryl groups include phenyl and naphthyl.
"Cycloalkyl" refers to cyclic alkyl groups of from 3 to 13 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like. One or more rings fused to the cycloalkyl group can be aromatic, provided that the point of attachment is through the non-aromatic ring, e.g. 9H-fluoren-9-yl, 1 , 2, 3, 4- tetrahydronaphthalen-2-yl, and the like.
"Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo and is preferably fluoro or chloro.
"Heteroaryl" refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl), wherein the condensed rings may or may not be aromatic and/or contain a heteroatom, provided that the point of attachment is through an atom of the aromatic group containing the heteroatom. In one implementation, the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→O), sulfinyl, or sulfonyl moieties. Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
"Heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 15 ring atoms, including 1 to 4 hetero atoms. These ring atoms are selected from the group consisting of nitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. In one implementation, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or -SO2- moieties.
"Phosphate" refers to a moiety selected from the group consisting Of -OP(O)(OH)2 (monophosphate or phospho), -OP(O)(OH)OP(O)(OH)2 (diphosphate or diphospho) and -OP(O)(OH)OP(O)(OH)OP(O)(OH)2 (triphosphate or triphospho) and salts thereof, including partial salts thereof.
"Phosphate ester" refers to a mono-, di- and tri-phosphate group, wherein one or more of the hydroxyl groups are replaced by an alkoxy group. "Phosphonate" refers to a moiety selected from the group consisting of - OP(O)(R6XOH) and -OP(O)(R6)(OR6) and salts thereof, including partial salts thereof, wherein each R6 is independently selected from hydrogen, alkyl, substituted alkyl, carboxylic acid, and carboxyl ester.
"Phosphorodiamidate" refers to
(R7)2N -P-;
(R7)2N where each R7 may be the same or different and each is hydrogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.
"Phosphoramidate monoester" refers to
R8
Figure imgf000013_0001
where R8 is hydrogen or alkyl and R9 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl.
"Phosphoramidate diester" refers to
Figure imgf000013_0002
where R8 is hydrogen or alkyl, R10 is aryl, substituted aryl, alkyl, or substituted alkyl, and each R9 is hydrogen, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl.
"Cyclic phosphoramidate" refers to
Figure imgf000013_0003
where n is 1 to 3.
"Cyclic phosphorodiamidate" refers to
Figure imgf000013_0004
where n is 1 to 3.
"Phosphonamidate" refers to
Figure imgf000014_0001
where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, or substituted cycloalkyl.
Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-O-C(O)-.
It is understood that the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are easily recognized by a person having ordinary skill in the art.
Additional active agents that may be included in the composition include an antiinflammatory. Exemplary active agents include analgesics, anesthetics, or anti-inflammatory agents. In some embodiments, active agents that may be used in the liquid formulations are anti-inflammatory agents (such as hydrocortisone, dexamethasone, fluocinolone, prednisone, prednisolone, methylprednisolone, fluorometholone, betamethasone and triamcinolone), ace-inhibitors, endogenous cytokines, agents that influence basement membrane, agents that influence the growth of endothelial cells, adrenergic agonists or blockers, cholinergic agonists or blockers, aldose reductase inhibitors, antibiotics (such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin, ciprofloxacin, aminosides, gentamycin, erythromycin, penicillin, quinolone, ceftazidime, vancomycin, imipeneme, sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, sulfisoxazole, nitrofurazone and sodium propionate), antifungals (such as amphotericin B, fluconazole, ketoconazole and miconazole), anti-allergics(such as sodium cromoglycate, antazoline, methapyriline, chlorpheniramine, cetirizine, pyrilamine and prophenpyridamine), antihypertensives, pressors, antiprotozoal agents, antiviral agents, antifungal agents, anti-infective agents, antitumor agents, antimetabolites, and antiangiogenic agents.
The vascular disrupting agents may also be used in combination with an additional agent or therapy used to inhibit angiogenesis. In some embodiments, the vascular disrupting agent is used in combination with verteporfin (Visudyne™). In some embodiments the vascular disrupting agent is used in combination with an inhibitor of Vascular Endothelial Growth Factor (VEGF). In some embodiments the vascular disrupting agent is used in combination with an inhibitor of Vascular Endothelial Growth Factor-A (VEGF-A). In some embodiments, the inhibitor of VEGF is a VEGF trap molecule including, without limitation, aflibercept. In some embodiments the inhibitor of VEGF is an antibody or fragment thereof directed to VEGF. In some embodiments the antibody or fragment thereof directed to VEGF is bevacizumab (i.e., Avastin™). In some embodiments the antibody or fragment thereof directed to VEGF is ranibizumab (i.e., Lucentis™).
Also provided are methods for treating or preventing PCV in a human subject comprising administration of a liquid formulation comprising a vascular disrupting agent such as a combretastatin or an analog or derivative thereof and an active agent such as ranibizumab (i.e., Lucentis™), bevacizumab (i.e., Avastin™), or a VEGF trap. In some embodiments, the methods for treating or preventing PCV in a human subject comprise administration of a liquid formulation comprising a combretastatin and ranibizumab (i.e., Lucentis™), bevacizumab (i.e., Avastin™), or a VEGF trap. In some embodiments, the liquid formulation comprising a combretastatin and ranibizumab (i.e., Lucentis™), bevacizumab (i.e., Avastin™), or a VEGF trap is administered intravenously, intravitreally, subconjunctival^, subtenonally, or topically. In some embodiments, the liquid formulation is administered intravitreally. In some embodiments, the total amount of Lucentis or Avastin is any of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, or about 0.7 mg. In some embodiments, the total amount of Lucentis or Avastin is 0.3 mg or 0.5 mg.
In some embodiments the vascular disrupting agent used in combination with an additional active agent may be administered simultaneously (i.e., simultaneous administration), sequentially (i.e., sequential administration), or independently of the additional active agents. In some embodiments the vascular disrupting agent and the additional active agent are administered by the same route of administration. In some embodiments, the vascular disrupting agent and additional active agent are both administered during one visit to the physician. In some embodiments, the vascular disrupting agent and additional active agent are both administered during the same physician visit. In some embodiments, the vascular disrupting agent and additional active agent are administered during more than one visit to the physician.
In some embodiments the vascular disrupting agent and the additional active agent are administered by the same route of administration. In some embodiments the vascular disrupting agent and the additional active agent are administered by different routes of administration.
In some embodiments the combination of administration of vascular disrupting agent and administration of additional active agent reduces the dose administered (e.g., dose volume, dose concentration, or amount of vascular disrupting agent) of one or both agents, as compared to the amount effect when used as a monotherapy. In some embodiments the combination of vascular disrupting agent and additional active agent increases or prolongs the time between administrations and/or decreases the frequency of administrations of one or both agents.
In some embodiments, the vascular disrupting agent is CA4P or a pharmaceutically acceptable salt thereof. In some embodiments, the additional active agent is verteporfin, bevacizumab, and/or ranibizumab.
In some embodiments, the formulations and pharmaceutical formulations described herein are used to prevent or delay onset of PCV where the subject, including but not limited to a human subject, is at heightened risk of developing PCV. A subject with a heightened risk of developing PCV is a subject with one or more indications that PCV is likely to develop in the particular subject. In some embodiments, a formulations or pharmaceutical formulation comprises a combretastatin compound such as CA4P, and is administered to treat, prevent, or delay onset of PCV.
The formulation, liquid formulations and methods described herein can be used to treat, prevent, inhibit, delay onset or cause to regress PCV in a subject. Polypoidal choroidal vasculopathy (PCV) is a disorder whose hallmark feature is grapelike clusters of vascular varicosities termed polypoids. These polypoids are terminal dilatations of more extensive background network of anomalous branching vessels which mainly occurs in the sub-retinal pigment epithelium (sub-RPE) space and choroid. These polypoids and abnormal vessels lead to exudation and hemorrhage which may occur in the retina, directly impairing vision or may occur sub-retinally producing the pigment epithelial detachments (PEDs) which are another characteristic feature of the disease.
As used herein, to "treat" PCV by administration of a vascular disrupting agent means that the progress of at least one detectable physical characteristic or symptom of PCV is slowed, stopped, or reversed following administration of the vascular disrupting agent. Exemplary detectable physical characteristics or symptoms of PCV include, without limitation, branching vascular networks detectable using indocyanine green angiography (ICGA), retinal thickness and edema datable using ocular coherence tomography (OCT), corneal neovascularization and lesion size detectable using fluorescein angiography (FA), and declining 'best corrected visual acuity' (BCVA).
As used herein, to "inhibit" PCV by administration of a vascular disrupting agent means that the progress of at least one detectable physical characteristic or symptom of PCV is slowed or stopped following administration of the vascular disrupting agent.
As used herein, to "prevent" PCV by administration of a vascular disrupting agent means that detectable physical characteristics or symptoms of PCV do not develop following administration of the vascular disrupting agent.
As used herein, to "delay onset of PCV by administration of a vascular disrupting agent means that at least one detectable physical characteristic or symptom of PCV develops later in time following administration of the vascular disrupting agent as compared to the progress of PCV without administration of the vascular disrupting agent.
As used herein, to "cause regression of" PCV by administration of a vascular disrupting agent means that the progress of at least one detectable physical characteristic or symptom of PCV is reversed to some extent following administration of the vascular disrupting agent.
A subject, including but not limited to a human subject, having a predisposition or in need of prevention may be identified by the skilled practitioner by established methods and criteria in the field given the teachings herein. The skilled practitioner may also readily diagnose individuals as in need of inhibition or treatment based upon established criteria in the field for identifying PCV given the teachings herein.
As used herein, a "subject" is generally any animal that may benefit from administration of the vascular disrupting agents described herein. In some embodiments the vascular disrupting agents are administered to a mammalian subject. In some embodiments the vascular disrupting agents are administered to a human subject.
B. Routes of Administration
The compositions, methods, and liquid formulations described herein deliver one or more vascular disrupting agents to a subject, including but not limited to a human subject.
In some embodiments, the compositions, methods, and liquid formulations described herein deliver one or more vascular disrupting agents to an aqueous medium of a human subject. In some embodiments, the compositions, methods, and liquid formulations described herein deliver one or more vascular disrupting agents to an eye of a subject, including the macula and the retina choroid tissues, in an amount and for a duration effective to treat, prevent, inhibit, delay the onset of, or cause the regression of PCV.
"Retina choroid" and "retina choroid tissues," as used herein, are synonymous and refer to the combined retina and choroid tissues of the eye.
As a non-limiting example, the compositions, liquid formulations, and methods described in herein may be administered to the vitreous, aqueous humor, sclera, conjunctiva, between the sclera and conjunctiva, the retina choroid tissues, macula, or other area in or proximate to the eye of a subject, either by direct administration to these tissues or by periocular routes, in amounts and for a duration effective to treat, prevent, inhibit, delay the onset of, or cause the regression of PCV. The effective amounts and durations may be different for each of treating, preventing, inhibiting, delaying the onset of, or causing the regression of PCV, and for each of the different sites of delivery.
Intravitreal administration is more invasive than some other types of ocular procedures. Because of the potential risks of adverse effects, intravitreal administration may not be optimal for treatment of relatively healthy eyes. By contrast, periocular administration, such as subconjunctival administration, is much less invasive than intravitreal administration. When a vascular disrupting agent is delivered by a periocular route, it may be possible to treat patients with healthier eyes than could be treated using intravitreal administration. In some embodiments, subconjunctival injection is used to prevent or delay onset of a disease or condition of the eye, where the eye of the subject has visual acuity of 20/40 or better.
"Subconjunctival" placement or injection, as used herein, refers to placement or injection between the sclera and conjunctiva. Subconjunctival is sometimes referred to herein as "sub-conj" administration.
Routes of administration that may be used to administer a liquid formulation include but are not limited to placement of the liquid formulation, for example by injection, into an aqueous medium in the subject, including but not limited to placement, including but not limited to by injection, into the eye of a subject, including but not limited to a human subject. The liquid formulation may be administered systemically, including but not limited to the following delivery routes: rectal, vaginal, infusion, intramuscular, intraperitoneal, intraarterial, intrathecal, intrabronchial, intracisternal, cutaneous, subcutaneous, intradermal, transdermal, intravenous, intracervical, intraabdominal, intracranial, intraocular, intrapulmonary, intrathoracic, intratracheal, nasal, buccal, sublingual, oral, parenteral, or nebulised or aerosolized using aerosol propellants.
Compositions and liquid formulations comprising vascular disrupting agent can be administered directly to the eye using a variety of procedures, including but not limited to procedures in which (1 ) the vascular disrupting agent is administered by injection using a syringe and hypodermic needle, (2) a specially designed device is used to inject the vascular disrupting agent, (3) prior to injection of the vascular disrupting agent, a pocket is surgically formed within the sclera to serve as a receptacle for the vascular disrupting agent or vascular disrupting agent composition. For example, in one administration procedure a surgeon forms a pocket within the sclera of the eye followed by injection of a solution or liquid formulation comprising the vascular disrupting agent into the pocket.
Other administration procedures include, but are not limited to procedures in which (1 ) a formulation of the vascular disrupting agent is injected through a specially designed curved cannula to place the vascular disrupting agent directly against a portion of the eye, (2) a compressed form of the vascular disrupting agent is placed directly against a portion of the eye, (3) the vascular disrupting agent is inserted into the sclera by a specially designed injector or inserter, (4) the liquid formulation comprising the vascular disrupting agent is incorporated within a polymer, (5) a surgeon makes a small conjunctival incision through which to pass a suture and any vascular disrupting agent delivery structure so as to secure the structure adjacent to the sclera, (6) a needle is used for injection directly into the vitreous of an eye, or into any other site described.
The liquid formulations described herein may be used directly, for example, by injection, as an elixir, for topical administration including but not limited to via eye drops, or in minitablets.
In some embodiments, the liquid formulations described herein may be administered by topical administration. In some embodiments, the topical administration is ocular topical administration. In some embodiments, the ocular topical administration includes, but is not limited to, administration via eye drops, contacts, punctual plugs, or other ocular devices. In some embodiments, the liquid formulation is applied topically, including topically to the eye, any of about 1 , 2, 3, 4, or 5 times per day. In some embodiments, the liquid formulation is applied topically, including topically to the eye, about once or less any of about every 1 , 2, 3, 4, 5, 6, 7, 10, 14, 21 , or 28 day(s). In some embodiments, the liquid formulation is applied topically, including topically to the eye, about once or less a day. In some embodiments, the liquid formulation is applied topically, including topically to the eye, about once or less every 5 days. In some embodiments, the liquid formulation is applied topically, including topically to the eye, about once or less of every 10 days.
In certain implementations, the vascular disrupting agent preferably is administered parenterally, e.g., intravenously, intramuscularly, intravenously, subcutaneously, or intraperitoneal^. The carrier or excipient or excipient mixture can be a solvent or a dispersive medium containing, for example, various polar or non-polar solvents, suitable mixtures thereof, or oils. As used herein "carrier" or "excipient" means a pharmaceutically acceptable carrier or excipient and includes any and all solvents, dispersive agents or media, coating(s), antimicrobial agents, iso/hypo/hypertonic agents, absorption-modifying agents, and the like. The use of such substances and the agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use in therapeutic compositions is contemplated. Moreover, other or supplementary active ingredients can also be incorporated into the final composition.
Solutions of the vascular disrupting agent may be prepared in suitable diluents such as water, ethanol, glycerol, liquid polyethylene glycol(s), various oils, and/or mixtures thereof, and others known to those skilled in the art.
The pharmaceutical forms suitable for injectable use include sterile solutions, dispersions, emulsions, and sterile powders. The final form must be stable under conditions of manufacture and storage. Furthermore, the final pharmaceutical form must be protected against contamination and must, therefore, be able to inhibit the growth of microorganisms such as bacteria or fungi. A single intravenous or intraperitoneal dose can be administered. Alternatively, a slow long term infusion or multiple short term daily infusions may be utilized, typically lasting from 1 to 8 days. Alternate day or dosing once every several days may also be utilized.
Sterile, injectable solutions are prepared by incorporating a compound in the required amount into one or more appropriate solvents to which other ingredients, known to those skilled in the art, may be added as required. Sterile injectable solutions are prepared by incorporating the vascular disrupting agent in the required amount in the appropriate solvent with various other ingredients as required. Sterilizing procedures, such as filtration, then follow. Typically, dispersions are made by incorporating the compound into a sterile vehicle which also contains the dispersion medium and the required other ingredients as indicated above. In the case of a sterile powder, the preferred methods include vacuum drying or freeze drying to which any required ingredients are added. In all cases the final form, as noted, must be sterile and must also be able to pass readily through an injection device such as a hollow needle. The proper viscosity may be achieved and maintained by the proper choice of solvents or excipients. Moreover, the use of molecular or particulate coatings such as lecithin, the proper selection of particle size in dispersions, or the use of materials with surfactant properties may be utilized.
Prevention or inhibition of growth of microorganisms may be achieved through the addition of one or more antimicrobial agents such as chlorobutanol, ascorbic acid, parabens, thimerosal, or the like. It may also be preferable to include agents that alter the tonicity such as sugars or salts.
With mammals, including humans, the effective amounts can be determined by standard method and administered on the basis of body surface area. The interrelationship of dosages varies for animals of various sizes and species, and for humans (based on mg/m2 of body surface) is described by E. J. Freireichet al., Cancer Chemother. Rep., 50(4) :219 (1966). Body surface area may be approximately determined from the height and weight of an individual (see, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y. pp. 537-538 (1970)). A suitable dose range is from 1 to 1000 mg of equivalent per m2 body surface area of a vascular disrupting agent, for instance from 5 to 500 mg/m2.
C. Formulations
The formulations described herein contain a vascular disrupting agent and may generally be any liquid or semi-liquid formulation, including but not limited to solutions, suspensions, emulsions, and gels.
Alternatively, the vascular disrupting agent can be topically applied as a solid or semi-solid formulation. In certain embodiments, the solid formulation is a bioadhesive minitablet. In some embodiments, a total amount of vascular disrupting agent in the solid formulation is less than about 5 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 5.0 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 4.5 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 4.0 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 3.5 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 3.0 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 2.5 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 2 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 1.2 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 1.0 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 0.8 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 0.6 mg is administered. In some embodiments, a total amount of vascular disrupting agent less than about 0.4 mg is administered. In some embodiments, a total amount of vascular disrupting agent administered is any of between about 20 μg and about 4000 μg, between about 10 μg and about 2000 μg, between about 10 μg and 1750 μg, between about 1500 μg and 1000 μg, or between about 10 μg and 1000 μg-
In some embodiments, a total volume of a liquid formulation described herein is topically administered to a subject's eye, including but not limited to a human subject's eye that is less than about 1000 μl, less than about 900 μl, less than about 800 μl, less than about 700 μl, less than about 600 μl, less than about 500 μl, less than about 400 μl, less than about 300 μl, less than about 200 μl, less than about 150 μl, less than about 100 μl, less than about 90 μl, less than about 80 μl, less than about 70 μl, less than about 60 μl, less than about 50 μl, less than about 40 μl, less than about 30 μl, less than about 20 μl, less than about 10 μl, less than about 5 μl, less than about 3 μl, or less than about 1 μl. In some embodiments, a volume of a liquid formulation described herein is topically administered to a subject's eye, including but not limited to a human subject's eye that is less than about 200 μl. In some embodiments, a volume of a liquid formulation described herein is topically administered to a subject's eye, including but not limited to a human subject's eye that is less than about 100 μl. In some embodiments, a volume of a liquid formulation described herein is topically administered to a subject's eye, including but not limited to a human subject's eye that is between about 0.1 μl and about 200 μl, between about 50 μl and about 200 μl, between about 200 μl and about 300 μl, between about 300 μl and about 400 μl, between about 400 μl and about 500 μl, between about 600 μl and about 700 μl, between about 700 μl and about 800 μl, between about 800 μl and about 900 μl, between about 900 μl and about 1000 μl, between about 50 μl and about 150 μl, between about 0.1 μl and about 100 μl, between about 0.1 μl and about 50 μl, between about 1 μl and about 40 μl, between about 1 μl and about 30 μl, between about 1 μl and about 20 μl, between about 1 μl and about 10 μl, or between about 1 μl and about 5 μl. In some embodiments, a total volume of a liquid formulation described herein is topically administered to a subject's eye, including but not limited to a human subject's eye that is between about 10 μl and about 200 μl. In some embodiments, a total volume of a liquid formulation described herein is administered topically to a subject's eye, including but not limited to a human subject's eye that is between about 0.1 μl and about 200 μl. In some embodiments, a total volume of a liquid formulation described herein is topically administered to a subject's eye, including but not limited to a human subject's eye that is between about 40 μl and about 160 μl. In some embodiments, a total volume of a liquid formulation described herein is topically administered to a subject's eye, including but not limited to a human subject's eye that is about 40 μl. In some embodiments, a total volume of a liquid formulation described herein is topically administered to a subject's eye, including but not limited to a human subject's eye that is about 80 μl.
In some embodiments, a total amount of vascular disrupting agent less than about 5 mg is administered topically in a liquid or solid formulation. In some embodiments, a total amount of vascular disrupting agent less than about 5.0 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 4.5 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 4.0 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 3.5 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 3.0 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 2.5 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 2 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 1.2 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 1.0 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 0.8 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 0.6 mg is administered topically. In some embodiments, a total amount of vascular disrupting agent less than about 0.4 mg is administered topically. In some embodiments, a volume of a formulation is administered that contains an amount of vascular disrupting agent described herein. In some embodiments, a total amount of vascular disrupting agent administered topically is any of between about 20 μg and about 4000 μg, between about 10 μg and about 2000 μg, between about 10 μg and 1750 μg, between about 1500 μg and 1000 μg, or between about 10 μg and 1000 μg. In some embodiments, a total amount of vascular disrupting agent administered topically is about 1660 μg. In some embodiments, a total amount of vascular disrupting agent administered topically is about 880 μg. In some embodiments, a total amount of vascular disrupting agent administered topically is 40 μg. In some embodiments, a total amount of vascular disrupting agent administered topically is about 28 μg.
When a certain volume of a liquid formulation is administered, it is understood that there is some imprecision in the accuracy of various devices that may be used to administer the liquid formulation. Where a certain volume is specified, it is understood that this is the target volume. However, certain devices such as insulin syringes are inaccurate to greater than 10%, and sometimes inaccurate to greater than 20% or more. Hamilton HPLC type syringes are generally considered precise to within 10%, and are recommended for volumes below 10 μl are to be injected.
In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous of a subject's eye, including but not limiting a human subject's eye that is less than about 500 μl, less than about 400 μl, less than about 300 μl, less than about 200 μl, less than about 100 μl, less than about 90 μl, less than about 80 μl, less than about 70 μl, less than about 60 μl, less than about 50 μl, less than about 40 μl, less than about 30 μl, less than about 20 μl, less than about 10 μl, less than about 5 μl, less than about 3 μl, or less than about 1 μl. In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous of a rabbit eye or subject's, including but not limited to a human subject's eye that is less than about 20 μl. In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous that is less than about 10 μl. In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous of a subject's eye, including but not limited to a human subject's eye that is between about 0.1 μl and about 200 μl, between about 50 μl and about 200 μl, between about 50 μl and about 150 μl, between about 0.1 μl and about 100 μl, between about 0.1 μl and about 50 μl, between about 1 μl and about 40 μl, between about 1 μl and about 30 μl, between about 1 μl and about 20 μl, between about 1 μl and about 10 μl, or between about 1 μl and about 5 μl. In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous of a subject's eye, including but not limited to a human subject's eye that is between about 1 μl and about 10 μl. In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous of a subject's eye, including but not limited to a human subject's eye that is between about 1 μl and about 5 μl. In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous of a subject's eye, including but not limited to a human subject's eye that is between about 0.1 μl and about 200 μl. In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous of a subject's eye, including but not limited to a human subject's eye that is any of about 2 μl, about 4 μl, about 5 μl, about 6 μl, about 8 μl, about 10 μl, about 12 μl, about 14 μl, about 16 μl, about 18 μl, or about 20 μl. In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous of a subject's eye, including but not limited to a human subject's eye that is about 2 μl. In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous of a subject's eye, including but not limited to a human subject's eye that is about 5 μl. In some embodiments, a volume of a liquid formulation described herein is administered to the vitreous of a subject's eye that is about 8 μl.
In some embodiments, a total amount of vascular disrupting agent administered intravitreally is any of between about 20 μg and about 750 μg, between about 20 μg and about 500 μg, or between about 30 μg and about 200 μg. In some embodiments, a total amount of vascular disrupting agent administered intravitreally is any of about 44 μg, about 110 μg, about 132 μg, about 133.5 μg, about 176 μg, about 264 μg, about 352 μg, about 440 μg or about 976 μg. In some embodiments, a total amount of vascular disrupting agent administered intravitreally is about 44 μg. In some embodiments, a total amount of vascular disrupting agent administered intravitreally is about 1 10 μg. In some embodiments, a total amount of vascular disrupting agent administered intravitreally is about 967 μg. In some embodiments, a liquid formulation containing an amount of vascular disrupting agent of 44 μg is intravitreally administered to a human subject by administering about 2 μl of a liquid formulation described herein. In some embodiments, a liquid formulation containing an amount of vascular disrupting agent of 1 10 μg is intravitreally administered to a human subject by administering about 5 μl of a liquid formulation described herein. In some embodiments, a liquid formulation containing an amount of vascular disrupting agent of 176 μg is intravitreally administered to a human subject by administering about 8 μl of a liquid formulation described herein.
In some embodiments, a total volume of a liquid formulation described herein is subconjunctival^ administered to a subject's eye, including but not limited to a human subject's eye that is less than about 1000 μl, less than about 900 μl, less than about 800 μl, less than about 700 μl, less than about 600 μl, less than about 500 μl, less than about 400 μl, less than about 300 μl, less than about 200 μl, less than about 100 μl, less than about 90 μl, less than about 80 μl, less than about 70 μl, less than about 60 μl, less than about 50 μl, less than about 40 μl, less than about 30 μl, less than about 20 μl, less than about 10 μl, less than about 5 μl, less than about 3 μl, or less than about 1 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is less than about 20 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is less than about 10 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is between about 0.11 and about 200 μl, between about 50 μl and about 200 μl, between about 200 μl and about 300 μl, between about 300 μl and about 400 μl, between about 400 μl and about 500 μl, between about 600 μl and about 700 μl, between about 700 μl and about 800 μl, between about 800 μl and about 900 μl, between about 900 μl and about 1000 μl, between about 50 μl and about 150 μl, between about 0.1 μl and about 100 μl, between about 0.1 μl and about 50 μl, between about 1 μl and about 40 μl, between about 1 μl and about 30 μl, between about 1 μl and about 20 μl, between about 1 μl and about 10 μl, or between about 1 μl and about 5 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is between about 1 μl and about 10 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is between about 1 μl and about 5 μl. In some embodiments, a volume of a liquid formulation described herein is administered to subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is between about 1 μl and about 5 μl. In some embodiments, a volume of a liquid formulation described herein is administered to subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is between about 0.1 μl and about 200 μl.
In some embodiments, a total volume of a liquid formulation is subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is less than about 150 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is any of about 10 μl, about 20 μl, about 30 μl, about 40 μl, about 50 μl, about 60 μl, about 70 μl, about 80 μl, about 90 μl, or about 100 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is about 10 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctivally administered to a subject's eye, including but not limited to a human subject's eye that is about 20 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctival^ administered to a subject's eye, including but not limited to a human subject's eye that is about 30 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctival^ administered to a subject's eye, including but not limited to a human subject's eye that is 40 μl. In some embodiments, a volume of a liquid formulation described herein is subconjunctival^ administered to a subject's eye, including but not limited to a human subject's eye that is any of between about 10 μl and about 50 μl, between about 15 μl and about 45 μl, between about 20 μl and about 40 μl, or between about 25 μl and about 35 μl.
In some embodiments, a total amount of vascular disrupting agent administered subconjunctival^ is any of between about 50 μg and about 3 mg, between about 150 μg and about 750 μg, between about 300 μg and about 1000 μg, between about 300 μg and about 950 μg, between about 400 μg and about 900 μg, between about 450 μg and about 850 μg, between about 500 μg and about 800 μg, between about 550 μg and about 750 μg, or between about 600 μg and about 700 μg. In some embodiments, a total amount of vascular disrupting agent administered subconjunctival^ is any of about 220 μg, about 440 μg, about 587 μg, about 630 μg, about 660 μg, about 880 μg, about 1320 μg, about 1760 μg, or about 2200 μg. In some embodiments, a total amount of vascular disrupting agent administered subconjunctival^ is about 220 μg. In some embodiments, a total amount of vascular disrupting agent administered subconjunctival^ is about 440 μg. In some embodiments, a total amount of vascular disrupting agent administered subconjunctival^ is about 660 μg. In some embodiments, a total amount of vascular disrupting agent administered subconjunctival^ is about 880 μg. In some embodiments, a liquid formulation containing an amount of vascular disrupting agent of 220 μg is subconjunctival^ administered to a human subject by administering about 10 μl of a liquid formulation described herein. In some embodiments, a liquid formulation containing an amount of vascular disrupting agent of 440 μg is subconjunctival^ administered to a human subject by administering about 20 μl of a liquid formulation described herein. In some embodiments, a liquid formulation containing an amount of vascular disrupting agent of 660 μg is subconjunctival^ administered to a human subject by administering about 30 μl of a liquid formulation described herein. In some embodiments, a liquid formulation containing an amount of vascular disrupting agent of 880 μg is subconjunctival^ administered to a human subject by administering about 40 μl of a liquid formulation described herein. In some embodiments, a total volume of a liquid formulation described herein is subtenonally administered to a subject's eye, including but not limited to a human subject's eye that is less than about 1000 μl, less than about 900 μl, less than about 800 μl, less than about 700 μl, less than about 600 μl, less than about 500 μl, less than about 400 μl, less than about 300 μl, less than about 200 μl, less than about 150 μl, less than about 100 μl, less than about 90 μl, less than about 80 μl, less than about 70 μl, less than about 60 μl, less than about 50 μl, less than about 40 μl, less than about 30 μl, less than about 20 μl, less than about 10 μl, less than about 5 μl, less than about 3 μl, or less than about 1 μl. In some embodiments, a volume of a liquid formulation described herein is subtenonally administered to a subject's eye, including but not limited to a human subject's eye that is less than about 200 μl. In some embodiments, a volume of a liquid formulation described herein is subtenonally administered to a subject's eye, including but not limited to a human subject's eye that is less than about 100 μl. In some embodiments, a volume of a liquid formulation described herein is subtenonally administered to a subject's eye, including but not limited to a human subject's eye that is between about 0.1 μl and about 200 pt, between about 50 μl and about 200 μl, between about 200 μl and about 300 μl, between about 300 μl and about 400 μl, between about 400 μl and about 500 μl, between about 600 μl and about 700 μl, between about 700 μl and about 800 μl, between about 800 μl and about 900 μl, between about 900 μl and about 1000 μl, between about 50 μl and about 150 μl, between about 0.1 μl and about 100 μl, between about 0.1 μl and about 50 μl, between about 1 μl and about 40 μl, between about 1 μl and about 30 μl, between about 1 μl and about 20 μl, between about 1 μl and about 10 μl, or between about 1 μl and about 5 μl. In some embodiments, a volume of a liquid formulation described herein is subtenonally administered to a subject's eye, including but not limited to a human subject's eye that is between about 10 μl and about 200 μl. In some embodiments, a volume of a liquid formulation described herein is administered subtenonally to a subject's eye, including but not limited to a human subject's eye that is between about 0.1 μl and about 200 μl. In some embodiments, a volume of a liquid formulation described herein is subtenonally administered to a subject's eye, including but not limited to a human subject's eye that is between about 50 μl and about 150 μl. In some embodiments, a volume of a liquid formulation described herein is subtenonally administered to a subject's eye, including but not limited to a human subject's eye that is about 30 μl. In some embodiments, a volume of a liquid formulation described herein is subtenonally administered to a subject's eye, including but not limited to a human subject's eye that is about 120 μl. In some embodiments, a total amount of vascular disrupting agent less than about 5 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 5.0 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 4.5 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 4.0 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 3.5 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 3.0 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 2.5 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 2 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 1.2 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 1.0 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 0.8 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 0.6 mg is administered subtenonally. In some embodiments, a total amount of vascular disrupting agent less than about 0.4 mg is administered subtenonally. In some embodiments, a volume of a formulation is administered that contains an amount of vascular disrupting agent described herein.
In some embodiments, a total amount less than about 30 mg of vascular disrupting agent described herein is parenterally administered to a subject, including but not limited to a human subject. In some embodiments, a total amount of vascular disrupting agent less than about 50 mg is administered parenterally. In some embodiments, a total amount of vascular disrupting agent less than about 25 mg is administered parenterally. In some embodiments, a total amount of vascular disrupting agent less than about 10 mg is administered parenterally. In some embodiments, a total amount of vascular disrupting agent less than about 7.5 mg is administered parenterally. In some embodiments, a total amount of vascular disrupting agent less than about 5.0 mg is administered parenterally. In some embodiments, a total amount of vascular disrupting agent less than about 2.5 mg is administered parenterally. In some embodiments, a total amount of vascular disrupting agent less than about 2.0 mg is administered parenterally. In some embodiments, a total amount of vascular disrupting agent less than about 1.8 mg is administered parenterally. In some embodiments, a total amount of vascular disrupting agent less than about 1.6 mg is administered parenterally. In some embodiments, a total amount of vascular disrupting agent less than about 1.4 mg is administered parenterally. In some embodiments, a total amount of vascular disrupting agent less than about 1.0 mg is administered parenterally. In some embodiments, a volume of a formulation is administered that contains an amount of vascular disrupting agent described herein.
In some embodiments, the vascular disrupting agent may be a combretastatin compound. In some embodiments, the vascular disrupting agent may be combretastatin A-4 or an analog, prodrug or derivative thereof. In some implementations, the vascular disrupting agent is combretastatin A-4 phosphate.
"Total amount of a vascular disrupting agent" as used herein refers to the total amount of a vascular disrupting agent administered during a single administration session by a patient and/or physician and/or other medical professional. In some embodiments, a single administration session will involve a single administration of the vascular disrupting agent. In some embodiments, one administration session will include more than one administration of the vascular disrupting agent. In some embodiments, one administration session will include a single route of administration. In some embodiments, one administration session will include multiple routes of administration. Thus, in some embodiments, portions of the total amount of the vascular disrupting agent are administered separately during a single administration session. In such embodiments, the portions of the total amount that are administered separately may be administered by the same and/or different routes of administration. In addition, in some embodiments, portions of the total amount that are administered separately may be administered in the same and/or different formulations.
"Total volume of a liquid formulation" as used herein refers to the total volume of a liquid formulation administered during a single administration session by a patient and/or physician and/or other medical professional. In some embodiments, a single administration session will involve a single administration of the liquid formulation. In some embodiments, one administration session will include more than one administration of the liquid formulation. In some embodiments, one administration session will include a single route of administration. In some embodiments, one administration session will include multiple, different routes of administration. Thus, in some embodiments, portions of the total volume are administered separately during a single administration session. In such embodiments, the portions of the total volume that are administered separately may be administered by the same and/or by different routes of administration.
In some embodiments, a vascular disrupting agent is administered in multiple ocular locations. In some embodiments, a vascular disrupting agent is administered intravitreally and subconjunctival^. In some embodiments, a vascular disrupting agent is first administered intravitreally and at least one subsequent administration is administered subconjunctival^. In some embodiments, a vascular disrupting agent is first administered subconjunctival^ and at least one subsequent administration is administered intravitreally. In some embodiments, a vascular disrupting agent is first administered intravitreally, subconjunctival^, or subtenonally and at least on subsequent administration is topically. In some embodiments, the same (i.e., identical) liquid formulation of the vascular disrupting agent is used for the first and subsequent administrations. In some embodiments, a different liquid formulation is used for the first and subsequent administrations. In some embodiments, administration to multiple ocular locations occurs during one visit to the physician. In some embodiments, administration to multiple ocular locations occurs during separate visits to the physician.
In some embodiments of the liquid formulations described herein, the vascular disrupting agent is a solution or suspension of CA4P in a liquid medium. The liquid formulations described herein may comprise a solubilizing agent component. In some embodiments the solubilizing agent component is a surfactant. Note that there is some overlap between components that may be solvents and solubilizing agents, and therefore the same component may in some systems be used as either a solvent or a solubilizing agent. A liquid formulation that comprises a vascular disrupting agent and a component that may be considered either a solvent or a solubilizing agent or surfactant will be considered a solvent if it is playing the role of a solvent; if the component is not playing the role of the solvent, the component may be considered a solubilizing agent or surfactant.
Generally, any solubilizing agent or combination of solubilizing agents may be used in the liquid formulations described herein. In some embodiments, the solubilizing agent is a surfactant or combination of surfactants. Many surfactants are possible. Combinations of surfactants, including combinations of various types of surfactants, may also be used. For instance, surfactants which are nonionic, anionic (i.e. soaps, sulfonates), cationic (i.e. CTAB), zwitterionic, polymeric or amphoteric may be used.
Surfactants that can be used may be determined by mixing a vascular disrupting agent of interest with a putative solvent and a putative surfactant, and observing the characteristics of the formulation after exposure to a medium. Examples of surfactants include but are not limited to fatty acid esters or amides or ether analogues, or hydrophilic derivatives thereof; monoesters or diesters, or hydrophilic derivatives thereof; or mixtures thereof; monoglycerides or diglycerides, or hydrophilic derivatives thereof; or mixtures thereof; mixtures having enriched mono- or/and diglycerides, or hydrophilic derivatives thereof; surfactants with a partially derivatized with a hydrophilic moiety; monoesters or diesters or multiple-esters of other alcohols, polyols, saccharides or oligosaccharides or polysaccharides, oxyalkylene oligomers or polymers or block polymers, or hydrophilic derivatives thereof, or the amide analogues thereof; fatty acid derivatives of amines, polyamines, polyimines, aminoalcohols, aminosugars, hydroxyalkylamines, hydroxypolyimines, peptides, polypeptides, or the ether analogues thereof.
Liquid formulations may optionally further comprise stabilizers, excipients, gelling agents, adjuvants, antioxidants, and/or other components as described herein.
In some embodiments all components in the liquid formulation, other than the vascular disrupting agent, are liquid at room temperature.
In some embodiments, the liquid formulation comprises a release modifying agent. In some embodiments, the release modifying agent is a film-forming polymer component. The film-forming polymer component may comprise one or more film-forming polymers. Any film- forming polymer may be used in the excipient component. In some embodiments, the film- forming polymer component comprises a water insoluble film forming polymer. In some embodiments, the release modifying agent component comprises an acrylic polymer, including but not limited to polymethacrylate, including but not limited to Eudragit RL.
In some embodiments the vascular disrupting agent in the liquid formulation comprises between about 0.01 to about 30% of the total weight of the composition; between about 0.05 to about 15%; between about 0.1 to about 10%; between about 1 to about 5%; or between about 5 to about 15%; between about 8 to about 10%; between about 0.01 to about 1%; between about 0.05 to about 5%; between about 0.1 to about 0.2%; between about 0.2 to about 0.3%; between about 0.3 to about 0.4%; between about 0.4 to about 0.5%; between about 0.5 to about 0.6%; between about 0.6 to about 0.7%; between about 0.7 to about 1 %; between about 1 to about 5%; between about 5 to about 10%; between about 15 to about 30%, between about 20 to about 30%; or between about 25 to about 30%.
In some embodiments the vascular disrupting agent in the liquid formulation comprises between about 0.001 to about 1.00% of the total weight of the composition. In some embodiments the vascular disrupting agent in the liquid formulation comprises any of about 0.07%, about 0.08%, 0.09%, 0.17%, 1.38%, 1.47%, 2%, 4%, 4.84%, or 5% of the total weight of the composition. In some embodiments, the vascular disrupting agent may be a combretastatin compound. In some embodiments, the vascular disrupting agent may be CA4 or an analog, prodrug or derivative thereof. In some embodiments, the vascular disrupting agent is CA4P. The solvent component of the liquid formulation may comprise, for instance, between about 0.01 to about 99.9% of the total weight of the composition; between about 0.1 to about 99%; between about 25 to about 55%; between about 30 to about 50%; or between about 35 to about 45%; between about 0.1 to about 10%; between about 10 to about 20%; between about 20 to about 30%; between about 30 to about 40%; between about 40 to about 45%; between about 40 to about 45%; between about 45 to about 50%; between about 50 to about 60%; between about 50 to about 70%; between about 70 to about 80%; between about 80 to about 90%; or between about 90 to about 100%.
The solubilizing agent component of the liquid formulation may comprise, for instance, between about 0.01 to about 30% of the total weight of the composition; between about 0.1 to about 20%; between about 2.5 to about 15%; between about 10 to about 15%; or between about 5 to about 10%; between about 8 to about 12%; between about 10 to about 20%; between about 20 to about 30%.
In some embodiments, the liquid formulations described herein have a viscosity of between 40% and 120% centipoise. In some embodiments the liquid formulations described herein have a viscosity of between 60% and 80% centipoise.
The liquid formulations described herein may be administered with or further comprise a viscosity modifying agent. One exemplary viscosity modifying agent that may be used is hyaluronic acid. Hyaluronic acid is a glycosaminoglycan. It is made of a repetitive sequence of glucuronic acid and glucosamine. Hyaluronic acid is present in many tissues and organs of the body, and contributes to the viscosity and consistency of such tissues and organs. Hyaluronic acid is present in the eye, including the vitreous of the eye, and along with collagen contributes to the viscosity thereof. The liquid formulations described herein may further comprise or be administered with hyaluronic acid. Other nonlimiting examples of viscosity modifying agents include polyalkylene oxides, glycerol, carboxymethyl cellulose, sodium alginate, chitosan, dextran, dextran sulfate and collagen. These viscosity modifying agents can be chemically modified.
In some embodiments the liquid formulations described herein comprise a vascular disrupting agent and a solvent component. The solvent component may comprise a single solvent or a combination of solvents. In some embodiments, the solvent is glycerin, N- methylpyrrolidone (NMP), dimethyl acetamide (DMA), dimethyl formamide, dimethyl sulfoxide (DMSO), glycerol formal, ethoxy diglycol, triethylene glycol dimethyl ether, triacetin, diacetin, corn oil, acetyl triethyl citrate (ATC), ethyl lactate, polyglycolated capryl glyceride, γ butyrolactone, dimethyl isosorbide, benzyl alcohol, ethanol, isopropyl alcohol, propylene glycol (PG), polyethylene glycol of various molecular weights, including but not limited to PEG 300 and PEG 400, or a mixture of one or more thereof.
In some embodiments, the solvent is polyethoxylated castor oil (e.g., Cremophor (PEG 35 castor oil)), monoglycerides and/or diglycerides of caprylic acid (e.g., Capmul MCM (C8)), nonionic polymer of the alkyl aryl polyether alcohol (e.g., tyloxapol (ethoxylated p-tert- octylphenol formaldehyde polymer)), 50% phosphatidylcholine in propylene glycol/ethanol carrier (e.g., Phosal® 50PG), propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, macrogol 15 hydroxystearate, ethanol, or a mixture of one or more thereof. In some variation, the solvent may comprise a combination of at least two solvents. In some embodiments, the at least two solvents comprising a first solvent such as polyethoxylated castor oil (e.g., Cremophor (PEG 35 castor oil)), propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, macrogol 15 hydroxystearate, or nonionic polymer of the alkyl aryl polyether alcohol (e.g., tyloxapol (ethoxylated p-tert- octylphenol formaldehyde polymer)) and a second solvent such as monoglycerides and/or diglycerides of caprylic acid (e.g., Capmul MCM (C8)). In some embodiments, the solvent may further comprise ethanol. In some embodiments, the solvent may further comprise water. In some embodiments, liquid formulation is topically administered. In some embodiments, the liquid formulation is administered as eye drops. In some embodiments, the liquid formulation is used to treat or prevent PCV.
The solvent component may comprise water, for instance, between about 0.01 to about 99.9% of the total weight of the composition; between about 0.1 to about 99%; between about 25 to about 55%; between about 30 to about 50%; or between about 35 to about 45%; between about 0.1 to about 10%; between about 10 to about 20%; between about 20 to about 30%; between about 30 to about 40%; between about 40 to about 45%; between about 40 to about 45%; between about 45 to about 50%; between about 50 to about 60%; between about 50 to about 70%; between about 70 to about 80%; between about 80 to about 90%; or between about 90 to about 100%. In some embodiments, water comprises between about 15 to about 30% (w/w) of the liquid formulation. In some embodiments, water comprises between about 80 to about 90% (w/w) of the liquid formulation. In some embodiments, water comprises at least 15% (w/w). In some embodiments, water comprises at least 20% (w/w) of the liquid formulation. In some embodiments, water comprises at least 25% (w/w) of the liquid formulation. In some embodiments, water comprises at least about 5 percent (w/w) of the liquid formulation. In some embodiments, water comprises about 16% (w/w) of the liquid formulation. In some embodiments, water comprises about 22% (w/w). In some embodiments, water comprises about 28% (w/w) of the liquid formulation. In some embodiments, water comprises about 83% (w/w) of the liquid formulation.
In some embodiments, the liquid formulations described herein are suspensions, and comprise a vascular disrupting agent and a diluent component. In some embodiments, the diluent component comprises one or more components listed herein as solvents or solubilizing agents, wherein the resulting mixture is a suspension. In some embodiments the liquid formulation is partly a solution and partly a suspension.
D. Compositions and Formulations for Delivery of Vascular Disrupting Agents
The compositions and formulations described herein may be used to deliver amounts of the vascular disrupting agents effective for treating, preventing, inhibiting, delaying on set of, or causing the regression of PCV. In some embodiments the compositions and formulations described herein deliver one or more vascular disrupting and/or additional active agents over an extended period of time.
An "effective amount," which is also referred to herein as a "therapeutically effective amount," of a vascular disrupting agent for administration as described herein is that amount of the vascular disrupting agent that provides the therapeutic effect sought when administered to the subject, including but not limited to a human subject. The achieving of different therapeutic effects may require different effective amounts of vascular disrupting agent. For example, the therapeutically effective amount of a vascular disrupting agent used for preventing a disease or condition may be different from the therapeutically effective amount used for treating, inhibiting, delaying the onset of, or causing the regression of the disease or condition. In addition, the therapeutically effective amount may depend on the age, weight, and other health conditions of the subject as is well know to those versed in the disease or condition being addressed. Further, the therapeutically effective amount can depend upon the route of administration. Thus, the therapeutically effective amount may not be the same in every subject to which the vascular disrupting agent is administered.
An effective amount of a vascular disrupting agent for treating, preventing, inhibiting, delaying the onset of, or causing the regression of PCV is also referred to herein as the amount of vascular disrupting agent effective to treat, prevent, inhibit, delay the onset of, or cause the regression of PCV.
To determine whether a level of vascular disrupting agent is a "therapeutically effective amount" to treat, prevent, inhibit, delay on set of, or cause the regression of PCV, formulations may be administered in animal models for PCV, and the effects may be observed. In addition, dose ranging human clinical trials may be conducted to determine the therapeutically effective amount of a vascular disrupting agent.
Generally, the vascular disrupting agent may be formulated in any composition or formulation capable of delivery of a therapeutically effective amount of the vascular disrupting agent to a subject or to the eye of a subject for the required delivery period. Compositions include liquid formulations.
In some embodiments, the formulations described herein are provided in one or more unit dose forms, wherein the unit dose form contains an amount of a liquid formulation described herein that is effective to treat or prevent the disease or condition for which it is being administered. In some embodiments, the formulations described herein are provided in one or more unit dose forms, wherein the unit dose form contains an amount of a liquid combretastatin formulation described herein that is effective to treat or prevent PCV.
In some embodiments, the unit dose form is prepared in the concentration at which it will be administered. In some embodiments, the unit dose form is diluted prior to administration to a subject. In some embodiments, a liquid formulation described herein is diluted in an aqueous medium prior to administration to a subject. In some embodiments the aqueous medium is an isotonic medium. In some embodiments, a liquid formulation described herein is diluted in a non-aqueous medium prior to administration to a subject.
In a further aspect, provided herein are kits comprising one or more unit dose forms as described herein. In some embodiments, the kit comprises one or more of packaging and instructions for use to treat one or more diseases or conditions. In some embodiments, the kit comprises a diluent which is not in physical contact with the formulation or pharmaceutical formulation. In some embodiments, the kit comprises any of one or more unit dose forms described herein in one or more sealed vessels. In some embodiments, the kit comprises any of one or more sterile unit dose forms.
In some embodiments, the unit dose form is in a container, including but not limited to a sterile sealed container. In some embodiments the container is a vial, ampule, or low volume applicator, including but not limited to a syringe. In some embodiments, a low- volume applicator is pre-filled with combretastatin, including but not limited to CA4P, for treatment of PCV. Described herein is a pre-filled low-volume applicator pre-filled with a formulation comprising a vascular disrupting agent, including but not limited to CA4P. In some embodiments a low-volume applicator is pre-filled with a solution comprising a vascular disrupting agent, including but not limited to CA4P, and optionally further comprises one or more additional components, including but nor limited to a solvent, surfactant and/or a stabilizer.
Described herein are kits comprising one or more containers. In some embodiments a kit comprises one or more low-volume applicators is pre-filled with a formulation described herein comprising a vascular disrupting agent, including but not limited to formulations comprising CA4P, and optionally further comprises one or more additional components. In some embodiments the kit comprises one or more containers, including but not limited to pre-filled low-volume applicators, with instructions for its use. In a further variation a kit comprises one or more low-volume applicators pre-filled with CA4P, with instructions for its use in treating PCV. In some embodiments, the containers described herein are in a secondary packaging.
V. EXAMPLE
Subjects suffering from polypoidal choroidal vasculopathy in at least one eye were diagnosed based on description of active ICGA features by Yannuzzi et al, 1999, i.e. those subject demonstrating at least one polypoidal varicosity (branching inner choroidal vessels external to the choriocapillaris with terminal dilations that demonstrate early, intense, focal or multifocal hyperfluorescence) when imaged with ICGA. Additionally, subjects included in the study had a best corrected visual acuity (BCVA) by ETDRS of 68 to 4 letters (Snellen equivalent approximately of 20/40 to 20/800) in the study eye.
Subjects were enrolled in one of five parallel treatment arms of placebo, 15, 25, 35, and 45 mg/m2 combretastatin A4 phosphate. Each subject received a single intravenous infusion of combretastatin A4 phosphate or placebo.
Baseline ophthalmologic and internal medicine status of each subject were monitored during an initial Screening period lasting up to 21 days. The infusion of study drug was performed on Day 1. Subjects returned for ophthalmologic assessments on Days 2, 8, 15, 29, and a final assessment at 3 months (approximately Day 85). Ophthalmologic assessments included one or more of BCVA by ETDRS, OCT, color fundus photography, ICGA, fluorescein angiography (FA), biomicroscopy, intraocular pressure (lOP) and dilated ophthalmoscopy performed for the retina, macula, choroid, and optic nerve head. Additionally, subjects returned for medical assessments on Days 2, 8, and 29.
Figure 1 illustrates the change in the number of PCV lesions in a patient receiving a single infusion of 45 mg/m2 combretastatin A4 phosphate as compared to a patient receiving the placebo. Figure 2 illustrates the percent change in the number of PCV lesions in the placebo patient and the patient receiving 45 mg/m2 combretastatin A4 phosphate. The patient receiving combretastatin A4 phosphate demonstrated a decrease in the number of lesion, whereas the placebo patient experienced an overall increase in the number of lesions. Thus, treatment with CA4P is anticipated to decrease or completely eliminate PCV lesions in the affected eye.
Figure 3 illustrates the area of branching vascular network as measured by ICGA for the patient receiving 45 mg/m2 combretastatin and the patient receiving placebo. The branching network area of the patient receiving combretastatin remained relatively stable while the branching network expanded in the patient receiving placebo. Similarly, the total lesion area for the patient receiving combretastatin remained relatively stable or increased only slightly, while the total lesion area increased substantially over the three month course of the trial (see Figure 4). Additional expected beneficial effects include stabilization or amelioration of visual acuity.
Retinal thickness was measured with OCT. The measured retinal thickness for nine patients, representing at least one patient from each treatment group, is provided in Figure 5.
Treatment with CA4P is anticipated to decrease or completely eliminate PCV lesions in the affected eye. Additional expected beneficial effects include a decrease in area of branching vascular network, and stabilization or amelioration of visual acuity.

Claims

WE CLAIM:
1. A method of treating polypoidal choroidal vasculopathy comprising administering a therapeutically effective amount of a vascular disrupting agent to a subject suffering from polypoidal choroidal vasculopathy.
2. The method of claim 1 , wherein the vascular disrupting agent is a combretastatin.
3. The method of claim 2, wherein the combretastatin is a compound of Formula I:
Figure imgf000039_0001
(I) wherein each of R1, R2 and R3, independently of the others, is selected from the group consisting of hydrogen, d-6 alkoxy, and halogen, wherein at least two of R1, R2 and R3 are non-hydrogen;
R4 is selected from the group consisting of R5, R6, R5 substituted with one or more of the same or different R7 or R6, -OR7 substituted with one or more of the same or R7 or R6, -B(OR7)2, -B(NR8R8)2, -(CH2)m-R6, -(CHR7)m-R6, -O-(CH2)m-R6, -S-(CH2)m-R6, -0-CHR7R6, -O-CR7(R6)2, -O-(CHR7)m-R6, -O- (CH2)m-CH[(CH2)mR6]R6, -S-(CH R7)m-R6, -C(O)N H-(CH2)m-R6, -C(O)N H-(CH R7)m-R6, -0-(CH2VC(O)NH-(CH2VR6, -S-(CH2VC(O)NH-(CH2),,,^6, -0-(CH R7)m-C(O)N H-(CH R7)m-R6, -S-(CH R7)m-C(O)N H-(CH R7)m-R6, -N H-(CH2VR6, -NH-(CHR7)m-R6, -NH[(CH2)mR6], -N[(CH2)mR6]2, -NH-C(O)-NH-(CH2VR6, -NH-C(O)-(CH2VCHR6R6 and -NH-(CH2)m-C(O)-NH-(CH2)m-R6; each R5 is independently selected from the group consisting of Ci-6 alkyl, C3-S cycloalkyl, C4-i 1 cycloalkylalkyl, C5-I0 aryl, C6-i6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-1 1 membered heterocyclylalkyl, 5-10 membered heteroaryl, 6-16 membered heteroarylalkyl, phosphate, phosphate ester, phosphonate, phosphorodiamidate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, cyclic phosphorodiamidate, and phosphonamidate each R6 is a suitable group independently selected from the group consisting of =0, -OR7, Ci-3 haloalkyloxy, -OCF3, =S, -SR7, =NR7, =NOR7, -NR8R8, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)R7, -S(O)2R7, -S(O)2OR7, -S(O)NR8R8, -S(O)2NR8R8, -OS(O)R7, -OS(O)2R7, -OS(O)2OR7, -OS(O)2NR8R8, -C(O)R7, -C(O)OR7, -C(O)NR8R8, -C(NH)NR8R8, -C(NR7)NR8R8, -C(NOH)R7, -C(NOH)NR8R8, -OC(O)R7, -OC(O)OR7, -OC(O)NR8R8, -OC(NH)NR8R8, -OC(N R7)N R8R8, -[NHC(O)JnR7, -[N R7C(O )]nR7, -[NHC(O)JnOR7, -[N R7C(O)JnO R7, -[NHC(O)JnNR8R8, -[NR7C(O)JnNR8R8, -[NHC(NH)JnNR8R8 and -[N R7C(N R7)]nN R8R8; each R7 is independently selected from the group consisting of hydrogen, Ci-6 alkyl, C3-S cycloalkyl, C4-n cycloalkylalkyl, C5-I0 aryl, C6-i6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-1 1 membered heterocyclylalkyl, 5-10 membered heteroaryl, 6-16 membered heteroarylalkyl, phosphate, phosphate ester, phosphonate, phosphorodiamidate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, cyclic phosphorodiamidate, and phosphonamidate; each R8 is independently R7 or, alternatively, two R8 are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered heterocyclyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R7 or suitable R6 groups; each m independently is an integer from 1 to 3; each n independently is an integer from O to 3; p is an integer from 1 to 5, and wherein two adjacent R4 groups and their intervening atoms can be bonded to form a 5-8 membered ring fused to the central phenyl group.
4. The method of claim 2, wherein the combretastatin is a phosphate prodrug of Formula II:
Figure imgf000040_0001
wherein
Ra is H or OP(O)(OR3)OR4; and
OR1, OR2, OR3 and OR4 are each, independently, OH, -0" QH+ or -O" M+, wherein M+ is a monovalent or divalent metal cation and Q is, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH+; or b) an organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation, QH+.
5. The method of claim 4, wherein Ra is H, one of OR1 and OR2 is hydroxyl, and the other is -0" QH+ where Q is tris(hydroxymethyl)amino methane
6. The method of claim 4, wherein Ra is H or OP(O)(OR3)OR4, and R1, R2, R3 and R4 are each, independently, an aliphatic organic amine, alkali metals, transition metals, heteroarylene, heterocyclyl, nucleoside, nucleotide, alkaloid, amino sugar, amino nitrile, or nitrogenous antibiotic
7. The method of claim 4, wherein Formula Il is represented by a compound of Formula
Figure imgf000041_0001
(III) wherein OR1, OR2, OR3 and OR4 are each, independently, OH, -0" QH+ or -O" M+, wherein M+ is a monovalent or divalent metal cation, and Q is, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH+; or b) an organic containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation, QH+.
8. The method of claim 7, wherein at least one of OR1, OR2, OR3 and OR4 is hydroxyl, and at least one of OR1, OR2, OR3 and OR4 is -0"QH+, where Q is tromethamine
9. The method of claim 2, wherein the combretastatin is administered intravenously, intravitreally, subconjunctival^, subtenonally, or topically.
10. Use of a vascular disrupting agent for the manufacture of a medicament for the treatment or prevention of polypoidal choroidal vasculopathy.
11. The method of claim 10, wherein the vascular disrupting agent is a combretastatin.
12. The method of claim 11 , wherein the combretastatin is a compound of Formula I:
Figure imgf000042_0001
(I) wherein each of R1, R2 and R3, independently of the others, is selected from the group consisting of hydrogen, d-6 alkoxy, and halogen, wherein at least two of R1, R2 and R3 are non-hydrogen; R4 is selected from the group consisting of R5, R6, R5 substituted with one or more of the same or different R7 or R6, -OR7 substituted with one or more of the same or R7 or
R6, -B(OR7)2, -B(NR8R8)2, -(CH2)m-R6, -(CHR7)m-R6, -O-(CH2)m-R6, -S-(CH2)m-R6, -0-CHR7R6, -O-CR7(R6)2, -O-(CHR7)m-R6, -O- (CH2)m-CH[(CH2)mR6]R6, -S-(CH R7)m-R6, -C(O)N H-(CH2)m-R6, -C(O)N H-(CH R7)m-R6, -0-(CH2VC(O)NH-(CH2VR6, -S-(CH2VC(O)NH-(CH2),,,^6, -0-(CH R7)m-C(O)N H-(CH R7)m-R6, -S-(CH R7)m-C(O)N H-(CH R7)m-R6, -NH-(CH2VR6,
-NH-(CHR7)m-R6, -NH[(CH2)mR6], -N[(CH2)mR6]2, -NH-C(O)-NH-(CH2VR6, -NH-C(O)-(CH2VCHR6R6 and -NH-(CH2)m-C(O)-NH-(CH2)m-R6; each R5 is independently selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, C4-i 1 cycloalkylalkyl, C5-I0 aryl, C6-i6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-1 1 membered heterocyclylalkyl, 5-10 membered heteroaryl, 6-16 membered heteroarylalkyl, phosphate, phosphate ester, phosphonate, phosphorodiamidate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, cyclic phosphorodiamidate, and phosphonamidate each R6 is a suitable group independently selected from the group consisting of =0,
-OR7, Ci-3 haloalkyloxy, -OCF3, =S, -SR7, =NR7, =NOR7, -NR8R8, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)R7, -S(O)2R7, -S(O)2OR7, -S(O)NR8R8, -S(O)2NR8R8, -OS(O)R7, -OS(O)2R7, -OS(O)2OR7, -OS(O)2NR8R8, -C(O)R7, -C(O)OR7, -C(O)NR8R8, -C(NH)NR8R8, -C(NR7)NR8R8, -C(NOH)R7, -C(NOH)NR8R8, -OC(O)R7, -OC(O)OR7, -OC(O)NR8R8, -OC(NH)NR8R8,
-OC(N R7)N R8R8, -[NHC(O)]nR7, -[N R7C(O )]nR7, -[NHC(O)]nOR7, -[N R7C(O)JnO R7, -[NHC(O)]nNR8R8, -[N R7C(O)JnNR8R8, -[NHC(NH)]nNR8R8 and -[N R7C(N R7)]nN R8R8; each R7 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C4-n cycloalkylalkyl, C5-10 aryl, C6-i6 arylalkyl, 2-6 membered heteroalkyl, 3-8 membered heterocyclyl, 4-1 1 membered heterocyclylalkyl, 5-10 membered heteroaryl, 6-16 membered heteroarylalkyl, phosphate, phosphate ester, phosphonate, phosphorodiamidate, phosphoramidate monoester, phosphoramidate diester, cyclic phosphoramidate, cyclic phosphorodiamidate, and phosphonamidate; each R8 is independently R7 or, alternatively, two R8 are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered heterocyclyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different R7 or suitable R6 groups; each m independently is an integer from 1 to 3; each n independently is an integer from 0 to 3; p is an integer from 1 to 5, and wherein two adjacent R4 groups and their intervening atoms can be bonded to form a 5-8 membered ring fused to the central phenyl group.
13. The method of claim 11 , wherein the combretastatin is a phosphate prodrug of Formula II:
Figure imgf000043_0001
wherein
Ra is H or OP(O)(OR3)OR4; and
OR1, OR2, OR3 and OR4 are each, independently, OH, -0" QH+ or -O" M+, wherein M+ is a monovalent or divalent metal cation and Q is, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH+; or b) an organic amine containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation, QH+.
14. The method of claim 13, wherein Ra is H, one of OR1 and OR2 is hydroxyl, and the other is -0"QH+ where Q is tris(hydroxymethyl)amino methane
15. The method of claim 13, wherein Ra is H or OP(O)(OR3)OR4, and R1, R2, R3 and R4 are each, independently, an aliphatic organic amine, alkali metals, transition metals, heteroarylene, heterocyclyl, nucleoside, nucleotide, alkaloid, amino sugar, amino nitrile, or nitrogenous antibiotic
16. The method of claim 13, wherein Formula Il is represented by a compound of Formula III:
Figure imgf000044_0001
(III) wherein
OR1, OR2, OR3 and OR4 are each, independently, OH, -0" QH+ or -O" M+, wherein M+ is a monovalent or divalent metal cation, and Q is, independently: a) an amino acid containing at least two nitrogen atoms where one of the nitrogen atoms, together with a proton, forms a quaternary ammonium cation QH+; or b) an organic containing at least one nitrogen atom which, together with a proton, forms a quaternary ammonium cation, QH+.
17. The method of claim 16, wherein at least one of OR1, OR2, OR3 and OR4 is hydroxyl, and at least one of OR1, OR2, OR3 and OR4 is -0"QH+, where Q is tromethamine
18. A method for treating or preventing PCV in a human subject comprising administration of a vascular disrupting agent and an active agent selected from the group consisting of ranibizumab, bevacizumab, and a VEGF trap.
19. The method of claim 18, wherein the vascular disrupting agent is a combretastatin or an analog or derivative thereof
20. The method of claim 19, wherein the combretastatin is administered intravenously, intravitreally, subconjunctival^, subtenonally, or topically
21. The method of claim 19, wherein the total amount of ranizumab or bevacizumab is any of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, or about 0.7 mg.
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EP2730565A4 (en) * 2011-07-05 2015-04-29 Nanjing Sanhome Pharmaceutical Co Ltd Tumor targeted drug combretastatin a4 derivative
CN105753787A (en) * 2011-07-05 2016-07-13 南京圣和药业股份有限公司 Tumor-targeting-medicine Combretastatin A4 derivatives
CN105753787B (en) * 2011-07-05 2018-05-15 南京圣和药业股份有限公司 Tumor-targeting drug Combretastatin A4 derivatives
WO2023019688A1 (en) * 2021-08-16 2023-02-23 海南鑫开源医药科技有限公司 Intravitreal injection agent, preparation method therefor and application thereof

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