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WO2010132498A1 - Agents d'interruption vasculaire utilises dans le traitement de la vasculopathie choroïdienne polypoïdale - Google Patents

Agents d'interruption vasculaire utilises dans le traitement de la vasculopathie choroïdienne polypoïdale Download PDF

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Publication number
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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WIPO (PCT)
Prior art keywords
vascular disrupting
disrupting agent
administered
independently
membered
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Ceased
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PCT/US2010/034442
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English (en)
Inventor
Patricia Walicke
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Oxi Gene Inc
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Oxi Gene Inc
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Publication of WO2010132498A1 publication Critical patent/WO2010132498A1/fr
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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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des méthodes de traitement de la vasculopathie choroïdienne polypoïdale, consistant à administrer une quantité thérapeutiquement efficace d'un agent d'interruption vasculaire à un patient souffrant de vasculopathie choroïdienne polypoïdale. Dans certains modes de réalisation, l'agent d'interruption vasculaire est une combretastatine, de préférence une combretastatine A-4, ou un dérivé, un promédicament ou un analogue de celle-ci. L'agent d'interruption vasculaire peut être administré de façon systémique, par intraveineuse par exemple, ou non systémique, dans l'oeil du patient, par exemple. La présente invention concerne également l'utilisation d'un agent d'interruption vasculaire dans la fabrication d'un médicament destiné au traitement ou à la prévention de la vasculopathie choroïdienne polypoïdale.
PCT/US2010/034442 2009-05-11 2010-05-11 Agents d'interruption vasculaire utilises dans le traitement de la vasculopathie choroïdienne polypoïdale Ceased WO2010132498A1 (fr)

Applications Claiming Priority (2)

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US17694309P 2009-05-11 2009-05-11
US61/176,943 2009-05-11

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WO2010132498A1 true WO2010132498A1 (fr) 2010-11-18

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2730565A4 (fr) * 2011-07-05 2015-04-29 Nanjing Sanhome Pharmaceutical Co Ltd Dérivé de combretastatine a4 utilisé en tant que médicament ciblant les tumeurs
CN105753787A (zh) * 2011-07-05 2016-07-13 南京圣和药业股份有限公司 肿瘤靶向药物Combretastatin A4衍生物
WO2023019688A1 (fr) * 2021-08-16 2023-02-23 海南鑫开源医药科技有限公司 Agent d'injection intravitréenne, son procédé de préparation et son application

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030055029A1 (en) * 1993-08-06 2003-03-20 D'amato Robert John Combbretastatin a-4 as an anti-angiogenic agent
US20030220298A1 (en) * 2000-04-27 2003-11-27 Pettit George R. Combrestatin a-1 phosphate and combrestatin b-1 phosphate prodrugs
US20060018909A1 (en) * 2001-10-11 2006-01-26 Oliner Jonathan D Angiopoietin-2 specific binding agents
US20060172980A1 (en) * 2000-09-14 2006-08-03 Venit John J Combretastatin A-4 phosphate prodrug mono-and di-organic amine salts, mono-and di-amino acid salts and mono-and di-amino acid ester salts
US20060293394A1 (en) * 2005-06-14 2006-12-28 Pinney Kevin G Combretastatin analogs with tubulin binding activity

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030055029A1 (en) * 1993-08-06 2003-03-20 D'amato Robert John Combbretastatin a-4 as an anti-angiogenic agent
US20030220298A1 (en) * 2000-04-27 2003-11-27 Pettit George R. Combrestatin a-1 phosphate and combrestatin b-1 phosphate prodrugs
US20060172980A1 (en) * 2000-09-14 2006-08-03 Venit John J Combretastatin A-4 phosphate prodrug mono-and di-organic amine salts, mono-and di-amino acid salts and mono-and di-amino acid ester salts
US20060018909A1 (en) * 2001-10-11 2006-01-26 Oliner Jonathan D Angiopoietin-2 specific binding agents
US20060293394A1 (en) * 2005-06-14 2006-12-28 Pinney Kevin G Combretastatin analogs with tubulin binding activity

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CIARDELLA ET AL.: "Polypoidal Choroidal Vasculopathy.", SURVEY OF OPHTHALMOLOGY, vol. 49, no. 1, February 2004 (2004-02-01), pages 25 - 37 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2730565A4 (fr) * 2011-07-05 2015-04-29 Nanjing Sanhome Pharmaceutical Co Ltd Dérivé de combretastatine a4 utilisé en tant que médicament ciblant les tumeurs
CN105753787A (zh) * 2011-07-05 2016-07-13 南京圣和药业股份有限公司 肿瘤靶向药物Combretastatin A4衍生物
CN105753787B (zh) * 2011-07-05 2018-05-15 南京圣和药业股份有限公司 肿瘤靶向药物Combretastatin A4衍生物
WO2023019688A1 (fr) * 2021-08-16 2023-02-23 海南鑫开源医药科技有限公司 Agent d'injection intravitréenne, son procédé de préparation et son application

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