WO2006002106A2 - Compositions et procedes pour la codelivrance de medicaments anticancereux, de medicaments anti-angiogeniques, et d'un polysaccharide - Google Patents

Compositions et procedes pour la codelivrance de medicaments anticancereux, de medicaments anti-angiogeniques, et d'un polysaccharide Download PDF

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WO2006002106A2
WO2006002106A2 PCT/US2005/021827 US2005021827W WO2006002106A2 WO 2006002106 A2 WO2006002106 A2 WO 2006002106A2 US 2005021827 W US2005021827 W US 2005021827W WO 2006002106 A2 WO2006002106 A2 WO 2006002106A2
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polysaccharide
composition
cancer
backbone
carbohydrate
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PCT/US2005/021827
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WO2006002106A3 (fr
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David Platt
Eliezer Zomer
Anatole Klyosov
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Pro-Pharmaceuticals, Inc.
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Priority to EP05786102A priority Critical patent/EP1765365A4/fr
Priority to JP2007518186A priority patent/JP2008503583A/ja
Priority to BRPI0512394-1A priority patent/BRPI0512394A/pt
Priority to CA002570570A priority patent/CA2570570A1/fr
Publication of WO2006002106A2 publication Critical patent/WO2006002106A2/fr
Publication of WO2006002106A3 publication Critical patent/WO2006002106A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to compositions and methods for treating malignant cancer and angiogenesis. Specifically, the instant invention is directed to the co-administration of one or more known chemotherapeutic agents together with a polysaccharide.
  • prostate cancer is the most commonly diagnosed cancer in American men as well as a leading cause of cancer death in males. It is projected that in 2004 there will be about 230,110 new cases of prostate cancer diagnosed in the U.S. and 38,000 deaths caused by prostate cancer. Approximately 50% of the patients diagnosed with prostate cancer have a form of the disease, which does not solely affect the prostate. Prostate cancer can metastasize to the skeletal system and patients typically die with overwhelming osseous metastatic disease. As yet, there is no effective curative therapy and very little palliative therapy for patients with metastatic disease.
  • tumor cell metastasis requires that cells depart from the primary tumor, invade the basement membrane, traverse through the bloodstream from tumor cell emboli, interact with the vascular endothelium of the target organ, extravasate, and proliferate to form secondary tumor colonies.
  • the present invention relates to chemically soluble ligand branched polysaccharides having a molecular weight in the range of about 50 kD to about 200 kD in combination with one or more therapeutic agents.
  • the invention pertains to a method of using the same in combination with at least one anti-cancer drug for treating and preventing malignant cancer.
  • the invention is directed to a method of using the composition of the present invention for treating and preventing angiogenesis.
  • a ligand branched polysaccharide comprising: a physiological soluble polymer made of a plurality of carbohydrate units, wherein each carbohydrate unit includes a carbohydrate backbone.
  • the carbohydrate backbone can contain a plurality of repeating units, wherein each repeating unit has at least one acidic molecule and at least one neutral carbohydrate molecule. At least one branching chain of carbohydrate can be attached to the backbone, including a plurality of neutral carbohydrates or carbohydrate derivatives.
  • This ligand branched polysaccharide has an average molecular weight in the range of about 50 kD to about 200 kD, or about 250 to about 1000 monosaccharides.
  • the backbone includes about one neutral carbohydrate molecule for every 20-25 acidic molecules.
  • the branching chain is connected by one or more neutral carbohydrate molecules.
  • the polysaccharide has a combination of hydrophobic and slightly negative charged moieties (such as uronic acid) that can interact with one or more putative therapeutic agents, effectively delivering these agents to a metastatic cancer, where they assert their biological activity.
  • the polysaccharide structure can have extended carbohydrate ligands that interact with the multiple multivalent lectin receptors scattered on the surface of cancer cells.
  • ligands perturb the tumor surface and potentially, further the enhancement of the delivery of chemotherapeutics into the tumor cells.
  • the putative anticancer agents are delivered to affected diseased cells more effectively, and fewer healthy cells are adversely affected.
  • the acidic molecule is an uronic acid in a salt form of, for example, potassium, sodium or magnesium.
  • the uronic acid includes a carboxylic unit and is alkylated or esterified at up to 10% of the total units. For example, methyl, acetyl, decyl,- or benzyl can be attached to the carboxylic unit.
  • a polysaccharide is described, where the acidic molecule is included and is a galacturonic acid and a neutral carbohydrate is included and is a rhamnose.
  • One aspect of the invention provides a polysaccharide wherein at least one branching chain is connected to a carbohydrate backbone via a rhamnose molecule.
  • Another embodiment of the present invention is directed to a polysaccharide where an acidic molecule is included and is a polygalacturonic acid containing up to 100 units and a neutral carbohydrate molecule resides at each end and is a rhamnose.
  • One aspect provides a polysaccharide wherein at least one branching chain is connected to a carbohydrate backbone via either a polygalacturonic acid molecule and/or a rhamnose molecule.
  • Another embodiments is directed to a method for treating a patient diagnosed with cancer or preventing cancer in a patient diagnosed as having a high risk of cancer, comprising the steps of: combining a therapeutically effective amount of at least one putative anti-cancer drug with a polysaccharide of the present invention to create a combination therapy; and delivering this combination to a patient.
  • Another embodiment is directed to a method of treating a patient diagnosed with tumor angiogenesis or preventing tumor angiogenesis in a patient diagnosed as having a high risk of angiogenesis, comprising the steps of: combining a therapeutically effective amount of a putative anti-angiogenic drug with a soluble branched polysaccharide of the present invention to create a combination therapy; and delivering this combination to a patient.
  • One aspect of this invention further comprises the step of combining a putative anti-cancer drug with the combination, before delivering the combination to the patient.
  • Still another embodiment is directed to a method of preventing tumor angiogenesis in a patient with cancer, comprising the steps of: combining a therapeutically effective amount of at least one putative anti-cancer drug, a therapeutically effective amount of at least one putative angiogenic drug, and a soluble branched ligand polysaccharide of the present invention to create a combination therapy; and delivering the combination to the patient.
  • Figure 1 shows digestion of 20 g/L of USP pectin with 1OmM H 2 O 2 , 1OmM ascorbate, and a combination of both at 5mM each, indicating a linear relation between digestion time and the viscometer measurements;
  • Figure 2 shows ⁇ -elimination in alkaline borohydrates results in a controlled process of chain cleavage accommodated by a loss of viscosity and decreased gelling properties
  • Figure 3a shows a chromatogram of the control, "Blank a," and Fig 3b shows a chromatogram of the polysaccharide of interest, "Standard B3a";
  • Figure 4 shows the MALLS Results For Commercial Rhamnogalactan Molecular Weight
  • Figure 5 shows a Zimm Plot for Rhamnogalactan.
  • the present invention relates to chemically soluble ligand branched polysaccharides having a molecular weight in the range of about 50 kD to about 200 kD.
  • the present invention is also directed to a method of using the polysaccharide of the present invention in combination with at least one putative anti-cancer drug for treating and preventing malignant cancer.
  • the invention further is directed to a method of using the polysaccharide of the present invention in combination with at least one putative anti-angiogenic drug for treating and preventing angiogenesis.
  • PS polysaccharide
  • EHS Eaglebreth- HoIm Swarm
  • DMEM Dulbecco's Soluble branched Eagle's Minimal Essential Medium
  • CMF-PBS Ca 2+ - and Mg 2+ -Free Phosphate-Buffered Saline, pH 7.2
  • BSA Bovine Serum Albumin
  • galUA galactopyranosyl uronic acid, also called galacturonic acid
  • gal galactose
  • man mannose
  • glc glucose
  • administering refers to oral, or parenteral including intravenous, subcutaneous, topical, transdermal, transmucosal, intraperitoneal, and intramuscular.
  • Subject refers to an animal such as a mammal, for example, a human. The term also includes patients.
  • Treatment of cancer refers to prognostic treatment of subjects at high risk of developing a cancer as well as subjects who have already developed a tumor.
  • treatment can be applied to the reduction or prevention of abnormal cell proliferation, cell aggregation and cell dispersal (metastasis) to secondary sites.
  • Cancer refers to any neoplastic disorder, including such cellular disorders as, for example, renal cell cancer, Kaposi's sarcoma, chronic leukemia, breast cancer, sarcoma, ovarian carcinoma, rectal cancer, throat cancer, melanoma, colon cancer, bladder cancer, mastocytoma, lung cancer, mammary adenocarcinoma, pharyngeal squamous cell carcinoma, and gastrointestinal or stomach cancer.
  • Depolymerization refers to partial or complete hydrolysis of the polysaccharide backbone occurring, for example, when the polysaccharide is treated chemically resulting in fragments of reduced size when compared to the original polysaccharide.
  • Effective dose refers to a dose of an agent that improves the symptoms of a subject or the longevity of the subject suffering from or at high risk of suffering from cancer.
  • saccharide refers to any simple carbohydrate including monosaccharides, monosaccharide derivatives, monosaccharide analogs, sugars, including those, which form the individual units in an oligosaccharide or a polysaccharide.
  • Methyl refers to a single carbohydrate unit; polyhydroxyaldehyde (aldose) or polyhdroxyketone (ketose) and derivatives and analogs thereof are examples of such.
  • Oletaccharide refers to a linear or branched chain of monosaccharides that includes up to about 40 saccharide units linked via glycosidic bonds.
  • Polysaccharide refers to polymers formed from about 40 to about 100,000 saccharide units linked to each other by hemiacetal or glycosidic bonds.
  • the polysaccharide can be either a straight chain, single branched, or multiple branched, wherein each branch can have additional secondary branches, and the monosaccharides can be standard D- or L- cyclic sugars in the pyranose (6- membered ring) or furanose (5-membered ring) forms such as D-fructose and D- galactose, respectively, or they can be cyclic sugar derivatives, for example, amino sugars such as D-glucosamine, deoxy sugars such as D-fucose or L- rhamnose, sugar phosphates such as D-ribose-5-phosphate, sugar acids such as D-galacturonic acid, or multi-derivatized sugars such as N-acetyl-D-glucosamine, N-acetylneuraminic
  • Backbone means the major chain of a polysaccharide, or the chain originating from the major chain of a starting polysaccharide, having saccharide moieties sequentially linked by either ⁇ or ⁇ glycosidic bonds.
  • a backbone can comprise additional monosaccharide moieties connected thereto at various positions along the sequential chain.
  • Esterification refers to the presence of methylesters or other ester groups at the carboxylic acid position of the uronic acid moieties of a saccharide.
  • “Monosaccharides and their derivatives” refers to, within the context of this invention, any of the standard and possible derivatives of monosaccharides (sugars), including, but not limited to, deoxymonosaccharides, dideoxymonosaccharides, sugar alcohols, sugar acids, sugar esters, sugar ethers, sugar halides, amino sugars, sugar phosphates, pyranose and furanose cyclic forms, open ring forms, sulfonic esters of sugars, glycosidic derivatives, glycols, glycolenes, keto sugars, diketo sugars, protected sugars, acetals such as benzilidenes and ketals such as isopropylidenes, nitro sugars, N-acetyl sugars, N- acetylmuramic acid, and antibiotic sugars such as nojirimycin and dihydronojirimycin.
  • Anti-cancer drug refers to, within the context of this application, any of a variety of compounds which exhibit efficacy in reducing the size, incidence, metastasis, proliferation, occurrence, or recurrence of cancer tumors or tumor cells, including, but not limited to: aminoglutethimide, Amsacrine, Anastrozole, asparaginase, BCG, bicalutamide, Bleomycin, Buserelin, Busulfan, Capecitabine, carboplatin, Carmustine, chlorambucil, cisplatin, Cladribine, Clodronate, cyclophosphamide, cyproterone, Cytarabine, dacarbazine, Dactinomycin, Daunorubicin, diethylstilbestrol, Docetaxel, Doxorubicin, Epirubicin, Estramustine, etoposide, Exemestane, Filgrastim, Fludarabine, Fludrocortisone, fluorouraci
  • Anti-angiogenic drug refers to, within the meaning of this application, any compound exhibiting anti-angiogenic effects in a subject with tumor angiogenesis, and includes, but is not limited to: angiogenin (ANG), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), epidermal growth factor (EGF), tumor necrosis factor-alpha (TNF- ⁇ ), tumor growth factor-alpha (TGF- ⁇ ), and tumor growth factor-beta (TGF- ⁇ ), platelet-derived growth factor (PDGF), platelet-derived endothelial cell growth factor (PD-ECGF), placental growth factor (PIGF), hepatocyte growth factor (HGF), platelet activating factor (PAF), insulin-like growth factor (IGF), interleukin-8 (IL-8), and granulocyte-colony stimulating factor (GCSF).
  • ANG angiogenin
  • VEGF vascular endothelial growth factor
  • a soluble branched polysaccharide having a uronic acid saccharide backbone or uronic ester saccharide backbones with neutral monosaccharides connected to the backbone averaging about every one-in-two to every one-in-twenty-five backbone units.
  • the resulting polysaccharide has at least one side chain comprised of mostly neutral saccharides and saccharide derivatives connected to the backbone via the about one-in-twenty to twenty-five neutral monosaccharides.
  • Some polysaccharides of the present invention have at least one side chain of saccharides further having substantially no secondary saccharide branches, with a terminal saccharide comprising galactose, glucose, arabinose, or derivatives thereof.
  • the soluble branched polysaccharide can average less than about 1-2 secondary branches per repeating unit.
  • Another aspect includes a soluble ligand branched polysaccharide section wherein secondary branching averages less than about 0.5 - 1 per repeating unit.
  • the soluble branched polysaccharide averages less than about 0.25 - 0.5 secondary branches per repeating unit.
  • the soluble branched polysaccharide averages less than about 0 - 0.25 secondary branches per repeating unit.
  • Other polysaccharides of the present invention can have at least one side chain of saccharides terminating with a saccharide soluble branched by a feruloyl group.
  • the soluble branched polysaccharide backbone is substantially de-esterified creating negatively charged entities.
  • the soluble branched polysaccharide backbone is de-esterified to less than about 1%.
  • the soluble branched polysaccharide backbone is de-esterified to less than about 0.5%.
  • the soluble branched polysaccharide backbone is de-esterified to less than about 0.25%.
  • the soluble branched polysaccharide backbone is de-esterified to less than about 0.1%.
  • soluble branched polysaccharides can be prepared by chemical modifying naturally occurring polymers.
  • natural polysaccharides can have molecular weights ranging between about 40, 000-1 , 000,000 with multiple branches of saccharides, for example, branches comprised of 1 to 20 monosaccharides such as glucose, arabinose, galactose. These branches are connected to the backbone via neutral monosaccharides, such as rhamnose. These molecules can further include one backbone or a chain of uronic acid saccharide backbones that can be esterified from as little as about 2% to as much as about 30%.
  • the multiple branches themselves can have multiple branches of saccharides, the secondary multiple branches optionally including neutral saccharides and neutral saccharide derivatives, thereby creating mainly hydrophobic entities.
  • the effective dose and dosage regimen of the polysaccharide and anti- cancer/anti-angiogenic drug is a function of variables such as the subject's age, weight, medical history and other variables deemed to be relevant.
  • the dose and dosage regimen is based on the molecular weight of the soluble branched polysaccharide component (disregarding the digestible carrier) and the anti- cancer/anti-angiogenic drug.
  • a typical regimen can consist of a daily dose of about 10 to about 1000 g per kg of body weight of the subject.
  • the dosages of the soluble branched polysaccharide and anti-cancer/anti-angiogenic drugs further depend on the disease state or condition being treated and other clinical factors such as weight and physical condition of the patient and the means of administration.
  • either or both agents can be administered between several times per day to once a week.
  • the present invention has application for both human and veterinary use.
  • the methods of the present invention contemplate single as well as multiple co-administrations, given either simultaneously or over an extended period of time, from about 10 to about 1000 g/kg every 24 hours to about 2.5 to 250g/kg every 6 hours.
  • Chemically soluble branched polysaccharides and known anti-cancer/anti- angiogenic drugs can be formulated for oral administration, either alone or together.
  • Other methods of administration include ophthalmic (including intravitreal or intracameral), nasal, topical (including buccal and sublingual), intradermal, intratracheal, and epidural, transdermal, intraperitoneal, intracranial, intracerebroventricular, intracerebral, intravaginal, intrauterine, rectal or parenteral (including intravenous, intraspinal, subcutaneous or intramuscular) means.
  • the soluble branched polysaccharide and the anti- cancer/anti-angiogenic drug can be incorporated into implanted biodegradable polymers allowing for sustained release of the compound (Brem et al., J. Neurosurg, (1991), vol. 74, pp. 441-446, the entire teaching of which is incorporated herein by reference).
  • the polymers being implanted in the vicinity of where drug delivery is desired, for example, at the site of a tumor, or implanted so that the soluble branched polysaccharide is slowly released systemically.
  • Osmotic mini-pumps can also be used to provide controlled delivery of high concentrations of soluble branched polysaccharide through cannulae to the site of interest, such as directly into a metastatic growth or into the vascular supply of that tumor.
  • the formulations can conveniently be presented in unit dosage form and can be prepared by conventional pharmaceutical techniques. Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Suitable digestible pharmaceutical carriers include gelatin capsules in which the polysaccharide is encapsulated in dry form, or tablets in which polysaccharide is admixed with hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, propylene glycol, zinc stearate and titanium dioxide and other appropriate binding and additive agents.
  • the composition can also be formulated as a liquid using distilled water, flavoring agents and some sort of sugar or sweetener as a digestible carrier to make a pleasant tasting composition when consumed by the subject.
  • a sustained-release matrix is a matrix made of materials, usually polymers, which are degradable by enzymatic or acid/base hydrolysis or by dissolution. Once inserted into the body, enzymes and body fluids act upon the matrix.
  • the sustained-release matrix desirably is chosen from biocompatible materials such as liposomes, polylactides (polylactic acid), polyglycolide (polymer of glycolic acid), polylactide co-glycolide (co-polymers of lactic acid and glycolic acid) polyanhydrides, poly(ortho)esters, polypeptides, hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinyl propylene, polyvinylpyrrolidone and silicone.
  • the metastasis-modulating therapeutic composition of the present invention can be a solid, liquid or aerosol and can be administered by any known route of administration.
  • solid therapeutic compositions include pills, creams, and implantable dosage units.
  • the pills can be administered orally; the therapeutic creams can be administered topically.
  • the implantable dosage units can be administered locally, for example, at a tumor site, or which can be implanted for systemic release of the therapeutic angiogenesis-modulating composition, for example subcutaneously.
  • liquid composition include formulations adapted for injection subcutaneously, intravenously, intra- arterially, and formulations for topical and intraocular administration.
  • aerosol formulation include inhaler formulation for administration to the lungs.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.
  • the formulations can be presented in unit- dose or multi-dose containers, for example, sealed ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.
  • Acceptable unit dosage formulations are those containing a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of the administered ingredient.
  • the formulations of the present invention includes other agents conventional in the art having regard to the type of formulation in question.
  • cytotoxic agents can be incorporated or otherwise combined with angiostatin proteins, or biologically functional peptide fragments thereof, to provide dual therapy to the patient.
  • a polysaccharide preparation of the present invention is co ⁇ administered with a known cancer drug at a therapeutic dose of the known anti ⁇ cancer drug that is known in the art to be effective against cancer.
  • a known cancer drug for example, 5-FU can be administered at 100 to 1000 mg/m 2 /day or Taxol can be administered at doses of 50 to 300 mg/m 2 /day.
  • anti-cancer drugs for example 5-FU and Taxol
  • a polysaccharide at doses of 20 to 300 mg/m 2 .
  • up to 80% improvement was seen in this form of combination therapy versus the control with no treatment.
  • soluble branched polysaccharide carbohydrate structures can have anti-angiogenic activity, inhibiting angiogenic factor-induced angiogenesis, as determined using the CAM assay, the corneal neovascularization assay (Gimbrone et al., 1974, J. Natl. Cancer Inst. 52:413- 427, the entire teaching of which is incorporated herein by reference), and other similar assays known in the art.
  • co-administration of a soluble branched polysaccharide with anti-angiogenic factors and anti-cancer drugs has a synergistic effect.
  • the method is directed to renal cancer, sarcoma, Kaposi's sarcoma, chronic leukemia, breast cancer, mammary adenocarcinoma, ovarian carcinoma, rectal cancer, colon cancer, bladder cancer, prostrate cancer, melanoma, mastocytoma, lung cancer, throat cancer, pharyngeal squamous cell carcinoma, gastrointestinal cancer or stomach cancer.
  • Procedures include peroxide/ascorbate scission of the glycosidic bond in the polymer backbone (See, Example 1), alkaline reductive de-polymerization (See, Example 2), or controlled de-polymerization into smaller, branched polysaccharide molecules (See, Example 3).
  • the first purification procedure is the extraction of a polysaccharide with alkaline and/or chelation solution to remove proteins, pigments and other impurities.
  • Example 5 To demonstrate the efficacy of chemically soluble branched polysaccharides co-administered in combination with putative anti-cancer drugs, a number of in vitro (See, Example 5) and in vivo (See, Example 6) assays were performed. Inhibition of metastasis is shown using cancer cell lines that normally aggregate in culture, but in the presence of the instant polysaccharide remain dispersed. Inhibition of metastasis is also demonstrated by a metastasis assay, in which MLL cells have enhanced levels of galectins-3 on their cell surface, since galectin-3 is associated with tumor endothelial cell adhesion.
  • Vertebrate galactoside-binding lectins occur in a variety of tissues and cells.
  • the lectins are divided into two abundant classes based on their sizes. Lectins with a molecular mass of about 14 kD are designated as galectin-1 and those with a molecular mass of about 30 kD are designated as galectin-3.
  • Galectin-3 represents a wide range of molecules including the murine 34 kD (mL- 34) and human 31 kD (hL-31) tumor-associated galactoside-binding lectins, the 35 kD fibroblast carbohydrate-binding protein (CBP35), the IgE-binding protein (cBP), the 32 kD macrophage non-integrin laminin-binding protein (Mac-2), and the rat, mouse, and human forms of the 29 kD galactoside-binding lectin (L-29). Molecular cloning studies have revealed that the polypeptides are identical.
  • Galectin-3 is highly expressed by activated macrophages and oncogenically transformed in metastatic cells. Many cancer cells, including MLL cells, express galectin-3 on their cell surface, and its expression has been implicated in metastatic processes in tumor cells. Elevated expression of the polypeptide is associated with an increased capacity for anchorage-independent growth, homotypic aggregation, and tumor cell lung colonization, which suggests that galectin-3 promotes tumor cell embolization in the circulation and enhances metastasis. Tumor-endothelial cell adhesion is thought to be a key event in the metastatic process.
  • Galectins that bind with high affinity to oligosaccharides containing poly-N-acetyllactosamine sequences also bind to the carbohydrate side chains of laminin in a specific sugar-dependent manner.
  • Laminin the major non-collagenous component of basement membranes, is an N-linked glycoprotein carrying poly-N-acetyllactosamine sequences, and is implicated in cell adhesion, migration, growth, differentiation, invasion and metastasis.
  • Tumor cells can interact with carbohydrate residues of glycoproteins via cell surface galectin-3 and this can be correlated with their ability to interact with the galactose residues of agarose (a polymer of D-galactose and L-anhydro- galactose) and to provide the minimal support needed for cell proliferation in this semi-solid medium.
  • Anti-galectin-3 monoclonal antibodies can inhibit the growth of tumor cells in agarose.
  • transfection of normal mouse fibroblasts with the mouse galectin-3 cDNA results in the acquisition of anchorage- independent growth. Referring to Example 1 , the in vivo results reported here with polysaccharides are consistent with previous studies performed on human prostate cancer tissue using galectin-3 (U.S. Patent No. 5,895,784, the entire teaching of which is incorporated herein by reference).
  • the polysaccharides described herein, when combined with anti-cancer drugs for co-administration, provide delivery, targeting and overall positive improvement in anti-metastatic effect in humans.
  • Example 1 Modifying Naturally Occurring Polysaccharides bv Peroxide/Ascorbate Scission
  • the solution is prepared using 20g/L of polysaccharide, such as USP pectin (Pelco), in distilled water and the pH is adjusted to pH 5.5 with 1 M sodium succinate.
  • the polysaccharide solution is then incubated at a fixed temperature, for example 20 0 C, and peroxide and /or ascorbate are added together (Figure 1) or sequentially.
  • H2O 2 facilitates a slow scission of USP Pectin at pH 5.5, at 10 mM.
  • the half time required to double the specific fluidity was 15 ⁇ 72 h ( Figure 1).
  • L- Ascorbate under the same condition and concentration induced faster scission.
  • Sequential addition of ascorbate to a polysaccharide solution already containing even 1mM H 2 O 2 caused further stimulation of scission.
  • the rate and extent of scission was determined by the dose of ascorbate added, the time of addition post H2O 2 addition, the pH, and the temperature.
  • AH 2 is ascorbate;
  • A is dehydroascorbate
  • This method can be further enhanced in presence of transition metals ions like Ca ++ , Cu ++ or Fe ++ .
  • transition metals ions like Ca ++ , Cu ++ or Fe ++ .
  • the most likely source of cleavage is a Fenton reaction (Halliwell, B. and Gutteridge, J. M. C. (1990) Methods Enzymol. 186, 1-85, the entire teaching of which is incorporated herein by reference), which generates ionized OH, and requires H 2 O 2 and the reduced form of a transition metal ion.
  • Cu + has been reported being 60 times more effective than Fe +2 .
  • the pH of the polysaccharide solution was increased to pH 10 with, for example, 3N NaOH. After a short incubation at 5-5O 0 C for 30-60 minutes, 10 to 20 % ethanol was added and the purified polysaccharide was precipitated. This removes proteins and pigments associated with polysaccharides.
  • the polysaccharide was then dissolved to a 20 g/L and an acid was added. For example, trifluoroacetic acid at final concentration of 0.01 to 1.0 M has been demonstrated to give a controlled de-polymerization.
  • acids or a combination of them such as sulfuric, HCI, acetate, propionic acid, or methansulfonic acid, can be used to shorten the hydrolysis time and improve the yield of a desired structure of branched polysaccharide without oxidation.
  • the solution was neutralized to pH 3-5, cooled to 4 0 C and centrifuged to remove any insoluble matter. Then the supernatant was neutralized to a final pH of about 6.0 to 8.0 with 1 N NaOH for example, and 20% ethanol was added to recover the soluble polysaccharide.
  • the ratio of polysaccharide to acid, the type of acid, the concentration, the pH, the temperature and the time interval were selected to generate a soluble branched polysaccharide that has a molecular weight of 50 kD, 60 kD, 75 kD, 90 kD, 105 kD, 125 kD, 150 kD, 175 kD, and up to 200 kD.
  • the resulting soluble branched polysaccharide product can further be washed with 70% ethanol or with 100% acetone to provide a final dry powder. Thereupon the soluble branched polysaccharide is re-solubilized in water to a final concentration of about 5-15% by weight for analytical identification, efficacy, and/ or toxicological studies.
  • the soluble branched polysaccharide can be further diluted for use according to embodiments of the invention in which concentrations of 0.01-10% can be provided to cells, depending on the desired soluble branched polysaccharide composition and molecular weight.
  • the pH of the polysaccharide solution was increased to pH 9 with, for example, 3N NaOH. After a short incubation at 5-5O 0 C for 30 to 60 minutes, 10% ethanol was added and the purified polysaccharide was precipitated. This removes proteins and pigments associated with polysaccharides. Then a reducing agent, such as a sodium borohydride, lithium borohydrate, sodium cyanoborohydride, sodium triacetoxyborohydride or other borohydrate salts, was added to create scission by an alkaline reductive mechanism of the glycosidic bonds. This forms fragments of a size corresponding to a repeating subunit (U.S. Pat. No. 5,554,386, the entire teaching of which is incorporated herein by reference).
  • a reducing agent such as a sodium borohydride, lithium borohydrate, sodium cyanoborohydride, sodium triacetoxyborohydride or other borohydrate salts
  • the temperature and time can shorten the hydrolysis time and improve the yield of the polysaccharide.
  • the solution is cooled to 4°C and centrifuged to remove any insoluble matter. Then the supernatant is neutralized to a final pH of about 6.0 with 1 N HCI for example, and 20% ethanol is added to recover the soluble polysaccharide.
  • the ratio of polysaccharide to reductive agent, the type of agent, concentration, pH, temperature and time interval are selected to generate a soluble branched polysaccharide that has a molecular weight of 50 kD, 60 kD, 75 kD, 90 kD, 105 kD, 125 kD, 150 kD, 175 kD, and up to 200 kD.
  • the resulting soluble branched polysaccharide product can further be fractionated with 20 to 70% ethanol and finally with 100% acetone to provide a final dry powder. Thereupon the soluble branched polysaccharide is resolubilized in water to a final concentration of about 5-15% by weight for analytical identification, efficacy or toxicological studies.
  • the soluble branched polysaccharide can be further diluted for use according to embodiments of the invention in which concentrations of 0.01-10% can be provided to cells. Depending on the desired soluble branched polysaccharide composition and molecular weight.
  • High Performance Liquid Chromatography using Gel Permeation Chromatography (GPC) separation technology (also known as Size Exclusion Chromatography - SEC) is a well-established technique for the characterization of polymers.
  • GPC Gel Permeation Chromatography
  • MALLS Multi Angle Laser Light Scattering
  • Rl Refractive Index
  • Another advantage of GPC-MALLS over classical GPC is that, besides molecular weights, additional information concerning radii and conformation in solution can be followed.
  • the principle of the GPC-MALLS method is based on the fact that light is more strongly scattered by large molecules than by small molecules.
  • the MALLS detector measures the degree of light scattering of a laser beam with detectors placed at fifteen different angles.
  • the output of the light scattering detector is proportional to the multiplication of the concentration and the molecular weight of macromolecules. Therefore, the shape of the light scattering peak is asymmetric. Further, it does not coincide with the Rl peak, because the Rl detector signal is proportional to the concentration only ( Figure 3).
  • the molecular weight of the polymer eluting from the column can be calculated from the quotient of MALLS and Rl signals.
  • a graph of the molecular weight versus the elution volume is obtained and (average) molecular weights and molecular weight distributions can be calculated.
  • Pro-Pharmaceuticals and their contract GMP facility have adapted the GPC /IR-MALLS technique to quantify the drug substance and characterize the molecular weight average and distribution throughout the R&D and scale up phases and finally incorporate it into the drug substance proof of structure as part of the drug Certificates of Analysis specifications.
  • Example 5 In vitro assays - Polysaccharide with Anti-cancer Drugs or further in combination with Anti-angioqenic Drugs
  • the assays below are conducted using a soluble branched polysaccharide of the present invention. Different sized molecules were tested ranging from 50 kD, 60 kD, 75 kD, 90 kD, 105 kD, 125 kD, 150 kD, 175 kD, and up to 200 kD. Amounts in w/v of soluble branched polysaccharide varied from 0.01 %-1% w/v in a physiological solvent.
  • Controls include polysaccharide alone with no additional agent, unsoluble branched polysaccharide; gal-, ara- or feruloyl-substituted monosaccharide; and anti ⁇ cancer drug alone, anti-angiogenic drug alone; anti-cancer drug with soluble branched polysaccharide; anti-angiogenic drug with soluble branched polysaccharide; and anti-cancer drug with anti-angiogenic drug in the absence of soluble branched polysaccharide.
  • the CAM assay, corneal neovascularization assay, and appropriate assays known in the art, were performed (Gimbrone et al., 1974, J. Natl. Cancer Inst. 52:413-427, the entire teaching of which is incorporated herein by reference).
  • B16-F1 murine melanoma cell adhesion assays which includes measuring a change in adhesion of cells to a laminin coated substrate and inhibition of asialofetuin-induced homotypic aggregation involving galectin-3.
  • the B16-F1 line (low incidence of lung colonization) is derived from pulmonary metastasis produced by intravenous injection of B16 melanoma cells (Lotan, R. et al., Int. J. Cancer, (1994), vol. 56, pp.
  • the cells were grown in a monolayer on plastic in Dulbecco's soluble branched Eagle's minimal essential medium (DMEM) supplemented with glutamine, essential amino acids, vitamins, antibiotics, and 10% heat-inactivated fetal bovine serum (FCS 10%).
  • DMEM Dulbecco's soluble branched Eagle's minimal essential medium
  • FCS 10% heat-inactivated fetal bovine serum
  • Laminin (EHS laminin) can be purchased from Sigma, St. Louis, Missouri, and the soluble branched polysaccharide in accordance with the present invention is prepared according to the above-described procedure.
  • Asialofetuin can be prepared from fetuin, available from Gibco Laboratories. The fetuin was subjected to mild acid hydrolysis using 0.05 N H 2 SO 4 at 80 0 C for one hour, according to the method of Spire; Grand Island Biological Co., Grand Island. N.Y. The released sialic acid was then removed from the fetuin by dialysis.
  • Tissue culture wells of 96-well plates were pre-coated overnight at 4° C with EHS laminin (2 g/well) in Ca 2+ - and Mg 2+ - free phosphate-buffered saline, pH 7.2 (CMF-PBS), and the remaining protein binding sites were blocked for 2 h at room temperature with 1% bovine serum albumin (BSA) in CMF-PBS.
  • BSA bovine serum albumin
  • Cells were harvested with 0.02% EDTA in CMF-PBS and suspended with serum-free DMEM.
  • a total of 5x10 4 cells were added to each well in DMEM with or without: 1) soluble branched polysaccharide and anti-cancer drug; 2) soluble branched polysaccharides of varying concentrations with non-varying doses of anti-cancer drug; or 3) soluble branched polysaccharide in a non-varying concentration with varying doses of anti-cancer drug.
  • Cells were stained with methylene blue followed by the addition of HCI-ethanol to release the dye and the optical density (650 m) was then measured by a plate reader
  • Cells were detached with 0.02% EDTA in CMF-PBS and suspended at a concentration of 1x10 6 cell/mL in CMF-PBS with or without 20 g/mL of asialofetuin and 0% to 0.5% soluble branched polysaccharide or 0% to 0.5% soluble branched polysaccharide. Aliquots containing 0.5 mL of cell suspension were then placed in siliconized glass tubes and agitated at 80 rpm for 60 minutes at 37° C. The aggregation was then terminated by fixing the cells with 1% formaldehyde in CMF-PBS.
  • Recombinant galectin-3 can also be extracted from bacteria cells by single-step purification through an asialofetuin affinity column. Recombinant galectin-3 eluted by lactose was extensively dialyzed against CMF-PBS before use.
  • a horseradish peroxidase (HRP)- conjugated rabbit anti-rat IgG+lgM and the 2, 2'-azino-di(3-ethylbenzthiazoline sulfonic acid) (ABTS) substrate kit can be purchased from Zymed, South San Francisco, CA.
  • B16-F1 murine melanoma cells were grown as cultures in Dulbecco's soluble branched Eagles' minimal essential medium (DMEM) 1 as described above.
  • DMEM Dulbecco's soluble branched Eagles' minimal essential medium
  • Tissue culture wells of 96-well plates were coated with CMF-PBS containing 0.5% MCP and 1% BSA and dried overnight.
  • Recombinant galectin-3 serially diluted in CMF-PBS containing 0.5% BSA and 0.05% Tween-20 (solution A) in the presence or absence of 50 mM lactose is added and incubated for 120 minutes, after which the wells were drained and washed with CMF-PBS containing 0.1% BSA and 0.05% Tveen-20 (solution B).
  • Rat antigalectin-3 in solution A was added and incubated for 60 minutes, followed by washing with solution B and incubation with HRP-conjugated rabbit anti-rat IgG+lgM in solution A for 30 minutes. After washing, relative amounts of bound enzyme conjugated in each well are ascertained by addition of ABTS. The extent of hydrolysis is measured at 405 n.
  • Cells were detached with 0.02% EDTA in CMF-PBS and suspended at 1x10 3 cell/mL in complete DMEM with or without: 1) soluble branched polysaccharide and anti-cancer drug; 2) soluble branched polysaccharides of varying concentrations with non-varying doses of anti-cancer drug; or 3) soluble branched polysaccharide in a non-varying concentration with varying doses of anti-cancer drug.
  • the cells were incubated for 30 min at 37° C and then mixed 1 :1 (v/v) with a solution of 1% agarose in distilled water-complete DMEM (1 :4, v/v) preheated at 45° C.
  • the MAT-LyLu (MLL) sub-line is a fast growing, poorly differentiated adenocarcinoma cell line.
  • the adhesion of Cr-labeled MLL cells to confluent monolayers of rat aortic endothelial (RAE) cells in the presence or absence of soluble branched polysaccharide was investigated.
  • MLL and RAE cells were grown in RPMI 1640 media supplemented with 10% fetal bovine serum.
  • RAE cells were grown to confluence in tissue culture wells.
  • a total of 2.4x10 6 MLL cells were incubated for 30 minutes with 5 Ci Na 5 CrO 4 at 37° C, in 2 mL of serum-free media with 0.5% bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • Attachment of MLL cells in the absence or presence of independently varied concentrations of combined soluble branched polysaccharide and anti ⁇ cancer drug for 90 minutes at 4 0 C was then assessed as follows. The cells were washed three times in cold phosphate-buffered saline to remove unbound cells, and then solubilized with 0.1 N NaOH for 30 minutes at 37° C, at which point the radioactivity in each well was determined in a beta-counter. The time course for the attachment of MLL cells to a confluent monolayer of RAE cells in the absence or presence of independently varied concentrations of soluble branched polysaccharide in combination with an anti-cancer drug was monitored.
  • MLL cell adhesion to RAE cells was monitored through fluorescence methods. First, 1x10 5 MLL cells were incubated for 30 minutes in 0.1% FITC to fluorescently label the cells. Following extensive washing the cells were added to RAE cell monolayers in 0.5% BSA. Independently varying concentrations of soluble branched polysaccharide and anti-cancer drug combinations were added for 30 or 60 minutes. The cultures were then washed to remove non-adherent cells and the level of adhesion, or non-adhesion, was assessed based on fluorescence measurements.
  • an enzyme-linked immunosorbent assay was employed. This determined whether recombinant galectin-3 was able to bind immobilized soluble branched polysaccharide in a dose-dependent manner, and whether the binding, if it occurred, was capable of being blocked by lactose. Results from such an assay allow assessment of the inhibitory effects on homotypic aggregation of a soluble branched polysaccharide co-administered in combination with an anti-cancer drug, in accordance with the present invention.
  • MLL cells were first detached from a cultured monolayer with 0.02% EDTA in Ca 2+ - and Mg 2+ - free (CMF)-PBS and suspended at a concentration of 4x10 3 cells/mL in complete RPMI - with or without soluble branched polysaccharide in varying concentrations. The cells were incubated for 30 minutes at 37°C, and then mixed 1 :1 (v/v) with a solution of 1% agarose in RPMI 1 :4 (v/v), which is preheated to 45° C.
  • CMF Ca 2+ - and Mg 2+ - free
  • Phase contrast photomicrographs are prepared to show MLL cells grown without or with 0.1% (w/v) soluble branched polysaccharide in combination with an anti-cancer drug.
  • Example 6 In vivo assays - Polysaccharide with Anti-cancer Drugs or in further combination with Anti-anqiogenic Drugs
  • the Dunning (R3327) rat prostate adenocarcinoma model of prostate cancer was developed by Dunning from a spontaneously occurring adenocarcinoma found in a male rat (Dunning, W., Natl. Cancer Inst. Mono., (1963), vol. 12, pp. 351-369, the entire teaching of which is incorporated herein by reference).
  • Several sub-lines have been developed from the primary tumor, which have varying differentiation and metastatic properties (Isaacs, J. et al., Cancer Res., (1978), vol. 38, pp. 4353-4359, the entire teaching of which is incorporated herein by reference).
  • the rats were first injected with 1x10 6 MLL cells in the hind limb on day 0. On day 4, when the primary tumors reached approximately 1 cm 3 in size, 0.01%, 0.1%, or 1.0% (w:v) soluble branched polysaccharide and anti-cancer drug was added to the drinking water of the rats on a continuous basis. On day 14, the rats were anesthetized and the primary tumors removed by amputating the hind limb. The rats are then followed to day 30 when all groups were sacrificed and autopsied. Control and treated animals were monitored for observable toxicity.
  • treated animals were monitored for apparent toxicity and weight gain, and results were compared to the control group receiving no polysaccharide.
  • Daily water intake was kept to 30 ⁇ 4 ml_/rat in both controls and treated groups. Hair texture, overall behavior, and stool color throughout the treatment period was also monitored and recorded for treated animals and control animals.
  • rats were orally administered a combination of anti-cancer drugs, anti-angiogenic drugs, and the soluble branched polysaccharide in their drinking water.
  • the protocol and procedures were analogous to that described above for administration of only an anti-cancer drug with the polysaccharide, except that additional controls were needed (such as soluble branched polysaccharide with anti-cancer drug; soluble branched polysaccharide with anti-angiogenic drug; anti-cancer drug and anti-angiogenic drug in the absence of soluble branched polysaccharide; anti-cancer drug alone; anti-angiogenic drug alone; and soluble branched polysaccharide alone).
  • This example treatment is designed to show an improved method of treating an animal using a non-toxic orally administered soluble branched polysaccharide in combination with a putative anti-cancer drug, or in combination with an anti-cancer drug and a putative anti-angiogenic drug to prevent spontaneous cancer metastasis and associated angiogenesis.

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Abstract

L'invention concerne des polysaccharides ramifiés ligands chimiquement solubles ayant un poids moléculaire compris entre environ 50 kD et environ 200 kD combinés à un ou plusieurs agents thérapeutiques. L'invention concerne aussi des procédés relatifs à l'utilisation de ces éléments en combinaison avec au moins un médicament anticancéreux pour le traitement et la prévention de cancer malin, et enfin des procédés relatifs à l'utilisation de la composition considérée pour le traitement et la prévention de l'angiogenèse.
PCT/US2005/021827 2004-06-22 2005-06-21 Compositions et procedes pour la codelivrance de medicaments anticancereux, de medicaments anti-angiogeniques, et d'un polysaccharide WO2006002106A2 (fr)

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JP2007518186A JP2008503583A (ja) 2004-06-22 2005-06-21 抗がん薬、抗血管形成薬、及び多糖類を共デリバリーするための組成物及び方法
BRPI0512394-1A BRPI0512394A (pt) 2004-06-22 2005-06-21 composições e métodos para co-distribuição de fármacos anticáncer, fármacos antiangiogênicos e um polissacarìdeo
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WO2011063775A2 (fr) 2009-11-25 2011-06-03 Zentiva, K.S. Complexes de sartans à base de pectine et compositions pharmaceutiques fabriquées à partir de ces complexes
WO2013166555A1 (fr) * 2012-05-10 2013-11-14 Murray Goulburn Co-Operative Co. Limited Procédés de traitement du cancer à l'aide de l'angiogénine ou d'un agoniste de l'angiogénine
WO2013166557A1 (fr) * 2012-05-10 2013-11-14 Murray Goulburn Co-Operative Co. Limited Procédés de traitement de l'émaciation
US9789168B2 (en) 2008-05-14 2017-10-17 Agriculture Victoria Services Pty Ltd Use of angiogenin or angiogenin agonists for treating diseases and disorders

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FR3022462B1 (fr) * 2014-06-18 2018-04-27 Laboratoire Francais Du Fractionnement Et Des Biotechnologies Composition orale d'anticorps anti-tnfalpha

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AU2013204721B2 (en) * 2008-05-14 2016-08-18 Agriculture Victoria Services Pty Ltd Methods for treating cachexia
US9789168B2 (en) 2008-05-14 2017-10-17 Agriculture Victoria Services Pty Ltd Use of angiogenin or angiogenin agonists for treating diseases and disorders
US10456453B2 (en) 2008-05-14 2019-10-29 Agriculture Victoria Services Pty Ltd Use of angiogenin or angiogenin agonists for treating diseases and disorders
WO2011063775A2 (fr) 2009-11-25 2011-06-03 Zentiva, K.S. Complexes de sartans à base de pectine et compositions pharmaceutiques fabriquées à partir de ces complexes
WO2011063774A2 (fr) 2009-11-25 2011-06-03 Zentiva, K.S. Complexes stéroïdes à base de pectine et compositions pharmaceutiques réalisées à partir de ces complexes
WO2013166555A1 (fr) * 2012-05-10 2013-11-14 Murray Goulburn Co-Operative Co. Limited Procédés de traitement du cancer à l'aide de l'angiogénine ou d'un agoniste de l'angiogénine
WO2013166557A1 (fr) * 2012-05-10 2013-11-14 Murray Goulburn Co-Operative Co. Limited Procédés de traitement de l'émaciation
CN104470533A (zh) * 2012-05-10 2015-03-25 墨累古尔本合作有限公司 使用血管生成素或血管生成素激动剂治疗癌症的方法
AU2013204740B2 (en) * 2012-05-10 2015-04-23 Agriculture Victoria Services Pty Ltd Methods of treating cancer using angiogenin or an angiogenin agonist
US20150150952A1 (en) * 2012-05-10 2015-06-04 Murray Goulburn Co-Operative Co., Ltd. Methods for treating cachexia
AU2013204740C1 (en) * 2012-05-10 2015-10-01 Agriculture Victoria Services Pty Ltd Methods of treating cancer using angiogenin or an angiogenin agonist
US9839676B2 (en) 2012-05-10 2017-12-12 Murray Goulburn Co-Operative Co., Limited Methods of treating cancer using angiogenin or an angiogenin agonist

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