WO2019089556A1 - Combinaisons d'agents chimiothérapeutiques et de particules antimicrobiennes et leurs utilisations - Google Patents

Combinaisons d'agents chimiothérapeutiques et de particules antimicrobiennes et leurs utilisations Download PDF

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Publication number
WO2019089556A1
WO2019089556A1 PCT/US2018/058165 US2018058165W WO2019089556A1 WO 2019089556 A1 WO2019089556 A1 WO 2019089556A1 US 2018058165 W US2018058165 W US 2018058165W WO 2019089556 A1 WO2019089556 A1 WO 2019089556A1
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Prior art keywords
chemotherapeutic agent
particle
composition
antimicrobial metal
subject
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PCT/US2018/058165
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English (en)
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Steve Gorlin
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Steve Gorlin
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Publication of WO2019089556A1 publication Critical patent/WO2019089556A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/30—Copper compounds
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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

  • the present invention relates to combinations of chemotherapeutic agents and antimicrobial metal ion eluting particles.
  • the invention further relates to methods of using the combinations to treat cancers, enhance the effectiveness of
  • chemotherapeutic agents and alter the microbiome in the region of a cancer.
  • One factor that may affect the characteristics of a cancer and/or the efficacy of a chemotherapeutic agent is the microbiome surrounding a cancer or tumor.
  • the presence of particular bacteria and other microorganisms in or around cancer cells may exert tremendous influence on the cancer and its treatment.
  • tissue and cancerous tissue showed differences in the bacterial composition, as did the microbiome of the urinary tract (Wang et al, Oncotarget 5:88122 (2017)).
  • the present invention addresses previous shortcomings in the art by providing a combination of chemotherapeutic agents and antimicrobial agents that can alter the microbial environment in and around cancer cells to enhance treatment effectiveness.
  • the present invention is based on the role played by the microbiome in and around cancer cells. By altering (e.g., decreasing or eliminating) bacteria and/or other microorganisms, the effectiveness of cancer treatments may be enhanced.
  • the invention relates to a composition comprising a chemotherapeutic agent and an antimicrobial metal-eluting particle.
  • composition of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the composition of the invention and a pharmaceutically acceptable carrier.
  • a further aspect of the invention relates to a kit of parts comprising a chemotherapeutic agent and an antimicrobial metal-eluting particle.
  • An additional aspect of the invention relates to a method of treating a cancer responsive to a chemotherapeutic agent in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the chemotherapeutic agent and an amount of an antimicrobial metal-eluting particle effective to kill microbes (e.g., bacteria) in the subject, thereby treating the cancer.
  • a therapeutically effective amount of the chemotherapeutic agent and an amount of an antimicrobial metal-eluting particle effective to kill microbes (e.g., bacteria) in the subject thereby treating the cancer.
  • Another aspect of the invention relates to a method of enhancing the effectiveness of a chemotherapeutic agent in a subject being treated for cancer, the method comprising administering to the subject a therapeutically effective amount of the chemotherapeutic agent and an amount of an antimicrobial metal-eluting particle effective to kill microbes (e.g., bacteria) in the subject, thereby enhancing the effectiveness of the chemotherapeutic agent.
  • a therapeutically effective amount of the chemotherapeutic agent and an amount of an antimicrobial metal-eluting particle effective to kill microbes (e.g., bacteria) in the subject, thereby enhancing the effectiveness of the chemotherapeutic agent.
  • a further aspect of the invention relates to a method of altering the microbiome in the region of a cancer in a subject being treated for cancer with a chemotherapeutic agent, the method comprising administering to the subject a therapeutically effective amount of the chemotherapeutic agent and an amount of an antimicrobial metal-eluting particle effective to alter the microbiome in the subject.
  • An additional aspect of the invention relates to a pharmaceutical composition comprising an antimicrobial metal-eluting particle and a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition comprising an antimicrobial metal-eluting particle, thereby treating the cancer.
  • a further aspect of the invention relates to a method of enhancing the effectiveness of a chemotherapeutic agent in a subject being treated for cancer, the method comprising administering to the subject an effective amount of the pharmaceutical composition comprising an antimicrobial metal-eluting particle, thereby enhancing the effectiveness of the chemotherapeutic agent.
  • An additional aspect of the invention relates to a method of altering the microbiome in the region of a cancer in a subject being treated for cancer, the method comprising administering to the subject an effective amount of the pharmaceutical composition comprising an antimicrobial metal-eluting particle, thereby altering the microbiome in the subject.
  • an "effective" amount as used herein is an amount that provides a desired effect.
  • a "therapeutically effective” amount as used herein is an amount that provides some improvement or benefit to the subject. Alternatively stated, a
  • therapeutically effective amount is an amount that will provide some alleviation, mitigation, or decrease in at least one clinical symptom in the subject (e.g., in the case of cancer, reduction in tumor size, reduction in tumor number, or slowing of cancer progression). Those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.
  • treat By the terms “treat,” “treating,” or “treatment of,” it is intended that the severity of the subject's condition is reduced or at least partially improved or modified and that some alleviation, mitigation or decrease in at least one clinical symptom is achieved.
  • cancer refers to any benign or malignant abnormal growth of cells.
  • Examples include, without limitation, breast cancer, prostate cancer, lymphoma, skin cancer, pancreatic cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head- neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head and neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymph
  • agents of the present invention are delivered to a cell or a subject.
  • the agents may be administered in a number of ways, including, but not limited to, direct introduction into a cell (i.e., intracellularly) and/or extracellular introduction into a cavity, interstitial space, regional circulation feeding a particular organ or tissue, or into a tissue or structure (e.g., a tumor).
  • One aspect of the present invention relates to a composition
  • a composition comprising, consisting essentially of, or consisting of a chemotherapeutic agent and an antimicrobial metal-eluting particle.
  • kits of parts comprising a chemotherapeutic agent and an antimicrobial metal-eluting particle.
  • the kit of parts may comprise the chemotherapeutic agent and an antimicrobial metal-eluting particle of the invention in a form suitable for administration to a subject or in a form suitable for compounding into a formulation.
  • the kit of parts may further comprise other therapeutic agents, carriers, buffers, containers, devices for administration, and the like.
  • the kit of parts may further comprise labels and/or instructions, for treatment of a disorder. Such labeling and/or instructions can include, for example, information concerning the amount, frequency and method of administration of the
  • chemotherapeutic agent and antimicrobial metal-eluting particle.
  • the chemotherapeutic agent may be any agent currently known or later found to be useful for the treatment of one or more types of cancer. Suitable chemotherapeutic agents include, without limitation, 1) vinca alkaloids (e.g.,
  • dactinomycin actinomycin D
  • daunorubicin daunomycin
  • suitable chemotherapeutic agents include, without limitation, anti- angiogenesis agents, such as antibodies to VEGF (e.g., bevacizumab (AVASTIN), ranibizumab (LUCENTIS)) and other promoters of angiogenesis (e.g., bFGF, angiopoietin-1), antibodies to alpha- v/beta-3 vascular integrin (e.g., VITAXI ), angiostatin, endostatin, dalteparin, ABT-510, CNG C peptide TNF alpha conjugate, cyclophosphamide, combretastatin A4 phosphate, dimethylxanthenone acetic acid, docetaxel, lenalidomide, enzastaurin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation (Abraxane), soy isoflavone (Genistein), tamoxifen citrate, thalidom
  • the chemotherapeutic agent is a cytidine deaminase substrate, including, without limitation, 5-azacytidine, gemcitabine, ara-C, tezacitabine, 5-fluoro-2'-deoxycytidine, cytochlor, or any combination thereof.
  • An additional aspect of the invention relates a method of treating a cancer responsive to a chemotherapeutic agent in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the chemotherapeutic agent and an amount of an antimicrobial metal-eluting particle effective to kill microbes (e.g., bacteria) in the subject, thereby treating the cancer.
  • An amount "effective to kill microbes” is an amount of antimicrobial metal-eluting particle sufficient to kill at least 20% of microbes when placed in contact with a microbial population in an in vitro assay, e.g., at least 20%, 30%, 40%, 50%, 60%, 70%, 80%>, or 90% or more.
  • Another aspect of the invention relates to a method of enhancing the effectiveness of a chemotherapeutic agent in a subject being treated for cancer, the method comprising administering to the subject a therapeutically effective amount of the chemotherapeutic agent and an amount of an antimicrobial metal-eluting particle effective to kill microbes (e.g., bacteria) in the subject, thereby enhancing the effectiveness of the chemotherapeutic agent.
  • Enhancing the effectiveness of a chemotherapeutic agent may encompass lowering the therapeutically effective dose of the agent, increasing the efficacy of the agent, decreasing the time to achieve a therapeutic response, and/or any other therapeutically beneficial enhancement of effect.
  • a further aspect of the invention relates to a method of altering the microbiome in the region of a cancer in a subject being treated for cancer with a chemotherapeutic agent, the method comprising administering to the subject a therapeutically effective amount of the chemotherapeutic agent and an amount of an antimicrobial metal-eluting particle effective to alter the microbiome in the subject.
  • Altering the microbiome may encompass increasing or decreasing the amount of particular strains present in the microbiome, decreasing the number of strains present, decreasing the total amount of microorganisms present, or any combination thereof.
  • the chemotherapeutic agent and the antimicrobial metal-eluting particle may be administered in any pattern and combination found to be effective.
  • the chemotherapeutic agent is administered at substantially the same time, e.g., concurrently as the antimicrobial metal-eluting particle.
  • concurrently means sufficiently close in time to produce a combined effect (that is, concurrently can be simultaneously, or it can be two or more events occurring within a short time period before or after each other).
  • the chemotherapeutic agent is administered prior to the antimicrobial metal-eluting particle.
  • the chemotherapeutic agent is administered after the antimicrobial metal-eluting particle.
  • the chemotherapeutic agent and the antimicrobial metal-eluting particle may be administered in the same composition or in separate compositions. In some embodiments, the chemotherapeutic agent and the antimicrobial metal-eluting particle may be administered in the same composition or in separate compositions. In some embodiments, the chemotherapeutic agent and the antimicrobial metal-eluting particle may be administered in the same composition or in separate compositions. In some embodiments, the chemotherapeutic agent and the
  • antimicrobial metal-eluting particle are administered in a single unit dosage form, e.g., a tablet, capsule, etc.
  • the chemotherapeutic agent and the antimicrobial metal-eluting particle are administered in multiple, separate unit dosage forms.
  • the chemotherapeutic agent and the antimicrobial metal-eluting particle may be delivered by any administration route found to be effective.
  • the chemotherapeutic agent and/or the antimicrobial metal-eluting particle is administered directly to a tumor, to a blood vessel feeding a tumor, and/or to a body cavity containing a tumor.
  • the antimicrobial metal-eluting particle may comprise any metal known to have an antimicrobial effect, e.g., an antibacterial effect.
  • the antimicrobial metal is silver, zinc, copper, or any combination thereof.
  • the antimicrobial metal-eluting particle may comprise any structure or material that elutes antimicrobial metal at an effective rate.
  • the particles comprise a single layer or multiple layers, e.g., 1, 2, 3, or 4 or more layers.
  • the particle comprises: an inner core comprising antimicrobial metallic particles and having an outer surface; and a shell layer which is a ceramic layer comprising biocompatible ceramic materials, and is attached to the outer surface of the inner core; wherein the shell layer is a crystalline structure which allows the metallic particles to be released to the outside of the shell layer from the inner core via crystal boundaries.
  • the shell layer may be deposited on the inner core by any method known in the art.
  • the shell layer is deposited on the inner core by physical vapor deposition (PVD).
  • PVD physical vapor deposition
  • the biocompatible ceramic materials are used to cover the outside surface of the functional metallic particles which have specific functions via the PVD process so as to form functional composite particles.
  • the ionic functional metallic particles of the functional composite particles are controllably released via crystal boundaries of the shell layer, leading to a longer action time of the functional metallic particles. Additionally, the coating structure prevents the functional metallic particles from being oxidized by ambient oxygen.
  • the antimicrobial metal-eluting particle may be microparticles and/or nanoparticles.
  • the particles have a particle diameter of about 1 nm to about 10 mm, e.g., about 5 nm to about 5 mm, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900 nm or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900 ⁇ , or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mm or more or any range therein.
  • the ceramic layer has a thickness of about 1 nm to about 100 ⁇ , e.g., about 5 nm to about 50 ⁇ , e.g., about 50 nm to about 5 ⁇ ⁇ ⁇ , e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 600, 700, 800, 900 nm or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100 ⁇ or more or any range therein.
  • the ceramic layer is a biocompatible ceramic layer.
  • the biocompatible ceramic layer may comprise a metal oxide or metal nitride of Zr, Ti, or Al, or any combination thereof, including, without limitation, ZrN, TiN, AlTiN, or A1 2 0 3 or any combination thereof.
  • the ceramic layer may have a suitable hardness for the present methods, e.g. , about 1000 HV (Vickers pyramid number) to about 4500 HV, e.g., about 3000 to 4000 HV, e.g., about 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 HV or any range therein.
  • the shell layer of the particle is a crystalline structure and has crystal boundaries which provide a passage leading to the outside of the shell layer for ions of the functional metallic particles of the inner core.
  • the functional metallic particles in the inner core are controllably released to the outside of the shell layer through the crystal boundaries in the form of ions.
  • the shell layer coated on the outer surface of the inner core can effectively prevent the functional metallic particles in the inner core from contacting the ambient oxygen to avoid premature oxidation; and on the other hand, the functional metallic particles in the inner core can also be controllably released through the crystal boundaries of the shell layer such that the action time of the functional metallic particles is prolonged.
  • a preparation method for the functional composite particles may comprise the following steps:
  • a PVD ceramic layer comprised of a biocompatible ceramic material on the outer surface of the functional metallic particles in the condensed state by means of a PVD process, to form a shell layer, wherein the shell layer is of a crystalline structure, has a crystal boundary, and allows ions of the functional metallic particles in the inner core to be controllably released to the outside of the shell layer through the crystal boundary.
  • the particle size of the functional metallic particles after condensation is affected by the heating power of the heating source.
  • the solid metallic block comprised of functional metallic particles may be hearted using an electron gun as the heating source, wherein the current intensity of the electron gun may be in the range of about 60 amperes (A) to 300 A, e.g., about 150 A to 250 A.
  • the step of depositing the PVD ceramic layer by means of a PVD process comprises: introducing nitrogen or oxygen with a purity of about 99.999% into the vacuum PVD process furnace; at a bias voltage of about 0 volts (V) to about 1000 V or any range therein, opening a target containing a biocompatible ceramic material, with an arc current of about 120 A to about 200 A and depositing a PVD ceramic layer on the outer surface of the condensed functional metallic particles by means of the PVD process.
  • the shell layer may be formed using a conventional PVD device by means of a conventional PVD process.
  • a further aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, consisting essentially of, or consisting of an antimicrobial metal-eluting particle and a pharmaceutically acceptable excipient.
  • the antimicrobial metal-eluting particle may be any particle as disclosed herein.
  • a further aspect of the invention relates to a kit comprising the
  • kits can comprise the pharmaceutical composition of the invention comprising an antimicrobial metal-eluting particle of the invention in a form suitable for administration to a subject or in a form suitable for compounding into a formulation.
  • the kit can further comprise other therapeutic agents, carriers, buffers, containers, devices for administration, and the like.
  • the kit can further comprise labels and/or instructions, for treatment of a disorder. Such labeling and/or instructions can include, for example, information concerning the amount, frequency and method of administration of the pharmaceutical composition.
  • An additional aspect of the invention relates to a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of the invention comprising an antimicrobial metal-eluting particle, thereby treating the cancer.
  • Another aspect of the invention relates to a method of enhancing the effectiveness of a chemotherapeutic agent in a subject being treated for cancer, the method comprising administering to the subject an effective amount of the pharmaceutical composition of the invention comprising an antimicrobial metal- eluting particle, thereby enhancing the effectiveness of the chemotherapeutic agent.
  • a further aspect of the invention relates to a method of altering the microbiome in the region of a cancer in a subject being treated for cancer, the method comprising administering to the subject an effective amount of the pharmaceutical composition of the invention comprising an antimicrobial metal-eluting particle, thereby altering the microbiome in the subject.
  • compositions of the invention can optionally comprise medicinal agents, pharmaceutical agents, carriers, adjuvants, dispersing agents, diluents, and the like.
  • the compounds of the invention can be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9 th Ed. 1995).
  • the compound (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier.
  • the carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which can contain from 0.01 or 0.5% to 95% or 99% by weight of the compound.
  • One or more compounds can be incorporated in the formulations of the invention, which can be prepared by any of the well-known techniques of pharmacy.
  • formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous,
  • intramuscular including skeletal muscle, cardiac muscle, diaphragm muscle and smooth muscle, intradermal, intravenous, intraperitoneal), topical (i.e., both skin and mucosal surfaces, including airway surfaces), intranasal, transdermal, intraarticular, intrathecal, and inhalation administration, administration to the liver by intraportal delivery, as well as direct organ or tumor injection (e.g., into the liver, into the brain for delivery to the central nervous system, into the pancreas, or into a tumor or the tissue surrounding a tumor).
  • direct organ or tumor injection e.g., into the liver, into the brain for delivery to the central nervous system, into the pancreas, or into a tumor or the tissue surrounding a tumor.
  • the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound which is being used.
  • the carrier will typically be a liquid, such as sterile pyrogen- free water, pyrogen-free phosphate-buffered saline solution, bacteriostatic water, or Cremophor EL[R] (BASF, Parsippany, N.J.).
  • the carrier can be either solid or liquid.
  • the compound can be administered in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions.
  • Compounds can be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers, such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talcum, magnesium carbonate and the like.
  • inactive ingredients examples include red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, edible white ink and the like.
  • Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric- coated for selective disintegration in the gastrointestinal tract.
  • Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
  • Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the compound in a flavored base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
  • Formulations suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient.
  • Aqueous and non-aqueous sterile suspensions can include suspending agents and thickening agents.
  • the formulations can be presented in unit ⁇ dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.
  • an injectable, stable, sterile composition comprising a compound of the invention, in a unit dosage form in a sealed container.
  • the compound or salt is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject.
  • the unit dosage form typically comprises from about 10 mg to about 10 grams of the compound or salt.
  • emulsifying agent which is pharmaceutically acceptable can be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier.
  • emulsifying agent is phosphatidyl choline.
  • Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These can be prepared by admixing the compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • one or more conventional solid carriers for example, cocoa butter
  • Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which can be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • Formulations suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration can also be delivered by iontophoresis ⁇ see, for example, Tyle, Pharm. Res. 5:318 (1986)) and typically take the form of an optionally buffered aqueous solution of the compound. Suitable formulations comprise citrate or bis/tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M of the compound.
  • the compound can alternatively be formulated for nasal administration or otherwise administered to the lungs of a subject by any suitable means, e.g., administered by an aerosol suspension of respirable particles comprising the compound, which the subject inhales.
  • the respirable particles can be liquid or solid.
  • aerosol includes any gas-borne suspended phase, which is capable of being inhaled into the bronchioles or nasal passages.
  • aerosol includes a gas-borne suspension of droplets, as can be produced in a metered dose inhaler or nebulizer, or in a mist sprayer. Aerosol also includes a dry powder composition suspended in air or other carrier gas, which can be delivered by insufflation from an inhaler device, for example. See Ganderton & Jones, Drug Delivery to the
  • Aerosols of liquid particles comprising the compound can be produced by any suitable means, such as with a pressure-driven aerosol nebulizer or an ultrasonic nebulizer, as is known to those of skill in the art. See, e.g., U.S. Patent No. 4,501,729. Aerosols of solid particles comprising the compound can likewise be produced with any solid particulate medicament aerosol generator, by techniques known in the pharmaceutical art.
  • the subject is a research subject, e.g., a laboratory animal.
  • the subject is one that has been diagnosed with a disorder that would benefit from treatment with the present invention, e.g., a. subject that has been diagnosed with cancer.
  • the subject may be one that is at risk of developing a disorder that would benefit from treatment with the present invention, such as cancer (e.g., predisposed due to hereditary factors, exposure to a carcinogen, detection of pre-cancerous cells, etc.).
  • compositions of the present invention can optionally be delivered in conjunction with other therapeutic agents.
  • the additional therapeutic agents can be delivered concurrently with the compositions of the invention.
  • the chemotherapeutic agent and the antimicrobial metal-eluting particle are administered to the subject in therapeutically effective amounts, as that term is defined above.
  • Dosages of pharmaceutically active compounds can be determined by methods known in the art, see, e.g., Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa).
  • the therapeutically effective dosage of the chemotherapeutic agent and the antimicrobial metal-eluting particle will vary somewhat patient to patient, and will depend upon the condition of the patient and the route of delivery. As a general proposition, a dosage from about 0.01 to about 500 mg/kg will have therapeutic efficacy.
  • Toxicity concerns at the higher level can restrict ' intravenous dosages to a lower level such as up to about 100 mg/kg.
  • a dosage from about 10 mg/kg to about 100 mg/kg can be employed for oral administration.
  • a dosage from about 0.5 mg/kg to 50 mg/kg can be employed for intramuscular injection.
  • more than one administration e.g., two, three, four, or more administrations
  • time intervals e.g., hourly, daily, weekly, monthly, etc.
  • the present invention finds use in veterinary and medical applications as well as research applications.
  • the term "subject" refers to humans and other animals. Suitable subjects include mammals such as primates, non-human primates, and humans, as well as those mammals of importance due to being endangered, such as Siberian tigers; of economic importance, such as animals raised on farms; animals of social importance to humans, such as animals kept as pets or in zoos; and research animals, such as mice, rabbits, guinea pigs, ferrets, dogs, cats, monkeys, and apes. Examples of such animals include but are not limited to:
  • carnivores such as cats and dogs
  • swine including pigs, hogs, and wild boars
  • ruminants and/or ungulates such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels; horses; and poultry.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des combinaisons d'agents chimiothérapeutiques et de particules d'élution d'ions métalliques antimicrobiennes. L'invention concerne en outre des procédés d'utilisation des combinaisons d'agents chimiothérapeutiques et de particules d'élution d'ions métalliques antimicrobiennes pour traiter des cancers, améliorer l'efficacité d'agents chimiothérapeutiques et modifier le microbiome dans la région d'un cancer.
PCT/US2018/058165 2017-10-31 2018-10-30 Combinaisons d'agents chimiothérapeutiques et de particules antimicrobiennes et leurs utilisations WO2019089556A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5864148A (en) * 1994-01-25 1999-01-26 Siemens Matsushita Components Gmbh & Co. Kg High-temperature gas sensor
US20040147541A1 (en) * 2001-02-19 2004-07-29 Heidi Lane Cancer treatment
WO2005110404A2 (fr) * 2004-04-20 2005-11-24 University Of Maryland Compositions et procédés pour améliorer l’efficacité d’un agent chimiothérapique
US20060222595A1 (en) * 2005-03-31 2006-10-05 Priyabrata Mukherjee Nanoparticles for therapeutic and diagnostic applications
RU2405546C1 (ru) * 2009-03-17 2010-12-10 Федеральное государственное учреждение "Московский научно-исследовательский онкологический институт им. П.А. Герцена Федерального агентства по высокотехнологичной медицинской помощи" РФ Способ профилактики и лечения энтеропатий, развивающихся на фоне полихимиотерапии
US20140264191A1 (en) * 2013-03-15 2014-09-18 Inkron Ltd Multi Shell Metal Particles and Uses Thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5864148A (en) * 1994-01-25 1999-01-26 Siemens Matsushita Components Gmbh & Co. Kg High-temperature gas sensor
US20040147541A1 (en) * 2001-02-19 2004-07-29 Heidi Lane Cancer treatment
WO2005110404A2 (fr) * 2004-04-20 2005-11-24 University Of Maryland Compositions et procédés pour améliorer l’efficacité d’un agent chimiothérapique
US20060222595A1 (en) * 2005-03-31 2006-10-05 Priyabrata Mukherjee Nanoparticles for therapeutic and diagnostic applications
RU2405546C1 (ru) * 2009-03-17 2010-12-10 Федеральное государственное учреждение "Московский научно-исследовательский онкологический институт им. П.А. Герцена Федерального агентства по высокотехнологичной медицинской помощи" РФ Способ профилактики и лечения энтеропатий, развивающихся на фоне полихимиотерапии
US20140264191A1 (en) * 2013-03-15 2014-09-18 Inkron Ltd Multi Shell Metal Particles and Uses Thereof

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