WO2020243536A1 - Procédés d'otoprotection contre des agents antinéoplasiques à base de platine - Google Patents

Procédés d'otoprotection contre des agents antinéoplasiques à base de platine Download PDF

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Publication number
WO2020243536A1
WO2020243536A1 PCT/US2020/035271 US2020035271W WO2020243536A1 WO 2020243536 A1 WO2020243536 A1 WO 2020243536A1 US 2020035271 W US2020035271 W US 2020035271W WO 2020243536 A1 WO2020243536 A1 WO 2020243536A1
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Prior art keywords
platinum
thiosulfate
administered
hours
subject
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PCT/US2020/035271
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English (en)
Inventor
John Lee
John R. SOGLIA
Qi-Ying Hu
Fuxin Shi
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Decibel Therapeutics, Inc.
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Priority claimed from US16/427,567 external-priority patent/US10813947B1/en
Priority to AU2020284122A priority Critical patent/AU2020284122A1/en
Priority to CA3142153A priority patent/CA3142153A1/fr
Priority to KR1020217042839A priority patent/KR20220047217A/ko
Priority to BR112021023684A priority patent/BR112021023684A2/pt
Priority to CN202080043662.0A priority patent/CN114302647A/zh
Application filed by Decibel Therapeutics, Inc. filed Critical Decibel Therapeutics, Inc.
Priority to MX2021014447A priority patent/MX2021014447A/es
Priority to EP20815470.8A priority patent/EP3975722A4/fr
Priority to JP2021571025A priority patent/JP2022534617A/ja
Priority to SG11202113053RA priority patent/SG11202113053RA/en
Publication of WO2020243536A1 publication Critical patent/WO2020243536A1/fr
Priority to IL288532A priority patent/IL288532A/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0046—Ear
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention provides methods of otoprotection against platinum-based antineoplastic agents.
  • Platinum-based antineoplastic agents are chemotherapeutic agents widely used to treat cancers and tumors. These agents are toxic and are known to induce hearing loss both in human and animal models. Thus, patients undergoing chemotherapy with platinum-based antineoplastic agents can suffer from hearing loss. There is a need for otoprotective compositions and methods to prevent or mitigate hearing loss associated with chemotherapeutic regimens including platinum-based antineoplastic agents.
  • the invention provides methods for mitigating platinum-induced ototoxicity in a subject in need thereof.
  • the method involves administering to the subject an effective amount of a thiosulfate salt.
  • the subject was administered a platinum-based neoplastic agent not more than 7 hours prior administering the thiosulfate salt or is scheduled to be administered a platinum-based antineoplastic agent within 4 hours. In certain embodiments, the subject was administered a platinum- based neoplastic agent not more than 7 hours prior administering the thiosulfate salt. In particular embodiments, the subject is scheduled to be administered a platinum-based antineoplastic agent within 4.5 hours. In further embodiments, the subject was administered a platinum-based neoplastic agent not more than 2.5 hours prior to administering the thiosulfate salt. In yet further embodiments, the subject was administered a platinum-based neoplastic agent not more than 1 hour prior to administering the thiosulfate salt.
  • administration of an effective amount of a thiosulfate salt to the subject produces a plasma thiosulfate Cmax that is 30 mM or less at the time of administration a platinum-based
  • a cochlear thiosulfate salt to the subject produces a cochlear thiosulfate Cmax is at least 30 times greater than a cochlear Cmax of the platinum-based antineoplastic agent.
  • the cochlear platinum concentrations and the cochlear Cmax are typically modeled by a pharmacokinetic simulation of intravenous infusion in a two-compartment model.
  • the pharmacokinetic simulation may be conducted using WinNonlin (Phoenix 64) PK simulation model 9 (IV infusion, 2 compartment).
  • the thiosulfate salt is administered auricularly. In certain embodiments, the thiosulfate salt is administered intratympanically, transtympanically, or by inner ear injection. In particular embodiments, the thiosulfate salt is administered transtympanically or by inner ear injection.
  • the method further includes administering the platinum-based antineoplastic agent.
  • the thiosulfate salt is an alkaline thiosulfate salt, ammonium thiosulfate salt, or a solvate thereof.
  • the effective amount of a thiosulfate salt is administered as a hypertonic pharmaceutical composition comprising the effective amount of a thiosulfate salt.
  • 200-1 ,000 mI_ (e.g., 200-900 mI_, 200-800 mI_, 200-700 mI_, 200-600 mI_, 200-500 mI_, 200- 400 mI_, 200-300 mI_, 300-900 mI_, 300-800 mI_, 300-700 mI_, 300-600 m ⁇ , 300-500 mI_, 300-400 m ⁇ , 400-900 m ⁇ , 400-800 m ⁇ , 400-700 m ⁇ , 400-600 mI_, or 400-500 m ⁇ ) of the hypertonic pharmaceutical composition are administered to the round window of the subject.
  • the calculated osmolarity of the hypertonic pharmaceutical composition is 500-5,000 mOsm/L (e.g., 600-5,000 mOsm/L, 700-5,000 mOsm/L, 800-5,000 mOsm/L, 900-5,000 mOsm/L, 1 ,000-5,000 mOsm/L, 1 ,500-5,000 mOsm/L, 2,000-5,000 mOsm/L, 2,500-5,000 mOsm/L, 3,000-5,000 mOsm/L, 500-4,000 mOsm/L, 600-4,000 mOsm/L, 700-4,000 mOsm/L, 800-4,000 mOsm/L, 900-4,000 mOsm/L, 1 ,000-4,000 mOsm/L, 1 ,500-4,000 mOsm/L, 2,000-4,000 mOsm/L, 2,500-4,000 mOsm/L, 3,000
  • the concentration of the thiosulfate salt in the hypertonic pharmaceutical composition is 0.5M-2.5M (e.g., about 0.05M to about 1 .5 M, about 0.05M to about 0.5M, about 0.05M to about 0.2M, about 0.05M to about 0.1 M, about 0.1 M to about 1 5M, about 0.1 M to about 0.5M, about 0.1 M to about 0.2M, about 0.2M to about 1 5M, about 0.2M to about 0.5M, about 0.5M to about 1 5M, 0.05M to about 1 .0 M, about 0.05M to about 0.5M, about 0.05M to about 0.2M, about 0.05M to about 0.1 M, about 0.1 M to about 1 .0M, about 0.1 M to about 0.5M, about 0.1 M to about 0.2M, about 0.2M to about 1 .0M, about 0.1 M to about 0.5M, about 0.1 M to about 1 .0M, about 0.1 M to about 0.5M, about 0.1
  • the effective amount is an amount that produces a plasma thiosulfate concentration that is 30 mM or less at the time the platinum-based antineoplastic agent is administered.
  • the effective amount is 0.1 -2.5 mmol of the thiosulfate salt. In particular embodiments, the effective amount is an amount that produces a maximum thiosulfate concentration of 0.6-10 mmol/L by 1 h post administration. In further embodiments, the effective amount is an amount that produces a thiosulfate concentration of 0.1 -2 mmol/L by 7 h post administration in the subject’s cochlea.
  • the subject is scheduled to be administered a platinum-based antineoplastic agent within about 1 hour to about 6 hours (e.g., within about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours, about 2 hours to about 3 hours, about 2 hours to about 4 hours, about 2 hours to about 5 hours, about 2 hours to about 6 hours, about 3 hours to about 4 hours, about 3 hours to about 5 hours, about 3 hours to about 6 hours, about 4 hours to about 5 hours, about 4 hours to about 6 hours, or about 5 hours to about 6 hours following administration of the thiosulfate salt).
  • a platinum-based antineoplastic agent within about 1 hour to about 6 hours (e.g., within about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours, about 2 hours to about 3 hours, about 2 hours to about 4 hours, about 2 hours to about 5 hours, about 2 hours to about 6 hours, about 3 hours to about 4
  • the subject is administered a platinum-based antineoplastic agent within about 1 hour to about 6 hours after administration of the thiosulfate salt (e.g., within about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours, about 2 hours to about 3 hours, about 2 hours to about 4 hours, about 2 hours to about 5 hours, about 2 hours to about 6 hours, about 3 hours to about 4 hours, about 3 hours to about 5 hours, about 3 hours to about 6 hours, about 4 hours to about 5 hours, about 4 hours to about 6 hours, or about 5 hours to about 6 hours after administration of the thiosulfate salt).
  • a platinum-based antineoplastic agent within about 1 hour to about 6 hours after administration of the thiosulfate salt (e.g., within about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours, about 2 hours to about 3 hours, about 2 hours to about 4 hours, about
  • the subject is administered a platinum-based antineoplastic agent within about 1 hour to about 6 hours before administration of the thiosulfate salt (e.g., within about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours, about 2 hours to about 3 hours, about 2 hours to about 4 hours, about 2 hours to about 5 hours, about 2 hours to about 6 hours, about 3 hours to about 4 hours, about 3 hours to about 5 hours, about 3 hours to about 6 hours, about 4 hours to about 5 hours, about 4 hours to about 6 hours, or about 5 hours to about 6 hours before administration of the thiosulfate salt).
  • a platinum-based antineoplastic agent within about 1 hour to about 6 hours before administration of the thiosulfate salt (e.g., within about 1 hour to about 5 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours, about 1 hour to about 2 hours, about 2 hours to about 3 hours, about 2 hours to about 4 hours, about
  • the invention is described by the following enumerated items.
  • a method of mitigating platinum-induced ototoxicity in a subject in need thereof comprising administering to the subject an effective amount of a thiosulfate salt, wherein the subject was administered a platinum-based neoplastic agent not more than 7 hours prior to administering the thiosulfate salt or is scheduled to be administered a platinum-based antineoplastic agent within 4 hours.
  • the effective amount is an amount that produces a plasma thiosulfate concentration that is 30 mM or less at the time the platinum-based antineoplastic agent is administered.
  • a method of mitigating platinum-induced ototoxicity in a subject in need thereof comprising administering to the subject an effective amount of a thiosulfate salt to produce (i) a plasma thiosulfate Cmax that is 30 mM or less at the time of administration a platinum-based antineoplastic agent and (ii) a cochlear thiosulfate Cmax is at least 30 times greater than a cochlear Cmax of the platinum-based antineoplastic agent, wherein the cochlear platinum concentrations and the cochlear Cmax are modeled by a pharmacokinetic simulation of intravenous infusion in a two compartment model.
  • thiosulfate salt is an alkaline thiosulfate salt, ammonium thiosulfate salt, or a solvate thereof.
  • alkaline salt represents a sodium or potassium salt of a compound.
  • Alkaline salts may be monobasic or, if the number of acidic moieties (e.g., -COOH, -SO3H, or
  • ammonium salt represents an NHV salt of a compound.
  • Ammonium salts may be monobasic or, if the number of acidic moieties (e.g., -COOH, -SO3H, or -P(0)(OH) n moieties) permits, dibasic or tribasic.
  • gelling agent refers to pharmaceutically acceptable excipient known in the art to produce a gel upon mixing with a solvent (e.g., an aqueous solvent).
  • a solvent e.g., an aqueous solvent.
  • gelling agents include hyaluronan, a polyoxyethylene-polyoxypropylene block copolymer (e.g., a poloxamer), poly(lactic-co-glycolic) acid, polylactic acid, polycaprolactone, alginic acid or a salt thereof, polyethylene glycol, a cellulose, a cellulose ether, a carbomer (e.g., Carbopol®), agar-agar, gelatin, glucomannan, galactomannan (e.g., guar gum, locust bean gum, or tara gum), xanthan gum, chitosan, pectin, starch, tragacanth, carrageenan, polyvinylpyrrolidone, poly
  • hypoertonic represents a pharmaceutical composition having a calculated osmolarity of 300 mOsm/L to 7,000 mOsm/L (e.g., 300 mOsm/L to 2,500 mOsm/L), which corresponds to 300 mmol to 7,000 mmol (e.g., 300 mOsm/L to 2,500 mmol) of ions and/or neutral molecules produced by dissolution of platinum-deactivating agent and any ionic, non-polymeric excipients in 1 L of solvent having calculated osmolarity of 0 mOsm/L.
  • the calculated osmolarity does not include ions and/or neutral molecules produced from polymeric excipients (e.g., from a gelling agent).
  • polymeric excipients e.g., a gelling agents
  • polymeric excipients are deemed as not contributing to the calculated osmolarity of the compositions disclosed herein.
  • injection means delivery to the round window by injection or infusion through an ear canal with a temporarily removed or lifted tympanic membrane or through a port created through an auditory bulla into the middle ear of a subject.
  • composition represents a composition formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal.
  • pharmaceutical dosage form represents those pharmaceutical compositions intended for administration to a subject as is without further modification (e.g., without dilution with, suspension in, or dissolution in a liquid solvent).
  • pharmaceutically acceptable excipient refers to any ingredient other than the thiosulfate salts and gelling agents described herein (e.g., a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially non-toxic and substantially non inflammatory in a patient.
  • Excipients may include, e.g., antioxidants, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), flavors, fragrances, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, liquid solvents, and buffering agents.
  • pharmaceutically acceptable salt represents those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example,
  • salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1 -19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008.
  • the salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable organic acid.
  • Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate,
  • benzenesulfonate benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • solvates means a compound as described herein wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered.
  • solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof.
  • solvents examples include ethanol, water (for example, mono-, di-, tri-, tetra-, and penta-hydrates), A/-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), L/,L/’-dimethylformamide (DMF), L/,L/’-dimethylacetamide (DMAC), 1 ,3-dimethyl-2-imidazolidinone (DMEU), 1 ,3-dimethyl-3, 4,5,6- tetrahydro-2-(1 FI)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like.
  • the solvate is water-based, the solvate is referred to as a hydrate.
  • platinum-based antineoplastic agent represents a coordination compound of Pt(ll) or Pt(IV).
  • Platinum-based antineoplastic agents are known in the art as platins.
  • platinum- based antineoplastic agents include at least two coordination sites at the platinum center that are occupied by nitrogenous spectator ligand(s).
  • the nitrogenous spectator ligands are monodentate or bidentate ligands, in which the donor atom is an sp 3 - or sp 2 -hybridized nitrogen atom within the ligand.
  • Non-limiting examples of nitrogenous spectator ligands are ammonia, 1 ,2-cyclohexanediamine, a picoline, phenanthrin, or 1 ,6-hexanediamine.
  • Non-limiting examples of platinum-based antineoplastic agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.
  • subject refers to an animal (e.g., a mammal, e.g., a human).
  • a subject to be treated according to the methods described herein may be one who is being treated with a therapeutic regimen including a platinum-based antineoplastic agent (e.g., for the treatment of a benign tumor, malignant tumor, or cancer).
  • the subject may have been diagnosed with a benign tumor, malignant tumor, or cancer by any method or technique known in the art.
  • a subject to be treated according to the invention may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to receiving a therapeutic regimen including a platinum-based antineoplastic agent.
  • substantially neutral used herein, refers to a pH level of 5.5 to about 8.5, as measured at 20 °C.
  • tonicity agent refers to a class of pharmaceutically acceptable excipients that are used to control osmolarity of pharmaceutical compositions.
  • a tonicity agent include substantially neutral buffering agents (e.g., phosphate buffered saline, tris buffer, or artificial perilymph), dextrose, mannitol, glycerin, potassium chloride, and sodium chloride (e.g., as a hypertonic, isotonic, or hypotonic saline).
  • Artificial perilymph is an aqueous solution containing NaCI (120-130 mM), KCI (3.5 mM), CaCL (1 .3-1 .5 mM), MgCL (1 .2 mM), glucose (5.0-1 1 mM), and buffering agents (e.g., NaHC03 (25 mM) and NaH2P04 (0.75 mM), or HEPES (20 mM) and NaOH (adjusted to pH of about 7.5)).
  • buffering agents e.g., NaHC03 (25 mM) and NaH2P04 (0.75 mM
  • HEPES (20 mM) and NaOH (adjusted to pH of about 7.5)
  • transtympanic in reference to a route of administration, means delivery to the round window by injection or infusion across tympanic membrane.
  • a transtympanic injection may be performed directly through the tympanic membrane or through a tube embedded in the tympanic membrane (e.g., through a tympanostomy tube or grommet).
  • inner ear injection refers to the direct injection of drug into the inner ear space.
  • FIG. 1 is a chart showing the profiles (0-24 h) of mean plasma thiosulfate concentrations over time for each tested human cohort.
  • the X-axis shows time (h), and the Y-axis shows mean plasma thiosulfate concentrations (ng/mL).
  • FIG. 2 is a chart showing the profiles (0-4 h) of mean plasma thiosulfate concentrations over time for each tested human cohort. The error bars shown are standard deviations. The X-axis shows time (h), and the Y-axis shows mean plasma thiosulfate concentrations (ng/mL).
  • FIG. 3 is a chart showing the profiles (0-672 h) of mean plasma thiosulfate concentrations over time for each tested human cohort.
  • the X-axis shows time (h), and the Y-axis shows mean plasma thiosulfate concentrations (ng/mL).
  • FIG. 4 is a scheme showing the timing of thiosulfate administration relative to cisplatin.
  • FIG. 5A is a chart showing the average threshold sound pressure levels at 4, 24, and 32 kHz measured during auditory brainstem response (ABR) tests for the control guinea pigs.
  • the baseline thresholds are shown as a shaded area curve.
  • the X-axis shows sound frequency in kHz, and the Y-axis shows the response threshold in decibel of sound pressure level (dB SPL).
  • FIG. 5B is a chart showing the average threshold sound pressure levels at 4, 24, and 32 kHz measured during auditory brainstem response (ABR) tests for the guinea pigs administered sodium thiosulfate to one ear each followed by a cisplatin challenge.
  • the baseline thresholds are shown as a shaded area curve.
  • the X-axis shows sound frequency in kHz, and the Y-axis shows the response threshold in decibel of sound pressure level (dB SPL).
  • the data shown are Mean ⁇ standard error of the mean (SEM); two way analysis of variance (ANOVA); ** P ⁇ 0.01 ; *** P ⁇ 0.001 Treated ears vs. Untreated ears (compare to FIG. 5A).
  • FIG. 6 is a chart showing the concentration dependence for thiosulfate (DB-020) in human tumor cell lines treated with cisplatin at 15 mM. The following tumor cell lines were used; SH-N-AS (brain,
  • neuroblastoma neuroblastoma
  • SNU899 lamina, squamous cell carcinoma
  • NCI-H23 lung, non-small cell
  • HLF Liver, undifferentiated hepatocellular carcinoma
  • A2780 African-Field, carcinoma
  • FIG. 7 is a chart showing the profiles (0-8 h) of mean thiosulfate concentrations (mM) over time in plasma (human) and perilymph (guinea pig) following administration of Hyaluronan Gel 1 (12% w/v, 0.5M sodium thiosulfate).
  • the horizontal solid line shows the 30 mM level below which plasma thiosulfate levels should be.
  • the horizontal dotted line shows the 660 mM (0.66mM) level above which perilymph thiosulfate levels should be.
  • FIG. 8A is a chart showing the changes in thiosulfate concentrations over time in plasma, perilymph, and cerebrospinal fluid in guinea pigs administered a gel containing 0.1 M sodium thiosulfate and 20% (w/v) poloxamer 407.
  • FIG. 8B is a chart showing the changes in thiosulfate concentrations over time in plasma, perilymph, and cerebrospinal fluid in guinea pigs administered a gel containing 0.5M sodium thiosulfate and 1 % (w/v) hyaluronan.
  • FIG. 9A is a chart showing the changes in thiosulfate concentrations over time in plasma, perilymph, and cerebrospinal fluid in guinea pigs administered a gel containing 0.1 M sodium thiosulfate and 2% (w/v) hyaluronan.
  • FIG. 9B is a chart showing the changes in thiosulfate concentrations over time in plasma, perilymph, and cerebrospinal fluid in guinea pigs administered a gel containing 0.5M sodium thiosulfate and 2% (w/v) hyaluronan.
  • FIG. 1 1 B is a chart showing the average threshold sound pressure levels at 4, 24, and 32 kHz measured during auditory brainstem response (ABR) tests for the guinea pigs administered vehicle or sodium thiosulfate to one ear each followed by a cisplatin challenge.
  • the baseline thresholds are shown as a shaded area curve.
  • FIG. 12 is a figure illustrating the cisplatin challenge test following administration of vehicle or sodium thiosulfate to one ear of a guinea pig.
  • FIG. 13 is a chart showing the average threshold sound pressure levels at 4, 24, and 32 kHz measured during auditory brainstem response (ABR) tests for the guinea pigs administered vehicle or sodium thiosulfate (0.1 M, 0.5M, or 1 M sodium thiosulfate gel) to one ear each followed by a cisplatin challenge.
  • the baseline thresholds are shown as a shaded area curve.
  • the invention provides method of mitigating platinum-induced ototoxicity in a subject by administering to the subject an effective amount of a thiosulfate salt.
  • the thiosulfate salt is administered auricularly (e.g., intratympanically or transtympanically).
  • the thiosulfate salt is administered to the subject scheduled to be administered a platinum- based antineoplastic agent within 4 hours (e.g., within 3 hours, within 2 hours, or within 1 hour).
  • the thiosulfate salt is administered within 7 hours (e.g., within 6 hours, within 5 hours, within 4 hours, within 3 hours, within 2 hours, or within 1 hour) after the administration of a platinum-based neoplastic agent.
  • the thiosulfate salt is administered to the subject scheduled to be administered platinum-based antineoplastic agent within 3 hours.
  • the thiosulfate salt is administered within 4 hours after the administration of a platinum-based neoplastic agent. More preferably, the thiosulfate salt is administered to the subject scheduled to be administered platinum-based antineoplastic agent within 1 hour.
  • the thiosulfate salt is administered within 1 hour after the administration of a platinum-based neoplastic agent.
  • An effective amount of a thiosulfate salt typically produces a plasma thiosulfate concentration that is 30 mM or less (e.g., 20 mM or less, 10 mM or less, or near endogenous concentration) at the time of administration a platinum-based antineoplastic agent.
  • an effective amount of a thiosulfate salt typically produces a cochlear thiosulfate concentration that is at least 30 times greater (e.g., 30 to 1000 times greater, 30 to 500 times greater, or 30 to 1 50 times greater) than a cochlear Cmax of the platinum-based antineoplastic agent, wherein the cochlear platinum concentrations and the cochlear Cmax are modeled by a pharmacokinetic simulation of intravenous infusion in a two compartment model.
  • Platinum-induced ototoxicity may occur in subjects receiving a platinum-based antineoplastic agent (e.g., a subject having a tumor or cancer).
  • a platinum-based antineoplastic agent e.g., a subject having a tumor or cancer
  • the platinum-based antineoplastic agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin.
  • a thiosulfate salt may mitigate (e.g., eliminate) hearing loss in a subject receiving a platinum-based antineoplastic agent, as measured by at least 50% (e.g., at least 60%, at least 70%, or at least 80%) reduction in the sound pressure level threshold elevation in the subject at a frequency 8 kHz or higher (e.g., between 8 kHz and 20 kHz) relative to a reference subject that receives the same platinum-based antineoplastic agent regimen but does not receive the thiosulfate salt.
  • a frequency 8 kHz or higher e.g., between 8 kHz and 20 kHz
  • Thiosulfate salts may exhibit otoprotective properties against platinum-based antineoplastic agents and may be used in a method of mitigating (e.g., eliminating) platinum-induced ototoxicity in subjects in need thereof.
  • a thiosulfate salt is administered to a round window of the subject.
  • the subject may be undergoing therapy with a platinum-based antineoplastic agent (e.g., cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin).
  • a platinum-based antineoplastic agent e.g., cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin.
  • a thiosulfate salt may be administered to a subject, e.g., before or after the administration of a platinum- based antineoplastic agent to the subject.
  • a thiosulfate salt may be administered, e.g., at the same time as the administration of a platinum-based antineoplastic agent.
  • a thiosulfate salt may be administered to a subject scheduled to be administered a platinum-based antineoplastic agent within 4 hours, e.g., within 3 hour, within 2 hours, or within 1 hour (e.g., at least 5 minute, at least 15 minutes, or at least 30 minutes prior to platinum-based antineoplastic agent administration).
  • a thiosulfate salt may be administered, e.g., not more than 7 hours (e.g., not more than 6 hours, not more than 5 hours, not more than 4 hours, not more than 3 hours, not more than 2 hours, or not more than 1 hour) after platinum-based antineoplastic agent administration (e.g., at least 5 minutes, at least 1 5 minutes, or at least 30 minutes after).
  • Administration of a platinum-based antineoplastic agent is typically preceded by administration of a hydration composition (e.g., saline optionally including, e.g., mannitol or furosemide).
  • administration of a platinum-based antineoplastic agent typically lasts for a period of at least 1 hour (e.g., 1 to 24 hours, e.g., 1 to 12 hours, 1 to 6 hours, 1 to 3 hours, or 1 to 2 hours).
  • 1 hour e.g., 1 to 24 hours, e.g., 1 to 12 hours, 1 to 6 hours, 1 to 3 hours, or 1 to 2 hours.
  • One of skill in the art would recognize the timing between the administrations of a thiosulfate salt and platinum- based neoplastic agent as being the time between the completion of the administration of one and the commencement of the administration of the other.
  • administration of a platinum-based neoplastic agent 30 minutes to 4 hours following the step of administration of a thiosulfate salt indicates that 30 minutes to 4 hours separate the end of the thiosulfate salt administration and the commencement of the platinum-based neoplastic agent administration (e.g., infusion of cisplatin).
  • the pharmaceutical composition of the invention may be administered by a route different from the platinum-based antineoplastic agent.
  • the methods of the invention may utilize a local route of administration, for example, the pharmaceutical composition of the invention may be administered intratympanically or transtympanically.
  • Transtympanic administration may include injection or infusion of an effective amount of the pharmaceutical composition of the invention through the tympanic membrane into the tympanic cavity, thereby providing the anti-platinum chemoprotectant agent to the round window.
  • a needle is used to pierce the tympanic membrane to instill drug into the middle ear space or traverse an existing PE tube or perforation of the ear drum to instill drug.
  • a separate ventilation hole in the tympanic membrane may or may not be created to allow air to escape the middle ear space.
  • the instilled drug may then target middle ear structures, cells or be designed to enter the inner ear via the round and oval membranes to affect specific targets. This may be accomplished, e.g., by instilling drug through the round window membrane, the oval window, a cochleostomy, or labrinthotomy approach.
  • tympanomeatal flap lifting up the ear drum
  • exposing the round window, stapes/oval window and promontory A stapedotomy hole may be created in the footplate and the drug instilled into the vestibule by pump, injection, or some other method.
  • the bony lip of the round window (RW) is removed (typically by drill) to expose the RW.
  • the RW may then be pierced with a needle and the drug infused or the RW may be fenestrated and the drug instilled directly through the fenestration.
  • an entirely separate entrance hole to the cochlea may be opened by drilling a cochleostomy hole into the cochlea and drug instilled.
  • a mastoidectomy may be performed and the facial recess opened to provide direct access to the oval and round windows as well as the promontory and the semicircular canals. Via this approach, all three sites can be used as just described.
  • the labyrinth may be opened, much like a cochleostomy, for the instillation of drug.
  • a separate opening into the RW or OW may be created to allow for excess perilymph to leak out.
  • Thiosulfate salts may be provided in a pharmaceutical composition.
  • Pharmaceutical compositions may be, e.g., hypertonic.
  • the higher tonicity of the pharmaceutical compositions disclosed herein is believed to improve the bioavailability of thiosulfate at the round window of a subject, relative to compositions with lower tonicity (e.g., hypotonic or isotonic).
  • the bioavailability is typically calculated using exposure (AUC) to thiosulfate following its administration to a subject.
  • the calculated osmolarity of the pharmaceutical composition may be, e.g., at least 400 mOsm/L (e.g., at least 500 mOsm/L, at least 600 mOsm/L, at least 700 mOsm/L, at least 800 mOsm/L, at least 900 mOsm/L, at least 1 ,000 mOsm/L, at least 1 ,500 mOsm/L, at least 2,000 mOsm/L, at least 2,500 mOsm/L, or at least 3,000 mOsm/L), and/or 5,000 mOsm/L or less (e.g., 4,000 mOsm/L or less, 3,000 mOsm/L or less, 2,000 mOsm/L or less, 1 ,900 mOsm/L or less, 1 ,800 mOsm/L or less, 1 ,
  • the calculated osmolarity of the pharmaceutical composition may be, e.g., 1 ,500-4,500 mOsm/L.
  • the calculated osmolarity of the pharmaceutical composition may be, e.g., 3,000-4,500 mOsm/L.
  • the measured osmolality of the pharmaceutical composition may be, e.g., at least 0.3 Osm/kg (e.g., at least 0.5 Osm/kg, at least 0.6 Osm/kg, at least 0.7 Osm/kg, at least 0.8 Osm/kg, at least 0.9 Osm/kg, at least 1 .0 Osm/kg, at least 1 .2 Osm/kg, at least 1 .4 Osm/kg, or at least 1 .8 Osm/kg).
  • Osm/kg e.g., at least 0.5 Osm/kg, at least 0.6 Osm/kg, at least 0.7 Osm/kg, at least 0.8 Osm/kg, at least 0.9 Osm/kg, at least 1 .0 Osm/kg, at least 1 .2 Osm/kg, at least 1 .4 Osm/kg, or at least 1 .8 Osm/kg.
  • the measured osmolality of the pharmaceutical composition may be, e.g., 2.5 Osm/kg or less (e.g., 2.1 Osm/kg or less).
  • the measured osmolality of the pharmaceutical composition may be, e.g., 0.3-2.5 Osm/kg (e.g., 0.5-2.5 Osm/kg, 0.6-2.5 Osm/kg, 0.7-2.5 Osm/kg, 0.8-2.5 Osm/kg, 0.9-2.5 Osm/kg, 1 .0-2.5 Osm/kg, 1 .2-2.5 Osm/kg, 1 .4-2.5 Osm/kg, 1 .8-2.5 Osm/kg, 0.5-2.1 Osm/kg, 0.6- 2.1 Osm/kg, 0.7-2.1 Osm/kg, 0.8-2.1 Osm/kg, 0.9-2.1 Osm/kg, 1 .0-2.1 Osm/kg,
  • Measured osmolality refers to the osmolality of a composition, as measured using an osmometer (typically, a membrane osmometer).
  • a preferred pharmaceutical dosage form of the invention is a gel.
  • At least 50 mI_ (preferably, at least 100 mI_; more preferably, at least 200 mI_) of the pharmaceutical composition are administered to theround windowof the subject.
  • 1 ml_ or less e.g., 0.8 ml_ or less or 0.5 ml_ or less
  • 1 ml_ or less e.g., 0.8 ml_ or less or 0.5 ml_ or less
  • 100 mI_ to 1 ml_ (e.g., 200 mI_ to 1 ml_, 100 mI_ to 0.8 ml_, 200 mI_ to 0.8 ml_, 100 mI_ to 0.5 ml_, 200 mI_ to 0.5 ml_, 0.5 ml_ to 1 .0 ml_, 0.5 ml_ to 0.8 ml_, or 0.8 ml_ to 1 .0 ml_) of the pharmaceutical composition are administered to the round window of the subject.
  • 100 mI_ to 1 ml_ e.g., 200 mI_ to 1 ml_, 100 mI_ to 0.8 ml_, 200 mI_ to 0.8 ml_, 100 mI_ to 0.5 ml_, 200 mI_ to 0.5 ml_, 0.5 ml_ to 1 .0 ml_, 0.5 ml_ to 0.8 ml_
  • a thiosulfate salt may be, e.g., the sole compound contributing to osmolarity of a pharmaceutical composition.
  • higher osmolalities than those afforded by the desired concentration of a thiosulfate salt may be achieved, e.g., through the use of tonicity agents.
  • a tonicity agent may be present in a hypertonic, isotonic, or hypotonic excipient (e.g., a hypotonic liquid solvent).
  • Non-limiting examples of tonicity agents include substantially neutral buffering agents (e.g., phosphate buffered saline, tris buffer, or artificial perilymph), dextrose, mannitol, glycerin, glycerol, potassium chloride, and sodium chloride (e.g., as a hypertonic, isotonic, or hypotonic saline).
  • substantially neutral buffering agents e.g., phosphate buffered saline, tris buffer, or artificial perilymph
  • dextrose e.g., phosphate buffered saline, tris buffer, or artificial perilymph
  • dextrose e.g., mannitol
  • glycerin glycerin
  • glycerol glycerol
  • potassium chloride e.g., potassium chloride
  • sodium chloride e.g., as a hypertonic, isotonic, or hypotonic saline
  • thiosulfate salts are believed to reduce or eliminate the toxicity of platinum-based antineoplastic agents by competitively ligating and substantially coordinatively saturating the platinum centers present in the platinum-based antineoplastic agents.
  • concentration of a thiosulfate salt in a pharmaceutical composition may be, e.g., at least about 0.05M (e.g., at least about 0.1 M, at least about 0.2M, at least about 0.3M, at least about 0.4M, at least about 0.5M, or at least about 1 M).
  • concentration of a thiosulfate salt in a pharmaceutical composition may be, e.g., about 2.5M or less (e.g., 2.0M or less,
  • Non-limiting examples of the concentrations of a thiosulfate salt in a pharmaceutical composition e.g., a
  • pharmaceutical dosage form may be, e.g., about 0.05M to about 1 .5 M, about 0.05M to about 0.5M, about 0.05M to about 0.2M, about 0.05M to about 0.1 M, about 0.1 M to about 1 .5M, about 0.1 M to about 0.5M, about 0.1 M to about 0.2M, about 0.2M to about 1 .5M, about 0.2M to about 0.5M, about 0.5M to about 1 .5M, 0.05M to about 1 .0 M, about 0.05M to about 0.5M, about 0.05M to about 0.2M, about 0.05M to about 0.1 M, about 0.1 M to about 1 .0M, about 0.1 M to about 0.5M, about 0.1 M to about 0.2M, about 0.2M to about 1 .0M, about 0.1 M to about 0.5M, about 0.1 M to about 0.2M, about 0.2M to about 1 .0M, about 0.1 M to about 0.5M, about 0.1 M to about
  • the concentration of a thiosulfate salt agent in a pharmaceutical composition is about 0.5M to about 1 .5M. More preferably, the concentration of a thiosulfate salt agent in a pharmaceutical composition (e.g., a pharmaceutical dosage form) is about 0.5M to about 1 .0M.
  • the thiosulfate salt is an alkaline or ammonium thiosulfate salt. More preferably, the thiosulfate salt is sodium thiosulfate.
  • compositions disclosed herein include a gelling agent.
  • Gelling agents may be used to increase the viscosity of the pharmaceutical composition, thereby improving the retention of the pharmaceutical composition at the targeted site.
  • Pharmaceutical compositions may contain, e.g., about 0.1 % to about 25% (w/v) (e.g., about 0.1 % to about 20% (w/v), about 0.1 % to about 10% (w/v), about 0.1 % to about 2% (w/v), about 0.5% to about 25% (w/v), about 0.5% to about 20% (w/v), about 0.5% to about 1 0% (w/v), about 0.5% to about 2% (w/v), about 1 % to about 20% (w/v), about 1 % to about 10% (w/v), about 1 % to about 2% (w/v), about 5% to about 20% (w/v), about 5% to about 10% (w/v), or about 7% to about 1 0% (w/v)) of a gelling agent relative to
  • compositions may contain, e.g., about 0.5% to about 25% (w/v) (e.g., about 0.5% to about 20% (w/v), about 0.5% to about 10% (w/v), about 0.5% to about 2% (w/v), about 1 % to about 20% (w/v), about 1 % to about 10% (w/v), about 1 % to about 2% (w/v), about 5% to about 20% (w/v), about 5% to about 10% (w/v), or about 7% to about 10% (w/v)) of a gelling agent relative to solvent.
  • w/v e.g., about 0.5% to about 25% (w/v)
  • w/v e.g., about 0.5% to about 20% (w/v), about 0.5% to about 10% (w/v), about 0.5% to about 2% (w/v), about 1 % to about 20% (w/v), about 5% to about 10% (w/v), or about 7% to about 10% (w/v)
  • Gelling agents that may be used in the pharmaceutical compositions disclosed herein are known in the art.
  • Non-limiting examples of gelling agents include hyaluronan, a polyoxyethylene-polyoxypropylene block copolymer (e.g., a poloxamer), poly(lactic-co-glycolic) acid, polylactic acid, polycaprolactone, alginic acid or a salt thereof, polyethylene glycol, a cellulose, a cellulose ether, a carbomer (e.g., Carbopol®), agar-agar, gelatin, glucomannan, galactomannan (e.g., guar gum, locust bean gum, or tara gum), xanthan gum, chitosan, pectin, starch, tragacanth, carrageenan, polyvinylpyrrolidone, polyvinyl alcohol, paraffin, petrolatum, silicates, fibroin, and combinations thereof.
  • the gelling agent is hyaluronan.
  • a pharmaceutical composition may contain, e.g., about 0.5% to about 2% (w/v) (e.g., about 1 % to about 2% (w/v)) of hyaluronan relative to solvent.
  • a pharmaceutical composition may contain, e.g., about 5% to about 10% (w/v) (e.g., about 6% to about 8% (w/v)) of methylcellulose relative to solvent.
  • composition may contain, e.g., hyaluronan and methylcellulose as a gelling agent (e.g., about 0.5% to about 2% (w/v) of hyaluronan and about 5% to about 10% (w/v) of methylcellulose relative to solvent).
  • a pharmaceutical composition may contain, e.g., a polyoxyethylene-polyoxypropylene block copolymer (e.g., poloxamer) as a gelling agent.
  • a pharmaceutical composition may contain, e.g., about 1 % to about 20% (w/v) (e.g., about 1 % to about 1 5% (w/v), about 1 % to about 10% (w/v), about 5% to about 20% (w/v), about 5% to about 15% (w/v), about 5% to about 10% (w/v), about 10% to about 20% (w/v), or about 10% to about 15% (w/v)) of a polyoxyethylene-polyoxypropylene block copolymer (e.g., poloxamer) relative to solvent.
  • the poloxamer may be poloxamer 407, poloxamer 188, or a combination thereof.
  • a pharmaceutical composition may contain, e.g., about 0.5% (w/v) to about 20% (w/v) of fibroin as a gelling agent relative to solvent.
  • Hyaluronan is a hyaluronic acid or a salt thereof (e.g., sodium hyaluronate).
  • Hyaluronans are known in the art and are typically isolated from various bacteria (e.g., Streptococcus zooepidemicus, Streptococcus equi, or Streptococcus pyrogenes) or other sources, e.g., bovine vitreous humor or rooster combs.
  • the weight-averaged molecular weight (Mw) of hyaluronan is typically about 50 kDa to about 10 MDa.
  • Mw of a hyaluronan is about 500 kDa to 6 MDa (e.g., about 500 kDa to about 750 kDa, about 600 kDa to about 1 .1 MDa, about 750 kDa to about 1 MDa, about 1 MDa to about 1 .25 MDa, about 1 .25 to about 1 .5 MDa, about 1 .5 MDa to about 1 .75 MDa, about 1 .75 MDa to about 2 MDa, about 2 MDa to about 2.2 MDa, about 2 MDa to about 2.4 MDa).
  • a hyaluronan e.g., sodium hyaluronate
  • Mw of a hyaluronan is about 500 kDa to 6 MDa (e.g., about 500 kDa to about 750 kDa, about 600 kDa to about 1 .1 MDa, about 750 kDa to about 1 MDa, about 1 MDa to
  • the Mw of a hyaluronan is about 620 kDa to about 1 .2 MDa or about 1 .2 MDa to about 1 .9 MDa.
  • Other preferred molecular weight ranges for a hyaluronan include, e.g., about 600 kDa to about 1 .2 MDa.
  • Polyoxyethylene-polyoxypropylene block copolymers are known in the art.
  • a non-limiting example of polyoxyethylene-polyoxypropylene block copolymers is a poloxamer, in which a single polyoxypropylene block is flanked by two polyoxyethylene blocks.
  • Poloxamers are commercially available under various trade names, e.g., Synperonic®, Pluronic®, Kolliphor®, and Lutrol®.
  • a pharmaceutical composition may contain, e.g., a polyoxyethylene-polyoxypropylene block copolymer (e.g., a poloxamer) includes a polyoxypropylene block with a number average molecular weight (M n ) of, e.g., about 1 ,100 g/mol to about 17,400 g/mol (e.g., about 2,090 g/mol to about 2,360 g/mol, about 7,680 g/mol to about 9,510 g/mol,
  • M n number average molecular weight
  • a polyoxyethylene-polyoxypropylene block copolymer may include a polyoxypropylene block with a number average molecular weight (M n ) of about 1 ,100 g/mol to about 4,000 g/mol and a calculated polyoxyethylene content of about 30% to about 85% (w/w).
  • a polyoxyethylene-polyoxypropylene block copolymer may include a polyoxypropylene block with a calculated molecular weight of, e.g., about 1 ,800 g/mol to about 4,000 g/mol.
  • the calculated polyoxyethylene content a polyoxyethylene-polyoxypropylene block copolymer may be, e.g., about 70% to about 80% (w/w).
  • a polyoxyethylene-polyoxypropylene block copolymer may have a number average molecular weight of, e.g., about 7,680 g/mol to about 14,600 g/mol.
  • Non-limiting examples of poloxamers are poloxamer 407 and poloxamer 1 88.
  • Celluloses and cellulose ethers are known in the art. Celluloses and cellulose ethers are commercially available under various tradenames, e.g., Avicel®, MethocelTM, Natrosol®, and Tylose®. Non-limiting examples of cellulose ethers include methylcellulose, carboxymethylcellulose, ethylcellulose, hydroxyethylcellulose, methyl hydroxyethylcellulose, hydroxypropyl methylcellulose, or
  • a cellulose ether e.g., methylcellulose
  • Mn number average molecular weight
  • Methyl-substituted celluloses e.g., methylcellulose, hydroxypropyl methyl cellulose, or methyl hydroxyethylcellulose
  • Fibroin is a protein present in silk created by numerous insects. Fibroins are known in the art and are commercially available from various vendors, e.g., Jiangsu SOHO International Group; Simatech,
  • the molecular weight of silk fibroin is typically about 10 kDa to about 500 kDa. Fibroins are described in WO 201 7/139684, the disclosure of which is incorporated herein by reference.
  • compositions may contain non-cross-linked or cross-linked gelling agents.
  • Gelling agents may be cross-linked using cross-linking agents known in the art.
  • the cross-linked gelling agent is covalently crosslinked.
  • Pharmaceutical compositions (e.g., pharmaceutical dosage forms) including cross-linked gelling agents may be used to control the release profile of an anti-platinum chemoprotectant agent.
  • the release of an anti-platinum chemoprotectant agent from a pharmaceutical composition (e.g., a pharmaceutical dosage form) containing a cross-linked gelling agent may be extended release relative to a reference composition that differs from the pharmaceutical composition only by the lack of cross-linking in the gelling agent in the reference composition.
  • the extension of the release of an anti-platinum chemoprotectant agent may be assessed by comparing T max values for the pharmaceutical composition and the reference composition.
  • Certain gelling agents e.g., those having carboxylate moieties (e.g., hyaluronan, alginic acid, and carboxymethylcellulose), can be cross-linked ionically using ionic cross-linking agents (e.g., a multivalent metal ion, e.g., Mg 2+ , Ca 2+ , or Al 3+ ).
  • ionic cross-linking agents e.g., a multivalent metal ion, e.g., Mg 2+ , Ca 2+ , or Al 3+.
  • gelling agents can be ionically cross-linked in an aqueous solution using multivalent metal ions, e.g., Mg 2+ , Ca 2+ , or Al 3+ , as ionic cross-linking agents.
  • multivalent metal ions e.g., Mg 2+ , Ca 2+ , or Al 3+
  • the metal ions are believed to coordinate to different molecules of the gelling agent (e.g., to pendant carboxylates residing on different molecules of the gelling agent), thereby forming a linkage between these different molecules of the gelling agent.
  • Certain gelling agents having reactive functional groups, e.g., -OH, -COOH, or -NH2 may be covalently cross-linked.
  • covalent cross-linking agents include: 1 ,4-butanediol diglycidyl ether (BDDE), divinyl sulfone, glutaraldehyde, cyanogen bromide, octeylsuccinic anhydride, acid chlorides, diisocyanates, methacrylic anhydride, boric acid, and sodium periodate/adipic acid dihydrazide.
  • BDDE 1,4-butanediol diglycidyl ether
  • divinyl sulfone divinyl sulfone
  • glutaraldehyde glutaraldehyde
  • cyanogen bromide octeylsuccinic anhydride
  • acid chlorides diisocyanates
  • methacrylic anhydride boric acid
  • sodium periodate/adipic acid dihydrazide sodium periodate/adipic acid dihydrazide.
  • compositions may contain pharmaceutically excipients other than gelling agents.
  • pharmaceutical compositions may contain, e.g., liquid solvents, tonicity agents, buffering agents, and/or coloring agents. Certain excipients may perform multiple roles.
  • a liquid solvent in addition to its function as a carrier may be used as a tonicity agent and/or buffering agent.
  • Such solvents are known in the art, e.g., salines (e.g., hypertonic saline, hypotonic saline, isotonic saline, or phosphate-buffered saline) and artificial perilymph.
  • salines e.g., hypertonic saline, hypotonic saline, isotonic saline, or phosphate-buffered saline
  • artificial perilymph e.g., salines (e.g., hypertonic saline, hypotonic saline, isotonic saline, or phosphate-buffered saline) and artificial perilymph.
  • Liquid solvents may be used in pharmaceutical compositions (e.g., pharmaceutical dosage forms) as a vehicle.
  • Liquid solvents are known in the art.
  • Non-limiting examples of liquid solvents include water, salines (e.g., hypertonic saline, hypotonic saline, isotonic saline, or phosphate-buffered saline), artificial perilymph, and tris buffer.
  • Artificial perilymph is an aqueous solution containing NaCI (120-130 mM), KCI (3.5 mM), CaCl2 (1 .3-1 .5 mM), MgCL (1 .2 mM), glucose (5.0-1 1 mM), and buffering agents (e.g., NaHCCb (25 mM) and NaH2PC>4 (0.75 mM), or HEPES (20 mM) and NaOH (adjusted to pH of about 7.5)).
  • buffering agents e.g., NaHCCb (25 mM) and NaH2PC>4 (0.75 mM
  • HEPES (20 mM) and NaOH (adjusted to pH of about 7.5)
  • Tonicity agents may be included in pharmaceutical compositions (e.g., pharmaceutical dosage forms) to increase osmolarity relative to that which is afforded by an anti-platinum chemoprotectant agent.
  • Tonicity agents are known in the art.
  • Non-limiting examples of tonicity agents include substantially neutral buffering agents (e.g., phosphate buffered saline, tris buffer, or artificial perilymph), dextrose, mannitol, glycerin, potassium chloride, and sodium chloride (e.g., as a hypertonic, isotonic, or hypotonic saline).
  • compositions include sufficient amount of tonicity agents to provide for administration to a subject a hypertonic pharmaceutical dosage form (e.g., a pharmaceutical dosage form having a calculated osmolarity of at least 400 mOsm/L (e.g., at least 500 mOsm/L, at least 600 mOsm/L, or at least 700 mOsm/L), and/or 2,500 mOsm/L or less (e.g., 2,000 mOsm/L, 1 ,900 mOsm/L or less, 1 ,800 mOsm/L or less, 1 ,700 mOsm/L or less, 1 ,600 mOsm/L or less, or 1 ,500 mOsm/L or less)).
  • a hypertonic pharmaceutical dosage form e.g., a pharmaceutical dosage form having a calculated osmolarity of at least 400 mOsm/L (e.g., at least 500 mO
  • the targeted concentration of a tonicity agent in a pharmaceutical composition can be determined, e.g., by (i) subtracting the calculated osmolarity contributions of an anti-platinum chemoprotectant agent and other non-polymeric excipients from the total targeted calculated osmolarity to obtain the targeted calculated osmolarity contribution from the tonicity agent, and (ii) determining the concentration of the tonicity agent by dividing the targeted calculated osmolarity contribution from the tonicity agent by the number of ions and/or molecules produced upon dissolution of the tonicity agent in a liquid solvent.
  • Buffering agents may be used to adjust the pH of a pharmaceutical composition (e.g., a pharmaceutical dosage form) a substantially neutral pH level. Buffering agents are known in the art. Non-limiting examples of buffering agents include, e.g., phosphate buffers and Good’s buffers (e.g., tris, MES, MOPS, TES, HEPES, HEPPS, tricine, and bicine). In addition to the pH control, buffering agents may be used to control osmolarity of the pharmaceutical composition (e.g., pharmaceutical dosage form).
  • a pharmaceutical composition (e.g., a pharmaceutical dosage form) of the invention may be prepared from an anti-platinum chemoprotectant agent, a gelling agent, and a liquid solvent.
  • a method of preparing a pharmaceutical composition (e.g., a pharmaceutical dosage form) of the invention includes (i) providing the anti-platinum chemoprotectant agent and the gelling agent, and (ii) mixing the anti-platinum chemoprotectant agent and the gelling agent with the liquid solvent to produce the pharmaceutical composition.
  • the anti-platinum chemoprotectant agent and the gelling agent may be provided, e.g., as a mixture or as separate ingredients.
  • the step (ii) may include, e.g.:
  • Hyaluronan Gel 1 (0.5M STS, 1 % (w/v) hyaluronan)
  • Sodium thiosulfate pentahydrate (619.75 mg) was dissolved in sterile, distilled water (5 mL) in a sterile vial to produce a clear solution.
  • Hyaluronan 50.30 mg ; Pharma Grade 80, Kikkoman Biochemifa company; 0.6-1 .2 mDa was added to the solution, and the resulting mixture was stirred for 8-10 min at 4°C. The resulting solution was filtered through 0.22 pm Millex-GV sterile filter.
  • Hyaluronan Gel 2 (0.1 M STS, 2% (w/v) hyaluronan)
  • Methylcellulose (351 .01 mg ; Methocel® A15 Premium LV, Dow Chemical Company) was dissolved in sterile, distilled water (2.0 mL), and the resulting solution was mixed with the sodium thiosulfate solution.
  • Hyaluronan (100.10 mg; Pharma Grade 80, Kikkoman Biochemifa company; 0.6-1 .2 mDa) was added to the resulting mixture and mixed at 4°C for 10-15 min.
  • Hyaluronan Gel 3 (0.5M STS, 2% (w/v) hyaluronan)
  • Methylcellulose (350.23 mg ; Methocel® A15 Premium LV, Dow Chemical Company) was dissolved in sterile, distilled water (2.0 ml_), and the resulting solution was mixed with the sodium thiosulfate solution.
  • Hyaluronan (100.65 mg; Pharma Grade 80, Kikkoman Biochemifa company; 0.6-1 .2 mDa) was added to the resulting mixture and mixed at 4°C for 10-15 min.
  • Hyaluronan Gel 4 (0.1 M STS, 1 % (w/v) hyaluronan, manitol)
  • Hyaluronan (50.09 mg; Pharma Grade 80, Kikkoman Biochemifa company; 0.6-1 .2 mDa) was added to water (5 ml_).
  • Sodium thiosulfate pentahydrate (124.9mgs) was added.
  • the pH of the resulting mixture was adjusted to pH7.12 by addition of sodium hydroxide (1 N, ca. 0.5 mI_).
  • the viscous solution was filtered through 0.22 pm Millex-GV filter.
  • Hyaluronan Gel 5 (0.1 M STS, 1 % (w/v) hyaluronan)
  • Hyaluronan Gel 5 was prepared according to the procedure described for Hyaluronan Gel 1 with the exception that the amount of sodium thiosulfate pentahydrate was adjusted to provide a 0.1 M concentration of sodium thiosulfate.
  • Hyaluronan Gel 6 (0.2M STS, 1 % (w/v) hyaluronan)
  • Hyaluronan Gel 6 was prepared according to the procedure described for Hyaluronan Gel 1 with the exception that the amount of sodium thiosulfate pentahydrate was adjusted to provide a 0.2M concentration of sodium thiosulfate.
  • Hyaluronan Gel 7 (0.3M STS, 1 % (w/v) hyaluronan)
  • Hyaluronan Gel 7 was prepared according to the procedure described for Hyaluronan Gel 1 with the exception that the amount of sodium thiosulfate pentahydrate was adjusted to provide a 0.3M concentration of sodium thiosulfate.
  • Hyaluronan Gel 8 (0.4M STS, 1 % (w/v) hyaluronan)
  • Hyaluronan Gel 8 was prepared according to the procedure described for Hyaluronan Gel 1 with the exception that the amount of sodium thiosulfate pentahydrate was adjusted to provide a 0.4M concentration of sodium thiosulfate.
  • Hyaluronan Gel 9 (0.5M STS, 1 % (w/v) hyaluronan, Tris (5x))
  • Hyaluronan (79.99 mg; Pharma Grade 80, Kikkoman Biochemifa company; 0.6-1 .2 mDa) was added to Tris buffer (8 ml_, AMRESCO-0497-500G). The pH of the resulting mixture was adjusted to pH7.13 by addition of HCI (5N). Sodium thiosulfate pentahydrate (992.60 mg) was added to the above solution. The viscous solution was filtered through 0.22 pm Millex-GV filter. Hyaluronan Gel 10 (0.5M STS, 1 % (w/v) hyaluronan, phosphate buffered saline (5x))
  • Hyaluronan (70.38 mg; Pharma Grade 80, Kikkoman Biochemifa company; 0.6-1 .2 mDa) was added to PBS buffer (7 ml_, 5c). Sodium thiosulfate pentahydrate (868.46 mg) was added. The pH of the resulting mixture was adjusted to pH6.99 by addition of NaOH (1 N). The viscous solution was filtered through 0.22 mM Millex-GV filter.
  • Hyaluronan Gel 1 1 (0.8M STS, 1 % (w/v) hyaluronan)
  • Hyaluronan Gel 1 1 was prepared according to the procedure described for Hyaluronan Gel 1 with the exception that the amount of sodium thiosulfate pentahydrate was adjusted to provide a 0.8M concentration of sodium thiosulfate.
  • Hyaluronan Gel 12 (1 M STS, 0.8% (w/v) hyaluronan)
  • Hyaluronan Gel 12 was prepared according to the procedure described for Hyaluronan Gel 1 with the exception that the amount of sodium thiosulfate pentahydrate was adjusted to provide a 1 M concentration of sodium thiosulfate, and the amount of hyaluronan was adjusted to provide a 0.8% (w/v) concentration of hyaluronan.
  • Hyaluronan Gel 13 (0.5M STS, 0.82% (w/v) hyaluronan (HYALGAN))
  • Hyaluronan Gel 13 was prepared by mixing of sodium thiosulfate pentahydrate with hyaluronan
  • Hyaluronan Gel 14 (0.5M STS, 1 % (w/v) hyaluronan (SINGCLEAN))
  • Hyaluronan Gel 14 was prepared according to the procedure described for Hyaluronan Gel 13 with the exception that hyaluronan (SINGCLEAN, Hangzhouh Singclean Medical Products Co., Ltd., Hangzhou, China) was used in the preparation of this gel.
  • hyaluronan SINGCLEAN, Hangzhouh Singclean Medical Products Co., Ltd., Hangzhou, China
  • Hyaluronan Gel 15 (0.5M STS, 1 % (w/v) hyaluronan (EUFLEXXA))
  • Hyaluronan Gel 15 was prepared according to the procedure described for Hyaluronan Gel 13 with the exception that hyaluronan (EUFLEXXA, Ferring Pharmaceuticals Inc., Parsippany, NJ) was used in the preparation of this gel.
  • hyaluronan EUFLEXXA, Ferring Pharmaceuticals Inc., Parsippany, NJ
  • Hyaluronan Gel 16 (0.5M STS, 1 % (w/v) hyaluronan (HEALON))
  • Hyaluronan Gel 16 was prepared according to the procedure described for Hyaluronan Gel 13 with the exception that hyaluronan (HEALON, Johnson & Johnson, New Brunswick, NJ) was used in the preparation of this gel.
  • hyaluronan HEALON, Johnson & Johnson, New Brunswick, NJ
  • Hyaluronan Gel 17 (1 M STS, 1 % (w/v) hyaluronan)
  • Hyaluronan Gel 17 was prepared according to the procedure described for Hyaluronan Gel 1 with the exception that the amount of sodium thiosulfate pentahydrate was adjusted to provide a 1 M concentration of sodium thiosulfate.
  • Hyaluronan Gel 18 (10% (w/v) N-Acetyl-L-cysteine, 1 % (w/v) hyaluronan)
  • Hyaluronan (39.38 mg; Pharma Grade 80, Kikkoman Biochemifa company; 0.6-1 .2 mDa) was added to water (4 ml_). N-Acetyl-L-cysteine (399.14 mg) was added. The pH of the resulting mixture was adjusted to pH 7.21 by addition of NaOH (10N, 240 mI_). The viscous solution was filtered through 0.22 mM Millex- GV filter. The osmotic pressure was measured as 1 .107 Osm/kg.
  • hyaluronan gels may be prepared using the procedures described herein.
  • 1 M and 1 .5M hyaluronan gels may be prepared according to the same procedure as described for, e.g.,
  • Brensted acids e.g., hydrochloric acid
  • bases e.g., sodium hydroxide
  • the predicted maximal plasma platinum concentration following cisplatin treatment was determined to be approximately 22 mM. Applying a 30-fold molar stoichiometric ratio results in a concentration of 660 mM (0.66 mM) which, when the molecular weight of thiosulfate is used, results in thiosulfate concentration of 74 pg/mL. Achieving this level of thiosulfate in the human cochlea is expected to provide complete (maximum) protection against cisplatin induced ototoxicity following high dose (e.g., 100 mg/m 2 ) cisplatin treatment.
  • high dose e.g. 100 mg/m 2
  • LC-MS/MS liquid chromatography with tandem mass spectrometry
  • Hyaluronan Gel 1 achieved maximal perilymph concentration, 868.5 pg/mL (approximately 7.8 mM) at the first time-point sampled (1 h). This maximum perilymph concentration is approximately 10-fold greater than the Hyaluronan Gel 1 concentration predicted to provide 100% protection (minimal efficacious concentration; 74 pg/mL, 0.66 mM) from cisplatin induced ototoxicity.
  • the perilymph ti/2 ranged from 2.7 to 6.4 hours.
  • the high perilymph Hyaluronan Gel 1 concentration combined with the relatively long half- life provide a treatment window of 3 h pre to 4 h post cisplatin treatment.
  • Cohort 1 was administered unilaterally, intratympanically 19 mg of sodium thiosulfate as a 0.15M sodium thiosulfate/hyaluronan gel, prepared as described for Hyaluronan Gel 1 .
  • Cohort 2 was administered unilaterally, intratympanically 62 mg of sodium thiosulfate as Hyaluronan Gel 1 .
  • Cohort 3 was administered unilaterally, intratympanically 124 mg of sodium thiosulfate as Hyaluronan Gel 1 7.
  • Cohort 4 was administered unilaterally,
  • Hyaluronan Gel 1 administered intratympanically (IT) to the left ear of guinea pigs either 24 hours, 6 hours, 3 hours, or 1 hour prior to, or 1 hour, 4 hours or 24 hours following cisplatin (single 10 mg/kg IV bolus; FIG. 4). All right control ears that were not treated with Hyaluronan Gel 1 demonstrated significant threshold shifts (i.e., hearing loss) compared to naive animals (FIG.
  • Hyaluronan Gel 1 dosed from 3 hours prior to 4 hours post cisplatin administration, provided protection from cisplatin-induced hearing loss relative to control ears untreated by Hyaluronan Gel 1 (FIG. 5B).
  • Hyaluronan Gel 1 was moderately less effective at protecting from cisplatin-induced hearing loss when administered more distally to cisplatin treatment (e.g., > 6 h prior or 24 h post cisplatin dose).
  • Albino guinea pigs (Hartley), body weight at 250-350 g, were used for the studies. For dosing, the animal was placed on its shoulder with the surgery ear up and auditory bulla was first exposed using
  • Sampling procedures are as follows, in brief. All sampling procedures are terminal. Animals were euthanized with CO2. 0.5 ml_ samples of blood were collected by cardiac puncture. Plasma was separated by centrifugation at 5,000 rpm at 4°C for 10 min and collected in a separate tube. 50 mI_ of cerebrospinal fluid were collected through the cisterna magma. Perilymph was collected ex vivo to avoid contamination from the cerebrospinal fluid influx via the cochlear aqueduct. The temporal bone was rapidly isolated, and the bulla was removed to expose the cochlea. Any visible remaining dosed compositions were carefully removed with absorbent points under the surgical microscope before perilymph sampling.
  • Cynomolgus monkey was administered tolfedine (4 mg/kg) subcutaneously. After 30 minutes, the animal was anesthetized via intravenous bolus of propofol (5.5 mg/kg). 2-3% isoflurane inhalation was then used to maintain the animal in anesthetized state. The animal was then immobilized and placed laterally in reverse Trendelenburg position to ensure the access to the round window. During the surgery process, the animal was kept on a warm blanket.
  • Intratympanic injection in right ear was conducted when the animal reaches the anesthetized state.
  • 1 .1 mL of epinephrine hydrochloride-saline (0.1 mg in 10 ml_ saline) and 0.5 ml_ of lidocaine hydrochloride (20 mg/mL) were injected subcutaneously into the skin of ear canal posterior wall of each ear respectively as local anesthetics.
  • An incision was then made in the post-auricular skin, and part of the temporal bone was drilled to expose middle ear.
  • 50 mI_ of the STS composition were injected into the round window membrane using a 25G needle.
  • IT intratympanic administration
  • TT transtympanic administration
  • zolazepam hydrochloride Zincil 50; 20 mg/kg
  • a self-retaining retractor was placed prior to creating a small hole (0.5mm diameter) either with a drilling in the posterior part of the bulla.
  • the bulla bone was uncapped in a dorsal and caudal direction using a pair of jeweler's tip forceps.
  • the bone was removed in a piecemeal fashion under high magnification. Care was exercised not to puncture the stapedial artery, which lies directly beneath the bulla cap, as bleeding from this artery may compromise the procedure.
  • the amount of bone removed was kept to a minimum to prevent excessive fluid entry to the middle ear while still allowing excellent visualization and access to the round window niche.
  • the delivered agent was allowed to rest within the round window niche for up to 30 min.
  • the small hole was covered with muscular tissue and tissue glue.
  • the animals were administered the gel formulations transtympanically.
  • the needle was inserted at the front of the sternal ridge at 4-6 or slightly forward.
  • CSF was collected after euthanasia.
  • a 0.5 * 20 intravenous infusion needle was slowly lowered from 90° to the foramen magnum. The needle reached a distance of 4.5-5 mm under the skin, and 50-200 mI of clear tissue fluid were withdrawn.
  • TT is transtympanic administration
  • IT intratympanic administration
  • TT transtympanic administration
  • Cisplatin was diluted with 0.9% (w/v) saline to a final concentration of 5 mg/mL.
  • Albino guinea pigs (Hartley), body weight at 250-350 g were used in the study. After a minimal 3 days acclamation, 28 animals were enrolled into the study. Under aseptic condition, cisplatin was administered
  • ABR auditory brainstem responses
  • TDT RZ6 Multi-I/O processor TDT RZ6 Multi-I/O processor.
  • Historical ABR data were used to define a baseline.
  • the animals were anesthetized with tiletamine hydrochloride and zolazepam hydrochloride (Zoletil).
  • Acoustic stimuli were delivered via an earphone. Needle electrodes were placed near the ear canal at the causoventral position, the vertex of the skull, and a ground at the lower leg.
  • the stimulus level was from 10 to 90 dB in 5 dB steps, and the tone-pip frequencies were 4, 24, and 32 kHz.
  • the ceiling sound pressure level was 90 dB.
  • ABR threshold was observed by visual inspection of stacked waveforms as the lowest sound pressure level, at which the waveform was above the noise floor.
  • the threshold at 32 kHz in naive animals was 39.8 dB.
  • the range of normal hearing was defined as a mean ⁇ 2SD, 27.9 to 51 .6 dB.
  • Cisplatin primarily induces hearing loss at high frequencies.
  • a clear pattern of hearing loss after cisplatin is defined as a threshold of 60 dB and above at 32 kHz.
  • STS Composition An aqueous composition of 0.5M sodium thiosulfate / 2% (w/v) hyaluronan (STS Composition) or vehicle was dosed intratympanically onto the round window in the left ear (LE) as described above, and the right ear (RE) was left untreated in the guinea pigs (FIG. 12). 60 min after STS Composition or vehicle dosing, the animals were injected with cisplatin at 10 mg/kg intraperitoneally. ABR at 4, 24, and 32 kHz was measured in both ears 7 days after cisplatin administration.
  • the untreated right ears was used to select the animals with hearing loss. There were 21 animals with right ear threshold >60 dB at 32 kHz.
  • the STS Composition-treated ears had significantly lower thesholds at both 32 kHz and 24 KHz compared to the vehicle-treated ears and untreated right ears ( *** P ⁇ 0.001 , two way ANOVA).
  • the average thresholds in the STS Composition treated ears were 40 dB and 48 dB at 24 kHz and 32 kHz, respectively, in contrast to 69 dB and 80 dB in their contralateral untreated right ears.
  • the normal hearing thresholds were 35 dB and 40 dB at 24 kHz and at 32 kHz, respectively, in the the naive animals.
  • the untreated ears after cisplatin had an averange of 34 dB and 40 dB threshold elevation at 24 kHz and 32 kHz, respectively, but STS Composition treated ears only had 5 dB and 8 dB shift. Therefore, sodium thiosulfate provided, on average, 80% protection at both 24 kHz and 32 kHz.
  • Hyaluronan Gel 5 (0.1 M), Hyaluronan Gel 1 (0.5M), and Hyaluronan Gel 1 7 (1 M) was tested.
  • the untreated ears demonstrated significant threshold shifts compared to naive animals (gray shaded areas).
  • the groups treated with Hyaluronan Gel 1 (0.5M) and Hyaluronan Gel 17 (1 M) showed hearing protection compared to the untreated contralateral control ears at all tested frequencies. No protection was seen with the vehicle treated ears. The results are summarized in FIG. 13. OTHER EMBODIMENTS

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Abstract

La présente invention concerne des procédés d'otoprotection contre des agents antinéoplasiques à base de platine par administration d'un sel de thiosulfate à un sujet qui en a besoin. Typiquement, le sel de thiosulfate est administré au sujet programmé pour être administré à un agent antinéoplasique à base de platine dans les 4 heures. En variante, le sel de thiosulfate est administré dans les 7 heures après l'administration d'un agent néoplasique à base de platine.
PCT/US2020/035271 2019-05-31 2020-05-29 Procédés d'otoprotection contre des agents antinéoplasiques à base de platine WO2020243536A1 (fr)

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SG11202113053RA SG11202113053RA (en) 2019-05-31 2020-05-29 Methods of otoprotection against platinum-based antineoplastic agents
CA3142153A CA3142153A1 (fr) 2019-05-31 2020-05-29 Procedes d'otoprotection contre des agents antineoplasiques a base de platine
KR1020217042839A KR20220047217A (ko) 2019-05-31 2020-05-29 백금계 항신생물제에 대한 내이보호 방법
BR112021023684A BR112021023684A2 (pt) 2019-05-31 2020-05-29 Métodos de otoproteção contra agentes antineoplásticos à base de platina
CN202080043662.0A CN114302647A (zh) 2019-05-31 2020-05-29 针对基于铂的抗肿瘤剂的耳保护方法
AU2020284122A AU2020284122A1 (en) 2019-05-31 2020-05-29 Methods of otoprotection against platinum-based antineoplastic agents
MX2021014447A MX2021014447A (es) 2019-05-31 2020-05-29 Metodos de otoproteccion contra agentes antineoplasicos a base de platino.
EP20815470.8A EP3975722A4 (fr) 2019-05-31 2020-05-29 Procédés d'otoprotection contre des agents antinéoplasiques à base de platine
JP2021571025A JP2022534617A (ja) 2019-05-31 2020-05-29 白金ベースの抗腫瘍剤に対する耳毒性保護の方法
IL288532A IL288532A (en) 2019-05-31 2021-11-29 Methods of self-defense against platinum-based antiplastic agents

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US8784870B2 (en) * 2008-07-21 2014-07-22 Otonomy, Inc. Controlled release compositions for modulating free-radical induced damage and methods of use thereof
US8496973B2 (en) * 2009-07-08 2013-07-30 Hope Medical Enterprises, Inc. Sodium thiosulfate-containing pharmaceutical compositions
US10596190B2 (en) * 2017-11-29 2020-03-24 Oregon Health & Science University Method for reducing ototoxicity in pediatric patients receiving platinum-based chemotherapy
EP3986423A1 (fr) * 2019-06-19 2022-04-27 Stichting Het Nederlands Kanker Instituut- Antoni van Leeuwenhoek Ziekenhuis Gel de thiosulfate de sodium pour prévenir ou réduire la perte auditive

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ANONYMOUS: "SIOPEL 6 clinical trials. (NCT00652132)", CLINICALTRIALS.GOV, 11 December 2018 (2018-12-11), XP055762743, Retrieved from the Internet <URL:https://clinicaltrials.gov/ct2/show/NCT00652132> [retrieved on 20181211] *
MEYER ET AL.: "Randomized controlled trial to test the efficacy of transtympanic injection of a sodium thiosulfate gel to prevent cisplatin-induced ototoxicity", J. CLINICAL ONCOLOGY, vol. 35, no. 15, 2017, XP055872546 *
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