WO2020047113A1 - Traitement du neuroblastome avec des produits d'hydrolyse de taurolidine - Google Patents

Traitement du neuroblastome avec des produits d'hydrolyse de taurolidine Download PDF

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Publication number
WO2020047113A1
WO2020047113A1 PCT/US2019/048592 US2019048592W WO2020047113A1 WO 2020047113 A1 WO2020047113 A1 WO 2020047113A1 US 2019048592 W US2019048592 W US 2019048592W WO 2020047113 A1 WO2020047113 A1 WO 2020047113A1
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Prior art keywords
taurinamide
taurultam
composition
methylene glycol
neuroblastoma
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PCT/US2019/048592
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English (en)
Inventor
Bruce Reidenberg
Robert Diluccio
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Cormedix Inc.
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Priority to CN201980071416.3A priority Critical patent/CN113347976A/zh
Priority to AU2019330954A priority patent/AU2019330954A1/en
Priority to KR1020217008971A priority patent/KR20210050544A/ko
Priority to JP2021511544A priority patent/JP2021535163A/ja
Priority to CA3111057A priority patent/CA3111057A1/fr
Priority to EP19856239.9A priority patent/EP3843746A4/fr
Publication of WO2020047113A1 publication Critical patent/WO2020047113A1/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • This invention relates to therapeutic methods and compositions in general, and more particularly to therapeutic methods and compositions for the treatment of neuroblastoma in a juvenile mammalian body.
  • NB Neuroblastoma
  • neuroblastoma extracranial solid cancer in childhood and the most common cancer in infancy, with an incidence of about six hundred fifty cases per year in the U.S., and a hundred cases per year in the UK. Nearly half of neuroblastoma cases occur in children younger than two years. It is a neuroendocrine tumor, arising from any neural crest element of the sympathetic nervous system (SNS) . Neuroblastoma most frequently originates in one of the adrenal glands, but can also develop in nerve tissues in the neck, chest, abdomen, or pelvis. Note that while neuroblastoma arises from nerve tissues, it is not a tumor of the central nervous system ( CNS ) .
  • CNS central nervous system
  • Neuroblastoma is one of the few human
  • Neuroblastoma is a disease exhibiting extreme heterogeneity, and is stratified into three risk categories: low-risk, intermediate-risk, and high- risk. Low-risk neuroblastoma is most common in infants and good outcomes are common with observation only or surgery, whereas high-risk neuroblastoma is difficult to treat successfully even with the most intensive multi-modal therapies available.
  • neuroblastoma lesion When the neuroblastoma lesion is localized, it is generally curable. However, long-term survival for children older than 18 months of age with advanced disease of age is poor, despite aggressive multimodal therapy, e.g., intensive chemotherapy, surgery, radiation therapy, stem cell transplant,
  • differentiation agent isotrentinoin (also called 13- cis-retinoic acid) , and frequently immunotherapy with anti-GD2 immunotherapy with anti-GD2 monoclonal antibody therapy.
  • High-risk neuroblastoma is generally treated with intensive chemotherapy, surgery, radiation therapy, bone marrow/hematopoietic stem cell transplantation, biological-based therapy with 13-cis-retinoic acid (isotretinoin or Accutane) and antibody therapy
  • cytokines GM-CSF and IL-2. cytokines
  • Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell
  • transplant conditioning are platinum compounds
  • topoisomerase I inhibitors topotecan and irinotecan in induction which have been found to be effective against recurrent disease.
  • selected hydrolysis products of taurolidine are used to treat neuroblastoma.
  • the selected hydrolysis products of taurolidine may comprise at least one from the group consisting of:
  • taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam: 7 taurinamide : 1 methylene glycol.
  • the taurinamide is given with a dosage range of from 5 mg/kg to 280 mg/kg, with optimal range between 5 mg/kg and 60 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
  • the taurultam is given with a dosage range of from 5 mg/kg to 280 mg/kg, with optimal range between 5 mg/kg and 60 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
  • the methylene glycol is given with a dosage range of from 2.5 mg/kg to 160 mg/kg, with optimal range between 2.5 mg/kg and 30 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
  • the taurultam and taurinamide (in a ratio of 1 taurultam:7 taurinamide) is given with a dosage range of Taurultam from 5 mg/kg to 280 mg/kg, with optimal range between 5 mg/kg and 40 mg/kg, combined with Taurinamide from 5 mg/kg to 280 mg/kg, with optimal range from 35 mg/kg to 40 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
  • the taurultam, taurinamide and methylene glycol (in a ratio of 1 taurultam: 7 taurinamide : 1 methylene glycol) is given with a dosage range of Taurultam from 5 mg/kg to 280 mg/kg, with optimal range between 5 mg/kg and 40 mg/kg, combined with Taurinamide with a dosage range of from 5 mg/kg to 280 mg/kg, with optimal range from 35 mg/kg to 40 mg/kg, further combined with methylene glycol with a dosage range of from 2.5 mg/kg to 160 mg/kg, with optimal range from 5 mg/kg to 40 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
  • the selected hydrolysis products i.e., the active
  • ingredients can be delivered systemically in a
  • shielded form so that they can reach the site of the neuroblastoma without premature degradation.
  • the hydrolysis products can be delivered in the form of a nanoparticle, where the nanoparticle comprises a core of the hydrolysis product and an exterior coating which is configured to prevent premature exposure of the hydrolysis product prior to the arrival of the nanoparticle to the tumor site.
  • the exterior coating breaks down as the nanoparticle travels from the site of the insertion to the site of the tumor so as to release the hydrolysis product intact at the site of the tumor.
  • the coating comprises an absorbable polymer or lipid which breaks down as the nanoparticle travels from the site of insertion to the site of the tumor.
  • the hydrolysis products may be delivered using a polymer system which is configured to delay degradation of the active ingredient.
  • the hydrolysis products may be "pegylated" using
  • PEGs polyethylene glycols
  • the selected hydrolysis products of taurolidine can be given systemically, as either a single agent or in combination with other oncolytic agents and/or radiotherapy .
  • Fig. 1 is a graph showing that leukemia cell lines appear more sensitive to the effects of
  • taurolidine compared to healthy lymphocytes in vitro ( not in vivo ) ;
  • Fig. 2 is a graph showing that neuroblastoma cell lines are more sensitive to a decrease in viability due to taurolidine when compared to healthy
  • Figs. 3-6 are graphs or photographs showing that taurolidine given to CB57 SCID mice with measurable tumors from a neuroblastoma cell line implanted subcutaneously in the CB57 SCID mice has efficacy in IMR5 tumors and measurable efficacy in SK-N-AS tumors in vivo (not in vitro) ;
  • Figs. 7 and 8 are graphs showing that
  • Fig. 9 illustrates the mechanism for the
  • Fig. 10 is a chart showing the mean
  • Fig. 11 is a chart showing the mean
  • Taurolidine is a well known antimicrobial with a published mechanism of action and antimicrobial spectrum. Taurolidine is unstable in circulation and therefore has not been successfully developed for systemic infections. Taurolidine has demonstrated efficacy in local application for peritonitis and for prevention of infection when infused as a catheter- lock solution.
  • Taurolidine has recently been investigated for oncolytic activity and found to have inhibitory effect on cell lines in culture, in combination with standard chemotherapy or alone. Despite claims that in vitro inhibitory concentrations are clinically achievable, the only published human pharmacokinetic study showed NO measurable concentration of taurolidine in healthy volunteers when 5 grams of taurolidine were given intravenously by 20 minute infusion. This is believed to be due to the rapid hydrolysis of taurolidine when administered systemically in a mammalian body.
  • neuroblastoma cell lines are more sensitive to a decrease in viability due to taurolidine when compared to healthy
  • taurolidine given to CB57 SCID mice with measurable tumors from a neuroblastoma cell line implanted subcutaneously in the CB57 SCID mice showed efficacy in IMR5 tumors and measurable efficacy in SK-
  • N-AS tumors in vivo (not in vitro) . See Figs . 3-6.
  • neuroepithelioma cell line is below 50% cell
  • the IC50 values are between 80-140 microMolar for neuroblastoma cell lines, and 200 microMolar for normal fibroblasts (see Fig. 2) .
  • taurolidine metabolizes to taurolidine hydrolysis products in vivo, this would support the conclusion that the hydrolysis products of taurolidine may have significant anti-neoplastic activity against neuroblastoma cells. In fact, it may be that the hydrolysis products of taurolidine have higher
  • hydrolysis products of taurolidine may be used to treat neuroblastoma.
  • the mechanism for the hydrolysis of taurolidine is shown in Fig. 9.
  • the selected hydrolysis products of taurolidine that may be used to treat neuroblastoma may comprise at least one from the group consisting of:
  • taurinamide taurultum
  • taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam: 7 taurinamide : 1 methylene glycol.
  • the taurinamide is given with a dosage range of from 5 mg/kg to 280 mg/kg, with optimal range between 5 mg/kg and 60 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
  • the mean pharmacokinetic parameters of taurinamide are shown in Fig. 10.
  • the taurultam is given with a dosage range of from 5 mg/kg to 280 mg/kg, with optimal range between 5 mg/kg and 60 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
  • the mean pharmacokinetic parameters of taurultam are shown in Fig. 11.
  • the methylene glycol is given with a dosage range of from 2.5 mg/kg to 160 mg/kg, with optimal range between 2.5 mg/kg and 30 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
  • the taurultam and taurinamide (in a ratio of 1 taurultam:7 taurinamide) is given with a dosage range of Taurultam from 5 mg/kg to 280 mg/kg, with optimal range between 5 mg/kg and 40 mg/kg, combined with Taurinamide from 5 mg/kg to 280 mg/kg, with optimal range from 35 mg/kg to 40 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
  • the taurultam, taurinamide and methylene glycol (in a ratio of 1 taurultam: 7 taurinamide : 1 methylene glycol) is given with a dosage range of Taurultam from 5 mg/kg to 280 mg/kg, with optimal range between 5 mg/kg and 40 mg/kg, combined with Taurinamide with a dosage range of from 5 mg/kg to 280 mg/kg, with optimal range from 35 mg/kg to 40 mg/kg, further combined with methylene glycol with a dosage range from 2.5 mg/kg to 160 mg/kg, with optimal range from 5 mg/kg to 40 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
  • AUC 0-inf Taurultam/AUC 0-inf Taurinamide 42.9/312.7
  • the target ratio when giving Taurultam and Taurinamide in combination is 0.14 or 1:7.
  • the target ratio when giving taurultam and taurinamide and methylene glycol in combination is 1:7:1.
  • the selected hydrolysis products can be delivered systemically in a "shielded form" so that they can reach the site of the neuroblastoma to avoid premature degradation.
  • the hydrolysis products can be delivered in the form of a nanoparticle, where the nanoparticle comprises a core of the hydrolysis product and an exterior coating which is configured to prevent premature exposure of the hydrolysis product prior to the arrival of the nanoparticle to the tumor site.
  • the exterior coating breaks down as the nanoparticle travels from the site of insertion to the site of the tumor so as to release the hydrolysis product intact at the site of the tumor.
  • the coating comprises an absorbable polymer or lipid which breaks down as the nanoparticle travels from the site of insertion to the site of the tumor.
  • the coating can be created from combinations of copolymers and multimers derived from polymers structured from 1- lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate.
  • the coating may also be associated with glycols such as polyethylene glycols (PEGs), which can either be linear or multi-arm structures .
  • the nanoparticle may comprise an excipient (e.g., a buffer for providing enhanced hydrolytic stability of the hydrolysis product within the nanoparticle) .
  • an excipient e.g., a buffer for providing enhanced hydrolytic stability of the hydrolysis product within the nanoparticle
  • the nanoparticle can further comprise a coating, wherein the coating is configured to target the nanoparticle to the site of a neuroblastoma so as to improve the efficacy of the hydrolysis product for treatment of the neuroblastoma.
  • the coating comprises binding molecules which are configured to target delivery of the nanoparticle to specific tissue.
  • the coating for the nanoparticle comprises a monoclonal antibody against N-type calcium channels (e.g., an anti-N-type calcium channel exofacial Fab fragment) for causing the nanoparticle to bind to neural tissue (e.g., to a neuroblastoma tumor) .
  • the hydrolysis products may be delivered using a polymer system which is configured to delay degradation of the active ingredient and/or optimize the release properties of the active ingredient.
  • the hydrolysis products may be "pegylated” using polyethylene glycols (PEGs) to delay premature of degradation of the active ingredient and/or
  • the selected hydrolysis products of taurolidine can be given systemically, as either a single agent or in combination with other oncolytic agents and/or radiotherapy. Examples of oncolytic agents that can be combined with the hydrolysis products of

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Abstract

Le neuroblastome est une tumeur affectant principalement l'enfant. La norme de soins actuelle n'est pas curative, sauf dans le cas rare d'une lésion résécable chirurgicalement, bien que des taux de survie aient été enregistrés pour un neuroblastome à faible risque et à risque modéré. La taurolidine a été mise au point en tant qu'anti-infectieux, mais on a découvert qu'elle possédait une étonnante activité oncolytique sur des cultures cellulaires et à présent sur un modèle de cancer de rongeur. L'efficacité sur le modèle de cancer de rongeur est supérieure à l'efficacité sur une culture cellulaire. L'invention concerne l'utilisation de produits d'hydrolyse de la taurolidine (taurultam et/ou taurinamide et/ou méthylène glycol et/ou des combinaisons choisies de ceux-ci) pour le traitement du neuroblastome chez des mammifères juveniles.
PCT/US2019/048592 2018-08-28 2019-08-28 Traitement du neuroblastome avec des produits d'hydrolyse de taurolidine WO2020047113A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CN201980071416.3A CN113347976A (zh) 2018-08-28 2019-08-28 用牛磺罗定水解产物进行的神经母细胞瘤治疗
AU2019330954A AU2019330954A1 (en) 2018-08-28 2019-08-28 Neuroblastoma treatment with taurolidine hydrolysis products
KR1020217008971A KR20210050544A (ko) 2018-08-28 2019-08-28 타우로리딘 가수분해 생성물을 이용한 신경모세포종 치료
JP2021511544A JP2021535163A (ja) 2018-08-28 2019-08-28 タウロリジン加水分解産物による神経芽細胞腫治療
CA3111057A CA3111057A1 (fr) 2018-08-28 2019-08-28 Traitement du neuroblastome avec des produits d'hydrolyse de taurolidine
EP19856239.9A EP3843746A4 (fr) 2018-08-28 2019-08-28 Traitement du neuroblastome avec des produits d'hydrolyse de taurolidine

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US201862723618P 2018-08-28 2018-08-28
US62/723,618 2018-08-28

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AU (1) AU2019330954A1 (fr)
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CN116769723B (zh) * 2023-08-09 2023-11-03 山东省成体细胞产业技术研究院有限公司 一种gd2嵌合抗原受体修饰的t细胞及其应用

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US20130085469A1 (en) * 2004-02-03 2013-04-04 Hans-Dietrich Polaschegg Taurolidine formulations and delivery: therapeutic treatments and antimicrobial protection against bacterial biofilm formation
US20170196875A1 (en) * 2016-01-11 2017-07-13 Cormedix Inc. Therapeutic nanoparticles for the treatment of neuroblastoma and other cancers

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Title
BOYER, IVAN J.; HELDRETH, BART A.: "Formaldehyde and Methylene Glycol", FINAL AMENDED REPORT , 12 October 2011 (2011-10-12), pages 1 - 41, XP009527048, Retrieved from the Internet <URL:https://pdfs.semanticscholar.org/cbc1/edd6962434ce2361419a6a00849e9d1253c4.pdf> [retrieved on 20191015] *
KEVIN MARLEY;STUART C HELFAND;JENNIFER SIMPSON;JOHN E MATA;WILLIAM G TRACEWELL;LISA BROWNLEE;SHAY BRACHA;BERNARD SÉGUIN: "Pharmacokinetic study and evaluation of the safety of taurolidine for dogs with Osteosarcoma", JOURNAL OF EXPERIMENTAL AND CLINICAL CANCER RESEARCH, vol. 32, no. 74, 11 October 2013 (2013-10-11), pages 1 - 11, XP021165358, DOI: 10.1186/1756-9966-32-74 *
REIDENBERG BRUCE E.; WANNER CHRISTOPH; POLSKY BRUCE; CASTANHEIRA MARIANA; SHELIP ALLA; STALLEICKEN DIRK; PFAFFLE ANTONY E.: "Postmarketing experience with Neutrolin (taurolidine, heparin, calciumcitrate) catheter lock solution in hemodialysis patients", EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY AND INFECTIOUS DISEASES, vol. 37, no. 4, 6 December 2017 (2017-12-06), pages 661 - 663, XP036464612, ISSN: 0934-9723, DOI: 10.1007/s10096-017-3157-7 *
See also references of EP3843746A4 *

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CA3111057A1 (fr) 2020-02-05
EP3843746A4 (fr) 2022-10-19
JP2021535163A (ja) 2021-12-16
EP3843746A1 (fr) 2021-07-07
AU2019330954A1 (en) 2021-04-22
CN113347976A (zh) 2021-09-03

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