WO2020047530A1 - Taurolidine treatment for myc-expressing tumors in mammalian bodies - Google Patents

Taurolidine treatment for myc-expressing tumors in mammalian bodies Download PDF

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Publication number
WO2020047530A1
WO2020047530A1 PCT/US2019/049266 US2019049266W WO2020047530A1 WO 2020047530 A1 WO2020047530 A1 WO 2020047530A1 US 2019049266 W US2019049266 W US 2019049266W WO 2020047530 A1 WO2020047530 A1 WO 2020047530A1
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Prior art keywords
composition
taurinamide
taurultam
dosage range
taurolidine
Prior art date
Application number
PCT/US2019/049266
Other languages
French (fr)
Inventor
Bruce Reidenberg
Robert Diluccio
Original Assignee
Cormedix Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cormedix Inc. filed Critical Cormedix Inc.
Priority to AU2019331913A priority Critical patent/AU2019331913A1/en
Priority to EP19854097.3A priority patent/EP3843747A4/en
Priority to KR1020217009412A priority patent/KR20210054544A/en
Priority to JP2021511591A priority patent/JP2021535167A/en
Priority to CA3111100A priority patent/CA3111100A1/en
Priority to CN201980072806.2A priority patent/CN113226325A/en
Publication of WO2020047530A1 publication Critical patent/WO2020047530A1/en

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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
    • 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
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • 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
    • 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 MYC-expressing tumors in mammalian bodies.
  • Taurolidine is a well known antimicrobial with a published mechanism of action and antimicrobial
  • 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 used as a catheter-lock solution .
  • Taurolidine has recently been investigated for oncolytic activity and found to have an 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
  • MYC oncogenes have been widely described in solid tumors and in lymphoma/ leukemia .
  • CORMEDIX-35 Taurolidine has demonstrated efficacy in treating neuroblastoma in a laboratory cell line. This cell line is known to overexpress N-myc genes.
  • Taurolidine has demonstrated efficacy in treating ovarian cancer in a human ovarian cell tumor line implanted in mice. This cell line is known to overexpress C-myc genes.
  • Taurolidine has demonstrated efficacy in treating lung cancer in a laboratory cell line. This cell line is known to overexpress L-myc genes.
  • taurolidine and/or the hydrolysis products of taurolidine, is/are used to treat tumors that
  • N-myc genes overexpress N-myc genes, C-myc genes and/or L-myc genes in mammalian bodies.
  • tumors that may overexpress N-myc genes, C-myc genes and/or L-myc
  • CORMEDIX-35 genes include, but are not limited to, lymphoma, melanoma, multiple myeloma, neuroblastoma, colon, breast and lung cancers.
  • the preferred 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 taurolidine 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
  • 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 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 with a dosage range of 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.
  • 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 taurolidine, and/or the hydrolysis products of taurolidine can be given systemically, preferably intramuscularly or intravenously.
  • the taurolidine, and/or the hydrolysis products of taurolidine is/are delivered systemically in a
  • taurolidine or the hydrolysis products of taurolidine, can reach the site of the tumor without premature degradation, whereupon
  • taurolidine can treat the tumor.
  • the taurolidine and/or the hydrolysis products of taurolidine can be delivered in the form of a nanoparticle, where the nanoparticle comprises a core of the taurolidine and/or the hydrolysis products of taurolidine and an exterior coating which is configured to prevent premature exposure of the taurolidine and/or the hydrolysis products of
  • 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 taurolidine and/or the hydrolysis products of taurolidine 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 taurolidine and/or the hydrolysis products of taurolidine may be delivered using a polymer system which is configured to delay premature degradation of the active ingredient.
  • the taurolidine and/or the hydrolysis products of taurolidine may be "pegylated” using polyethylene glycols (PEGs) to delay premature degradation of the active ingredient.
  • taurolidine, and/or the hydrolysis products of taurolidine may be delivered 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 is a chart showing the effect of delayed administration of a single 3-day i.p.
  • taurolidine (20 mg/mouse/in ection) on the occurrence of i.p. human tumor xenografts in female nude mice after the i.p. administration of 5 x 10 6 SKOV-3 human ovarian tumor cells;
  • Fig. 10 illustrates the mechanism for the hydrolysis of taurolidine
  • Fig. 11 is a chart showing the mean
  • Fig. 12 is a chart showing the mean
  • Taurolidine was developed as an anti-infective, but has been found to have oncolytic activity against neuroblastoma tumors in a laboratory cell line. This laboratory cell line is known to overexpress N-myc
  • taurolidine has been found to have surprising oncolytic activity in cell cultures of human cancer cells expressing N-myc, and now in a rodent cancer model based on an N-myc expressing human cancer cell line.
  • 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 dramatic efficacy in IMR5 tumors and measurable efficacy in SK-N-AS tumors in vivo (not in vitro) .
  • CORMEDIX-35 treat mice with a different cell line (SK-N-AS) also derived from neuroblastoma, though overall survival of the mice implanted with the tumor was not
  • Taurolidine has also demonstrated efficacy in treating ovarian cancer in a human ovarian cell tumor line implanted in mice.
  • This cell line is known to overexpress C-myc genes.
  • Fig. 9 shows the effect of delayed administration of a single 3-day i.p. ( intraperitoneal ) bolus injection regimen of taurolidine (20 mg/mouse/in ection) on the occurrence of i.p. human tumor xenografts in female nude mice after the i.p. administration of 5 x 10 6 SKOV-3 human ovarian tumor cells.
  • taurolidine therapy was initiated on the day of tumor cell
  • mice in all of the groups were sacrificed, and the peritoneal cavity was examined for the presence of tumors.
  • CORMEDIX-35 number of animals in each group ranged from 15-21 (Cancer Res., 2001 Sep 15; 61 ( 18 ) : 6816-21 ,
  • Taurolidine cytotoxic and mechanistic evaluation of a novel antineoplastic agent, Calabresi Pi, Goulette FA, Darnowski JW) .
  • Taurolidine has also demonstrated efficacy in treating lung cancer in a laboratory cell line.
  • This cell line is known to overexpress L-myc genes.
  • taurolidine is/are used to treat tumors that
  • N-myc genes overexpress N-myc genes, C-myc genes and/or L-myc genes in mammalian bodies.
  • tumors that may overexpress N-myc genes, C-myc genes and/or L-myc genes include, but are not limited to, lymphoma, melanoma, multiple myeloma, neuroblastoma, colon, breast and lung cancers.
  • Fig. 10 The mechanism for the hydrolysis of taurolidine is shown in Fig. 10.
  • the preferred hydrolysis products of taurolidine that may be used to treat tumors that overexpress N-myc genes, C-myc genes
  • CORMEDIX-35 and/or L-myc genes in mammalian bodies may comprise at least one from the group consisting of:
  • taurultam 7 taurinamide
  • taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam: 7 taurinamide : 1 methylene glycol.
  • the taurolidine 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 mean pharmacokinetic parameters of taurultam are shown in Fig. 11.
  • 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. 12.
  • 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 with a dosage range of 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.
  • CORMEDIX-35 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, from once daily through weekly, 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.
  • 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. And the target ratio when giving
  • CORMEDIX-35 taurultam and taurinamide and methylene glycol in combination is 1:7:1.
  • the taurolidine, and/or the hydrolysis products of taurolidine can be given systemically, preferably intramuscularly or intravenously.
  • taurolidine is/are delivered systemically in a
  • taurolidine can treat the tumor.
  • the taurolidine, and/or the hydrolysis products of taurolidine is/are delivered in the form of a nanoparticle, where the nanoparticle comprises a core comprising taurolidine and/or the hydrolysis products of taurolidine, and an exterior coating which is configured to prevent premature exposure of the taurolidine, and/or the hydrolysis products of
  • 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
  • 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
  • the coating may also be associated with glycols such as polyethylene glycols (PEGs), which can either be linear or multi-arm structures.
  • PEGs polyethylene glycols
  • the nanoparticle may comprise an excipient (e.g., a buffer for providing enhanced hydrolytic stability of the taurolidine and/or
  • the nanoparticle can further comprise a coating, wherein the coating is configured to target the nanoparticle to the site of a tumor so as to improve the efficacy of the taurolidine and/or hydrolysis product for treatment of the tumor.
  • the coating comprises binding molecules which are configured to target delivery of the nanoparticle to specific tissue .
  • taurolidine may be delivered using a polymer system which is configured to delay premature degradation of the taurolidine, and/or the hydrolysis products of taurolidine, and/or to optimize the release properties of the taurolidine, and/or the hydrolysis products of taurolidine.
  • the taurolidine, and/or the hydrolysis products of taurolidine may be "pegylated” using polyethylene glycols (PEGs) to delay premature degradation of the taurolidine, and/or the hydrolysis products of
  • taurolidine and/or to optimize the release properties of the taurolidine, and/or the hydrolysis products of taurolidine .
  • the taurolidine (and/or the hydrolysis products of taurolidine) may be delivered as either a single agent or in combination with other oncolytic agents and/or radiotherapy.
  • oncolytic agents that can be combined with taurolidine and/or the hydrolysis products of taurolidine for systemic
  • CORMEDIX-35 delivery are platinum compounds (cisplatin,
  • alkylating agents cyclophosphamide, ifosfamide, melphalan, topoisomerase II inhibitor
  • vinca alkaloids vincristine
  • topoisomerase I inhibitors topotecan and irinotecan

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Abstract

A method for treating a cancer which overexpresses any of N-myc genes, C-myc genes and/or L-myc genes in a mammalian body, the method comprising : administering a composition to the mammalian body, wherein the composition comprises at least one from the group consisting of taurolidine; taurultam; taurinamide; methylene glycol; taurultam and taurinamide in a ratio of 1 taurultam:7 taurinamide; and taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam:7 taurinamide:1 methylene glycol.

Description

TAUROLIDINE TREATMENT FOR MYC-EXPRESSING TUMORS IN
MAMMALIAN BODIES
Applicant
CorMedix Inc.
Inventors
Bruce Reidenberg
Robert DiLuccio
Reference To Pending Prior Patent Applications
This patent application:
(i) is a continuation-in-part of pending prior U.S. Patent Application Serial No. 15/403,876, filed 01/11/2017 by CorMedix Inc. and Robert DiLuccio for THERAPEUTIC NANOPARTICLES FOR THE TREATMENT OF NEUROBLASTOMA AND OTHER CANCERS (Attorney's Docket No. CORMEDIX-14 ) , which patent application claims benefit of prior U.S. Provisional Patent Application Serial No. 62/277,243, filed 01/11/2016 by CorMedix Inc. and Robert DiLuccio for NANOPARTICLE SYSTEM FOR THE
CORMEDIX-35 TREATMENT OF NEUROBLASTOMA (Attorney's Docket No.
CORMEDIX-14 PROV) ; and
(ii) claims benefit of pending prior U.S.
Provisional Patent Application Serial No. 62/725,650, filed 08/31/2018 by CorMedix Inc. and Bruce Reidenberg et al. for TAUROLIDINE TREATMENT FOR MYC-EXPRESSING TUMORS IN MAMMALIAN BODIES (Attorney's Docket No.
CORMEDIX-35 PROV) .
The three (3) above-identified patent
applications are hereby incorporated herein by
reference .
Field Of The Invention
This invention relates to therapeutic methods and compositions in general, and more particularly to therapeutic methods and compositions for the treatment of MYC-expressing tumors in mammalian bodies.
Background Of The Invention
Taurolidine is a well known antimicrobial with a published mechanism of action and antimicrobial
CORMEDIX-35 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 used as a catheter-lock solution .
Taurolidine has recently been investigated for oncolytic activity and found to have an 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.
MYC oncogenes have been widely described in solid tumors and in lymphoma/ leukemia .
CORMEDIX-35 Taurolidine has demonstrated efficacy in treating neuroblastoma in a laboratory cell line. This cell line is known to overexpress N-myc genes.
Taurolidine has demonstrated efficacy in treating ovarian cancer in a human ovarian cell tumor line implanted in mice. This cell line is known to overexpress C-myc genes.
Taurolidine has demonstrated efficacy in treating lung cancer in a laboratory cell line. This cell line is known to overexpress L-myc genes.
A need exists for a new method and composition which are effective against MYC-expressing tumors in mammalian bodies.
Summary Of The Invention
In accordance with the present invention, taurolidine, and/or the hydrolysis products of taurolidine, is/are used to treat tumors that
overexpress N-myc genes, C-myc genes and/or L-myc genes in mammalian bodies. Examples of tumors that may overexpress N-myc genes, C-myc genes and/or L-myc
CORMEDIX-35 genes include, but are not limited to, lymphoma, melanoma, multiple myeloma, neuroblastoma, colon, breast and lung cancers.
The preferred hydrolysis products of taurolidine may comprise at least one from the group consisting of :
taurultam;
taurinamide ;
methylene glycol;
taurultam and taurinamide in a ratio of 1
taurultam:7 taurinamide; and
taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam: 7 taurinamide : 1 methylene glycol.
The taurolidine 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
CORMEDIX-35 for an effective period of time based on individual patient response.
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 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 with a dosage range of 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.
CORMEDIX-35 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 taurolidine, and/or the hydrolysis products of taurolidine, can be given systemically, preferably intramuscularly or intravenously.
In one preferred form of the invention, the taurolidine, and/or the hydrolysis products of taurolidine, is/are delivered systemically in a
"shielded form" so that the taurolidine, or the hydrolysis products of taurolidine, can reach the site of the tumor without premature degradation, whereupon
CORMEDIX-35 the taurolidine, or the hydrolysis products of
taurolidine, can treat the tumor.
More particularly, in one preferred form of the invention, the taurolidine and/or the hydrolysis products of taurolidine can be delivered in the form of a nanoparticle, where the nanoparticle comprises a core of the taurolidine and/or the hydrolysis products of taurolidine and an exterior coating which is configured to prevent premature exposure of the taurolidine and/or the hydrolysis products of
taurolidine 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 taurolidine and/or the hydrolysis products of taurolidine intact at the site of the tumor. In one preferred form of the invention, 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.
CORMEDIX-35 In another form of the invention, the taurolidine and/or the hydrolysis products of taurolidine (i.e., the active ingredient) may be delivered using a polymer system which is configured to delay premature degradation of the active ingredient. By way of example but not limitation, the taurolidine and/or the hydrolysis products of taurolidine may be "pegylated" using polyethylene glycols (PEGs) to delay premature degradation of the active ingredient.
The taurolidine, and/or the hydrolysis products of taurolidine, may be delivered as either a single agent or in combination with other oncolytic agents and/or radiotherapy.
Brief Description Of The Drawings
These and other objects and features of the present invention will be more fully disclosed or rendered obvious by the following detailed description of the preferred embodiments of the invention, which is to be considered together with the accompanying
CORMEDIX-35 drawings wherein like numbers refer to like parts, and further wherein:
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
fibroblasts (BJ on graph) in vitro (not in vivo);
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
statistically significant decreases in tumor size were achieved when taurolidine was administered to treat mice with a different cell line (SK-N-AS) also derived
CORMEDIX-35 from neuroblastoma but overall survival was not significantly different from control;
Fig. 9 is a chart showing the effect of delayed administration of a single 3-day i.p.
( intraperitoneal ) bolus injection regimen of
taurolidine (20 mg/mouse/in ection) on the occurrence of i.p. human tumor xenografts in female nude mice after the i.p. administration of 5 x 106 SKOV-3 human ovarian tumor cells;
Fig. 10 illustrates the mechanism for the hydrolysis of taurolidine;
Fig. 11 is a chart showing the mean
pharmacokinetic parameters of taurultam; and
Fig. 12 is a chart showing the mean
pharmacokinetic parameters of taurinamide.
Detailed Description Of The Invention
Taurolidine was developed as an anti-infective, but has been found to have oncolytic activity against neuroblastoma tumors in a laboratory cell line. This laboratory cell line is known to overexpress N-myc
CORMEDIX-35 genes. More particularly, taurolidine has been found to have surprising oncolytic activity in cell cultures of human cancer cells expressing N-myc, and now in a rodent cancer model based on an N-myc expressing human cancer cell line.
It has been found that leukemia cell lines appear more sensitive to the effects of taurolidine compared to healthy lymphocytes in vitro (not in vivo) . See Fig. 1.
It has also been found that neuroblastoma cell lines are more sensitive to a decrease in viability due to taurolidine when compared to healthy
fibroblasts in vitro (not in vivo) . See Fig. 2.
Furthermore, taurolidine given to CB57 SCID mice with measurable tumors from a neuroblastoma cell line implanted subcutaneously in the CB57 SCID mice showed dramatic efficacy in IMR5 tumors and measurable efficacy in SK-N-AS tumors in vivo (not in vitro) .
See Figs . 3-6.
Statistically significant decreases in tumor size were achieved when taurolidine was administered to
CORMEDIX-35 treat mice with a different cell line (SK-N-AS) also derived from neuroblastoma, though overall survival of the mice implanted with the tumor was not
statistically different from the control. See Figs. 7 and 8.
Taurolidine has also demonstrated efficacy in treating ovarian cancer in a human ovarian cell tumor line implanted in mice. This cell line is known to overexpress C-myc genes. See Fig. 9 which shows the effect of delayed administration of a single 3-day i.p. ( intraperitoneal ) bolus injection regimen of taurolidine (20 mg/mouse/in ection) on the occurrence of i.p. human tumor xenografts in female nude mice after the i.p. administration of 5 x 106 SKOV-3 human ovarian tumor cells. In this study, taurolidine therapy was initiated on the day of tumor cell
inoculation or up to 5 days thereafter. Fourteen days after the final taurolidine injection, mice in all of the groups were sacrificed, and the peritoneal cavity was examined for the presence of tumors. Each
experiment was repeated three times, and the pooled
CORMEDIX-35 number of animals in each group ranged from 15-21 (Cancer Res., 2001 Sep 15; 61 ( 18 ) : 6816-21 ,
Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic agent, Calabresi Pi, Goulette FA, Darnowski JW) .
And Taurolidine has also demonstrated efficacy in treating lung cancer in a laboratory cell line. This cell line is known to overexpress L-myc genes.
In accordance with the present invention, taurolidine, and/or the hydrolysis products of
taurolidine, is/are used to treat tumors that
overexpress N-myc genes, C-myc genes and/or L-myc genes in mammalian bodies. Examples of tumors that may overexpress N-myc genes, C-myc genes and/or L-myc genes include, but are not limited to, lymphoma, melanoma, multiple myeloma, neuroblastoma, colon, breast and lung cancers.
The mechanism for the hydrolysis of taurolidine is shown in Fig. 10. The preferred hydrolysis products of taurolidine that may be used to treat tumors that overexpress N-myc genes, C-myc genes
CORMEDIX-35 and/or L-myc genes in mammalian bodies may comprise at least one from the group consisting of:
taurultam;
taurinamide ;
methylene glycol;
taurultam and taurinamide in a ratio of 1
taurultam: 7 taurinamide; and
taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam: 7 taurinamide : 1 methylene glycol.
The taurolidine 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 mean pharmacokinetic parameters of taurultam are shown in Fig. 11.
CORMEDIX-35 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. 12.
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 with a dosage range of 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:! methylene
CORMEDIX-35 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, from once daily through weekly, 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.
Dose selection for the hydrolysis products of taurolidine were calculated as follows:
AUC 0-inf Taurultam/AUC 0-inf Taurinamide = 42.9/312.7
= 0.14.
Since the molecular weight difference is only a single methyl group, the use of weight-based AUC does not need to be corrected. Therefore the target ratio when giving taurultam and taurinamide in combination is 0.14 or 1:7. And the target ratio when giving
CORMEDIX-35 taurultam and taurinamide and methylene glycol in combination is 1:7:1.
Effective dosage was computed by computing the human equivalent dosage from the effective mouse dose using the formula:
[Human equivalent dose = mouse mg/kg dose x 1 adult human/12 mice x 25 child BSA ratio/37 adult BSA ratio = child dose in mg/kg
( https : / /www . fda . gov/downloads /drugs /guidances /ucmO 789 32.pdf) ] .
The taurolidine, and/or the hydrolysis products of taurolidine, can be given systemically, preferably intramuscularly or intravenously.
In one preferred form of the invention, the taurolidine, and/or the hydrolysis products of
taurolidine, is/are delivered systemically in a
"shielded form" so that the taurolidine, or the hydrolysis products of taurolidine, can reach the site
CORMEDIX-35 of the tumor without premature degradation, whereupon the taurolidine, or the hydrolysis products of
taurolidine, can treat the tumor.
More particularly, in one preferred form of the invention, the taurolidine, and/or the hydrolysis products of taurolidine, is/are delivered in the form of a nanoparticle, where the nanoparticle comprises a core comprising taurolidine and/or the hydrolysis products of taurolidine, and an exterior coating which is configured to prevent premature exposure of the taurolidine, and/or the hydrolysis products of
taurolidine, 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
taurolidine, and/or the hydrolysis products of
taurolidine, intact at the site of the tumor. In one preferred form of the invention, 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. By way of example but not
CORMEDIX-35 limitation, 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.
If desired, the nanoparticle may comprise an excipient (e.g., a buffer for providing enhanced hydrolytic stability of the taurolidine and/or
hydrolysis product within the nanoparticle) .
Additionally, if desired, the nanoparticle can further comprise a coating, wherein the coating is configured to target the nanoparticle to the site of a tumor so as to improve the efficacy of the taurolidine and/or hydrolysis product for treatment of the tumor. In one preferred form of the invention, the coating comprises binding molecules which are configured to target delivery of the nanoparticle to specific tissue .
CORMEDIX-35 In another form of the invention, the
taurolidine, and/or the hydrolysis products of
taurolidine, may be delivered using a polymer system which is configured to delay premature degradation of the taurolidine, and/or the hydrolysis products of taurolidine, and/or to optimize the release properties of the taurolidine, and/or the hydrolysis products of taurolidine. By way of example but not limitation, the taurolidine, and/or the hydrolysis products of taurolidine, may be "pegylated" using polyethylene glycols (PEGs) to delay premature degradation of the taurolidine, and/or the hydrolysis products of
taurolidine, and/or to optimize the release properties of the taurolidine, and/or the hydrolysis products of taurolidine .
The taurolidine (and/or the hydrolysis products of taurolidine) may be delivered as either a single agent or in combination with other oncolytic agents and/or radiotherapy. Examples of oncolytic agents that can be combined with taurolidine and/or the hydrolysis products of taurolidine for systemic
CORMEDIX-35 delivery are platinum compounds (cisplatin,
carboplatin) , alkylating agents (cyclophosphamide, ifosfamide, melphalan, topoisomerase II inhibitor), vinca alkaloids (vincristine), and topoisomerase I inhibitors (topotecan and irinotecan) .
Modifications
While the present invention has been described in terms of certain exemplary preferred embodiments, it will be readily understood and appreciated by those skilled in the art that it is not so limited, and that many additions, deletions and modifications may be made to the preferred embodiments discussed above while remaining within the scope of the present invention .
CORMEDIX-35

Claims

What Is Claimed Is:
1. A method for treating a cancer which
overexpresses any of N-myc genes, C-myc genes and/or L-myc genes in a mammalian body, the method
comprising :
administering a composition to the mammalian body, wherein the composition comprises at least one from the group consisting of:
taurolidine ;
taurultam;
taurinamide ;
methylene glycol;
taurultam and taurinamide in a ratio of 1
taurultam:7 taurinamide; and
taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam: 7 taurinamide : 1 methylene glycol.
2. A method according to claim 1 wherein the composition comprises taurolidine.
CORMEDIX-35
3. A method according to claim 2 wherein the dosage range is from 5 mg/kg to 280 mg/kg from once daily through weekly, for an effective period of time based on individual patient response.
4. A method according to claim 3 wherein the dosage range is from between 5 mg/kg and 60 mg/kg from once daily through weekly, for an effective period of time based on individual patient response.
5. A method according to claim 2 wherein the composition is administered in conjunction with an oncolytic agent and/or radiotherapy.
6. A method according to claim 1 wherein the composition comprises taurultam.
7. A method according to claim 6 wherein the dosage range is from 5 mg/kg to 280 mg/kg from once daily through weekly, for an effective period of time based on individual patient response.
CORMEDIX-35
8. A method according to claim 7 wherein the dosage range is from between 5 mg/kg and 60 mg/kg from once daily through weekly, for an effective period of time based on individual patient response.
9. A method according to claim 6 wherein the composition is administered in conjunction with an oncolytic agent and/or radiotherapy.
10. A method according to claim 1 wherein the composition comprises taurinamide.
11. A method according to claim 10 wherein the dosage range is from 5 mg/kg to 280 mg/kg from once daily through weekly, for an effective period of time based on individual patient response.
12. A method according to claim 11 wherein the dosage range is from between 5 mg/kg and 60 mg/kg from
CORMEDIX-35 once daily through weekly, for an effective period of time based on individual patient response.
13. A method according to claim 10 wherein the composition is administered in conjunction with an oncolytic agent and/or radiotherapy.
14. A method according to claim 1 wherein the composition consists of methylene glycol.
15. A method according to claim 14 wherein the dosage range is from 2.5 mg/kg to 160 mg/kg from once daily through weekly, for an effective period of time based on individual patient response.
16. A method according to claim 15 wherein the dosage range is from 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.
CORMEDIX-35
17. A method according to claim 14 wherein the composition is administered in conjunction with an oncolytic agent and/or radiotherapy.
18. A method according to claim 1 wherein the composition consists of taurultam and taurinamide in a ratio of 1 taurultam: 7 taurinamide.
19. A method according to claim 18 wherein the dosage range for taurultam is from 5 mg/kg to 280 mg/kg, combined with taurinamide with a dosage range of from 5 mg/kg to 280 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
20. A method according to claim 19 wherein the dosage range for taurultam is from 5 mg/kg to 40 mg/kg, combined with taurinamide with a dosage range of from 35 mg/kg to 40 mg/kg, from once daily through weekly, for an effective period of time based on individual patient response.
CORMEDIX-35
21. A method according to claim 18 wherein the composition is administered in conjunction with an oncolytic agent.
22. A method according to claim 1 wherein the composition consists of taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam: 7
taurinamide : 1 methylene glycol.
23. A method according to claim 22 wherein the dosage range for taurultam is from 5 mg/kg to 280 mg/kg, combined with taurinamide with a dosage range of from 5 mg/kg to 280 mg/kg, combined with methylene glycol with a dosage range of from 2.5 mg/kg to 160 mg/kg, from once daily through weekly, for an
effective period of time based on individual patient response .
24. A method according to claim 23 wherein the dosage range for taurultam is optimally from 5 mg/kg
CORMEDIX-35 to 40 mg/kg, combined with taurinamide with a dosage range of from 35 mg/kg to 40 mg/kg, combined with methylene glycol with a dosage range of from 5 mg/kg to 40, from once daily through weekly, for an
effective period of time based on individual patient response .
25. A method according to claim 22 wherein the composition is administered in conjunction with an oncolytic agent and/or radiotherapy.
26. A method according to claim 1 wherein the composition is delivered to the patient using one from the group consisting of parenteral delivery,
intramuscular delivery and intravenous delivery.
27. A method according to claim 1 wherein the composition is included in a nanoparticle, and further wherein the nanoparticle is configured to delay exposure of the composition until the nanoparticle reaches the site of a tumor.
CORMEDIX-35
28. A method according to claim 27 wherein the nanoparticle comprises a core of the composition and an exterior coating, wherein the exterior coating is configured to prevent exposure of the composition prior to arrival of the nanoparticle at the site of the tumor .
29. A method according to claim 28 wherein the exterior 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.
30. A method according to claim 1 wherein the composition is delivered using a polymer system which is configured to delay premature degradation of the composition .
31. A method according to claim 30 wherein the composition is "pegylated" using polyethylene glycols
CORMEDIX-35 (PEGs) to delay premature degradation of the composition .
CORMEDIX-35
PCT/US2019/049266 2018-08-31 2019-09-03 Taurolidine treatment for myc-expressing tumors in mammalian bodies WO2020047530A1 (en)

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KR1020217009412A KR20210054544A (en) 2018-08-31 2019-09-03 Taurolidine Treatment for MYC-expressing Tumors in Mammalian Body
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CA3111100A CA3111100A1 (en) 2018-08-31 2019-09-03 Taurolidine treatment for myc-expressing tumors in mammalian bodies
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5593665A (en) * 1990-03-15 1997-01-14 Ed Geistlich S ohne AG f ur Chemische Industrie Pharmaceutical compositions
US20020091123A1 (en) * 1998-07-31 2002-07-11 Redmond H. Paul Use of taurolidine and/or taurultam for treatment of abdominal cancer and/or for the prevention of metastases
US20050119254A1 (en) * 2003-09-29 2005-06-02 Ed. Geistlich Soehne Ag Treatment of mesothelioma
WO2007020509A1 (en) * 2005-08-15 2007-02-22 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Combination of methylol transfer agents with tumour-inhibiting proteins or peptides and the use thereof for the treatment of cancer or tumor growth
US20130089606A1 (en) * 2010-06-01 2013-04-11 Geistlich Pharma Ag Methods and compositions for oral pharmaceutical therapy
US20170196875A1 (en) * 2016-01-11 2017-07-13 Cormedix Inc. Therapeutic nanoparticles for the treatment of neuroblastoma and other cancers

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60030770T2 (en) * 1999-12-06 2007-09-06 Rhode Island Hospital USE OF TAUROLIDINE OR TAURULTAM FOR THE PREPARATION OF A MEDICAMENT FOR THE TREATMENT OF OVARIAN CARCINOMES
CN100519525C (en) * 1999-12-06 2009-07-29 葛兰素集团有限公司 Aromatic sulfones and their medical use
US20080171738A1 (en) * 2001-04-03 2008-07-17 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Treatment of Breast Cancer
WO2007077528A1 (en) * 2006-01-06 2007-07-12 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Irradiated compositions and treatment of cancers with radiation in combination with taurolidine and/or taurultam
JP6933659B2 (en) * 2016-03-18 2021-09-08 ガイストリッヒ・ファルマ・アーゲーＧｅｉｓｔｌｉｃｈ Ｐｈａｒｍａ Ａｇ How to treat triple-negative breast cancer

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5593665A (en) * 1990-03-15 1997-01-14 Ed Geistlich S ohne AG f ur Chemische Industrie Pharmaceutical compositions
US20020091123A1 (en) * 1998-07-31 2002-07-11 Redmond H. Paul Use of taurolidine and/or taurultam for treatment of abdominal cancer and/or for the prevention of metastases
US20050119254A1 (en) * 2003-09-29 2005-06-02 Ed. Geistlich Soehne Ag Treatment of mesothelioma
WO2007020509A1 (en) * 2005-08-15 2007-02-22 Ed. Geistlich Soehne Ag Fuer Chemische Industrie Combination of methylol transfer agents with tumour-inhibiting proteins or peptides and the use thereof for the treatment of cancer or tumor growth
US20130089606A1 (en) * 2010-06-01 2013-04-11 Geistlich Pharma Ag Methods and compositions for oral pharmaceutical therapy
US20170196875A1 (en) * 2016-01-11 2017-07-13 Cormedix Inc. Therapeutic nanoparticles for the treatment of neuroblastoma and other cancers

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