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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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• 2019
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