CA3111057A1 - Neuroblastoma treatment with taurolidine hydrolysis products - Google Patents
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- CA3111057A1 CA3111057A1 CA3111057A CA3111057A CA3111057A1 CA 3111057 A1 CA3111057 A1 CA 3111057A1 CA 3111057 A CA3111057 A CA 3111057A CA 3111057 A CA3111057 A CA 3111057A CA 3111057 A1 CA3111057 A1 CA 3111057A1
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—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)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
Abstract
Neuroblastoma is a tumor primarily affecting children. The current standard of care is not curative except in the rare case of a surgically- resectable lesion, although very high survival rates have been documented for low-risk neuroblastoma and moderate-risk neuroblastoma. Taurolidine was developed as an anti-infective, but it has been found to have surprising oncolytic activity in cell cultures and now in a rodent cancer model. The efficacy in rodent model is superior to the efficacy in cell culture. This invention relates to the use of taurolidine hydrolysis products (tarultam and/or taurinamide and/or methylene glycol and/or selected combinations thereof) for the treatment of neuroblastoma in juvenile mammals.
Description
NEUROBLASTOMA TREATMENT WITH TAUROLIDINE HYDROLYSIS
PRODUCTS
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
PROV
PRODUCTS
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
PROV
2 TREATMENT OF NEUROBLASTOMA (Attorney's Docket No.
CORMEDIX-14 PROV); and (ii) claims benefit of pending prior U.S.
Provisional Patent Application Serial No. 62/723,618, filed 08/28/2018 by Cormedix Inc. and Bruce Reidenberg et al. for NEUROBLASTOMA TREATMENT WITH TAUROLIDINE
HYDROLYSIS PRODUCTS (Attorney's Docket No. CORMEDIX-33 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 neuroblastoma in a juvenile mammalian body.
Background Of The Invention Neuroblastoma (NB) is the most common extracranial solid cancer in childhood and the most
CORMEDIX-14 PROV); and (ii) claims benefit of pending prior U.S.
Provisional Patent Application Serial No. 62/723,618, filed 08/28/2018 by Cormedix Inc. and Bruce Reidenberg et al. for NEUROBLASTOMA TREATMENT WITH TAUROLIDINE
HYDROLYSIS PRODUCTS (Attorney's Docket No. CORMEDIX-33 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 neuroblastoma in a juvenile mammalian body.
Background Of The Invention Neuroblastoma (NB) is the most common extracranial solid cancer in childhood and the most
3 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).
Neuroblastoma is one of the few human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular appearance.
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
Note that while neuroblastoma arises from nerve tissues, it is not a tumor of the central nervous system (CNS).
Neuroblastoma is one of the few human malignancies known to demonstrate spontaneous regression from an undifferentiated state to a completely benign cellular appearance.
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
4 only or surgery, whereas high-risk neuroblastoma is difficult to treat successfully even with the most intensive multi-modal therapies available.
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.
Biologic and genetic characteristics have been identified which, when added to classic clinical staging, has allowed patient assignment to risk groups for planning treatment intensity. These criteria include age of the patient, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc oncogene amplification (N-myc regulate micro RNAs). These criteria are used to classify the neuroblastoma into low-risk, intermediate-risk, and high-risk disease. A recent biology study (COG ANBLOOB1) analyzed 2,687 neuroblastoma patients and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low-risk, 18% of neuroblastoma cases are intermediate-risk, and 45% of neuroblastoma cases are high-risk. Note that there is some evidence that the high- and low-risk types of neuroblastoma are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.
The therapies for these different risk categories are very different.
Low-risk neuroblastoma can frequently be observed without any treatments at all or cured with surgery alone.
Intermediate-risk neuroblastoma is generally treated with surgery and chemotherapy.
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 (usually administered with the cytokines GM-CSF and IL-2. cytokines).
With current treatments, patients with low-risk neuroblastoma and intermediate-risk neuroblastoma have an excellent prognosis, with cure rates above 90% for low-risk neuroblastoma and 70-90% cure rates for intermediate-risk neuroblastoma. In contrast, therapy for high-risk neuroblastoma over the past two decades has resulted in cures only about 30% of the time. The addition of antibody therapy has raised survival rates for high-risk neuroblastoma significantly. In March 2009, an early analysis of a Children's Oncology Group (COG) study with 226 high-risk neuroblastoma patients showed that two years after stem cell transplant 66%
of the group randomized to receive ch14.18 antibody with GM-CSF and IL-2 were alive and disease-free compared to only 46% in the group that did not receive the antibody. The randomization was stopped so all patients enrolling in the trial could receive the antibody therapy.
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 (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan, topoisomerase II inhibitor) and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in induction which have been found to be effective against recurrent disease.
However, a need exists for a new method and composition which are effective against neuroblastoma.
Summary Of The Invention In accordance with the present invention, 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:
taurinamide;
taurultam;
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 taurinamide is given with a dosage range of from 5 mg/kg to 280 mg/kg, with optimal range between 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
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.
Biologic and genetic characteristics have been identified which, when added to classic clinical staging, has allowed patient assignment to risk groups for planning treatment intensity. These criteria include age of the patient, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc oncogene amplification (N-myc regulate micro RNAs). These criteria are used to classify the neuroblastoma into low-risk, intermediate-risk, and high-risk disease. A recent biology study (COG ANBLOOB1) analyzed 2,687 neuroblastoma patients and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low-risk, 18% of neuroblastoma cases are intermediate-risk, and 45% of neuroblastoma cases are high-risk. Note that there is some evidence that the high- and low-risk types of neuroblastoma are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.
The therapies for these different risk categories are very different.
Low-risk neuroblastoma can frequently be observed without any treatments at all or cured with surgery alone.
Intermediate-risk neuroblastoma is generally treated with surgery and chemotherapy.
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 (usually administered with the cytokines GM-CSF and IL-2. cytokines).
With current treatments, patients with low-risk neuroblastoma and intermediate-risk neuroblastoma have an excellent prognosis, with cure rates above 90% for low-risk neuroblastoma and 70-90% cure rates for intermediate-risk neuroblastoma. In contrast, therapy for high-risk neuroblastoma over the past two decades has resulted in cures only about 30% of the time. The addition of antibody therapy has raised survival rates for high-risk neuroblastoma significantly. In March 2009, an early analysis of a Children's Oncology Group (COG) study with 226 high-risk neuroblastoma patients showed that two years after stem cell transplant 66%
of the group randomized to receive ch14.18 antibody with GM-CSF and IL-2 were alive and disease-free compared to only 46% in the group that did not receive the antibody. The randomization was stopped so all patients enrolling in the trial could receive the antibody therapy.
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 (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan, topoisomerase II inhibitor) and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in induction which have been found to be effective against recurrent disease.
However, a need exists for a new method and composition which are effective against neuroblastoma.
Summary Of The Invention In accordance with the present invention, 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:
taurinamide;
taurultam;
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 taurinamide is given with a dosage range of from 5 mg/kg to 280 mg/kg, with optimal range between 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 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.
In one preferred form of the invention, 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.
More particularly, in one preferred form of the invention, 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. 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.
In another form of the invention, the hydrolysis products may be delivered using a polymer system which is configured to delay degradation of the active ingredient. By way of example but not limitation, the hydrolysis products may be "pegylated" using polyethylene glycols (PEGs) to delay premature of degradation of the active ingredient.
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.
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 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 from neuroblastoma but overall survival was not significantly different from control;
Fig. 9 illustrates the mechanism for the hydrolysis of taurolidine;
Fig. 10 is a chart showing the mean pharmacokinetic parameters of taurinamide; and Fig. 11 is a chart showing the mean pharmacokinetic parameters of taurultam.
Detailed Description Of The Invention 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.
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 efficacy in IMR5 tumors and measurable efficacy in SK-N-AS tumors in vivo (not in vitro). See Figs. 3-6.
Note that the in vitro efficacy for neuroblastoma cell lines is seen at the highest two concentrations tested, i.e., above 40 microMolar [1 Mole/Liter x 284 gm/Mole x 1Mole/1,000,000 microMoles x 40 microMolar x 1000 mg/gram = 11 mg/ liter = 11 mcg/mL], as seen in Fig. 2 (where only the SK-N-MC cell line, a neuroepithelioma cell line, is below 50% cell viability). The IC50 values are between 80-140 microMolar for neuroblastoma cell lines, and 200 microMolar for normal fibroblasts (see Fig. 2).
The efficacy observed with taurolidine treatment of IMR5 cell implants in vivo (Figs. 3-6), despite IRM5's relatively high IC50 in vitro (Fig. 2), supports the conclusion that the hydrolysis products of taurolidine may have independent anti-neoplastic activity. In other words, taurolidine treatment of neuroblastoma cells in vivo appears to be significantly more effective than taurolidine treatment of neuroblastoma cells in vitro. Since it is known that 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 efficacy against neuroblastoma cells than taurolidine which has not been hydrolyzed.
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 from neuroblastoma, though overall survival of the mice implanted with the tumor was not statistically different from the control. See Figs. 7 and 8.
It has now been discovered that selected 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;
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 taurinamide is given with a dosage range of from 5 mg/kg to 280 mg/kg, with optimal range between 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 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.
Dose selection for the hydrolysis products 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 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/ucm0789 32.pdf).
In one preferred form of the invention, the selected hydrolysis products (active ingredient) can be delivered systemically in a "shielded form" so that they can reach the site of the neuroblastoma to avoid premature degradation.
More particularly, in one preferred form of the invention, 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. 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 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 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 neuroblastoma so as to improve the efficacy of the hydrolysis product for treatment of the neuroblastoma.
In one preferred form of the invention, the coating comprises binding molecules which are configured to target delivery of the nanoparticle to specific tissue. By way of example but not limitation, 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).
In another form of the invention, 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. By way of example but not limitation, the hydrolysis products may be "pegylated"
using polyethylene glycols (PEGs) to delay premature of degradation of the active ingredient and/or optimize the release properties of the active ingredient.
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 taurolidine for systemic 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.
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 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.
In one preferred form of the invention, 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.
More particularly, in one preferred form of the invention, 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. 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.
In another form of the invention, the hydrolysis products may be delivered using a polymer system which is configured to delay degradation of the active ingredient. By way of example but not limitation, the hydrolysis products may be "pegylated" using polyethylene glycols (PEGs) to delay premature of degradation of the active ingredient.
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.
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 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 from neuroblastoma but overall survival was not significantly different from control;
Fig. 9 illustrates the mechanism for the hydrolysis of taurolidine;
Fig. 10 is a chart showing the mean pharmacokinetic parameters of taurinamide; and Fig. 11 is a chart showing the mean pharmacokinetic parameters of taurultam.
Detailed Description Of The Invention 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.
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 efficacy in IMR5 tumors and measurable efficacy in SK-N-AS tumors in vivo (not in vitro). See Figs. 3-6.
Note that the in vitro efficacy for neuroblastoma cell lines is seen at the highest two concentrations tested, i.e., above 40 microMolar [1 Mole/Liter x 284 gm/Mole x 1Mole/1,000,000 microMoles x 40 microMolar x 1000 mg/gram = 11 mg/ liter = 11 mcg/mL], as seen in Fig. 2 (where only the SK-N-MC cell line, a neuroepithelioma cell line, is below 50% cell viability). The IC50 values are between 80-140 microMolar for neuroblastoma cell lines, and 200 microMolar for normal fibroblasts (see Fig. 2).
The efficacy observed with taurolidine treatment of IMR5 cell implants in vivo (Figs. 3-6), despite IRM5's relatively high IC50 in vitro (Fig. 2), supports the conclusion that the hydrolysis products of taurolidine may have independent anti-neoplastic activity. In other words, taurolidine treatment of neuroblastoma cells in vivo appears to be significantly more effective than taurolidine treatment of neuroblastoma cells in vitro. Since it is known that 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 efficacy against neuroblastoma cells than taurolidine which has not been hydrolyzed.
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 from neuroblastoma, though overall survival of the mice implanted with the tumor was not statistically different from the control. See Figs. 7 and 8.
It has now been discovered that selected 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;
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 taurinamide is given with a dosage range of from 5 mg/kg to 280 mg/kg, with optimal range between 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 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.
Dose selection for the hydrolysis products 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 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/ucm0789 32.pdf).
In one preferred form of the invention, the selected hydrolysis products (active ingredient) can be delivered systemically in a "shielded form" so that they can reach the site of the neuroblastoma to avoid premature degradation.
More particularly, in one preferred form of the invention, 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. 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 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 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 neuroblastoma so as to improve the efficacy of the hydrolysis product for treatment of the neuroblastoma.
In one preferred form of the invention, the coating comprises binding molecules which are configured to target delivery of the nanoparticle to specific tissue. By way of example but not limitation, 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).
In another form of the invention, 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. By way of example but not limitation, the hydrolysis products may be "pegylated"
using polyethylene glycols (PEGs) to delay premature of degradation of the active ingredient and/or optimize the release properties of the active ingredient.
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 taurolidine for systemic 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.
Claims (27)
1. A method for treating neuroblastoma, the method comprising:
administering a composition to a patient, wherein the composition consists of at least one from the group consisting of:
taurinamide;
taurultam;
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.
administering a composition to a patient, wherein the composition consists of at least one from the group consisting of:
taurinamide;
taurultam;
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 consists of taurinamide.
3. A method according to claim 2 wherein the dose 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 dose range is optimally 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 consists of taurultam.
7. A method according to claim 6 wherein the dose 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.
8. A method according to claim 7 wherein the dose range is optimally 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 consists of methylene glycol.
11. A method according to claim 10 wherein the dose 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.
12. A method according to claim 11 wherein the dose range is optimally 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.
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 taurultam and taurinamide in a ratio of 1 taurultam:7 taurinamide.
15. A method according to claim 14 wherein 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.
16. A method according to claim 14 wherein the composition is administered in conjunction with an oncolytic agent and/or radiotherapy.
17. 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.
18. A method according to claim 17 wherein 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 a dosage range of Taurinamide 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.
19. A method according to claim 17 wherein the composition is administered in conjunction with an oncolytic agent and/or radiotherapy.
20. 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.
21. A method according to claim 1 wherein the composition is included in a nanoparticle, and further wherein the nanoparticle is configured to delay hydrolysis of the composition until the nanoparticle reaches the site of a tumor.
22. A method according to claim 21 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.
23. A method according to claim 22 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.
24. A method according to claim 1 wherein the composition is delivered using a polymer system which is configured to delay hydrolysis of the composition.
25. A method according to claim 24 wherein the composition is "pegylated" using polyethylene glycols (PEGs) to delay premature of hydrolysis of the composition.
26. A method according to claim 1 wherein the composition comprises at least two from the group consisting of taurinamide, taurultam and methylene glycol.
27. A method according to claim 1 wherein the composition comprises all three from the group consisting of taurinamide, taurultam and methylene glycol.
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| US62/723,618 | 2018-08-28 | ||
| PCT/US2019/048592 WO2020047113A1 (en) | 2018-08-28 | 2019-08-28 | Neuroblastoma treatment with taurolidine hydrolysis products |
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| KR (1) | KR20210050544A (en) |
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| AU (1) | AU2019330954A1 (en) |
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Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5602150A (en) * | 1992-10-02 | 1997-02-11 | Research Foundation For Mental Hygiene, Inc. | Treatment of central nervous system disorders associated with psychotic behavior and dementia with a combination of neuroleptic drugs and taurine, or derivatives thereof, to prevent the development of tardive dyskinesia |
| US20050096314A1 (en) * | 2001-04-03 | 2005-05-05 | Ed. Geistlich Soehne Ag Fuer Chemische Industrie | Treatment of cancers with methylol-containing compounds and at least one electrolyte |
| JP2003515558A (en) * | 1999-12-06 | 2003-05-07 | ロード アイランド ホスピタル， ア ライフスパン パートナー | Use of a methylol-containing compound to treat a tumor |
| JP2007537200A (en) * | 2004-05-14 | 2007-12-20 | ハンス−ディートリヒ・ポラシェグ | Taurolidine formulation and administration: therapeutic treatment and antibacterial protection against bacterial microfilm formation |
| EP3402527B1 (en) * | 2016-01-11 | 2022-09-28 | CorMedix Inc. | Therapeutic nanoparticles for the treatment of neuroblastoma and other cancers |
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