KR20210054544A - Taurolidine Treatment for MYC-expressing Tumors in Mammalian Body - Google Patents

Abstract

A method of treating cancer that overexpresses any N-myc gene, C-myc gene and/or L-myc gene in a mammalian body, the method comprising: taurolidin; Taurultam; Taurinamide; Methylene glycol; Taurultam and taurinamide in a ratio of taurultam 1: taurinamide 7; And, it comprises the step of administering a composition, comprising at least one from the group consisting of taurultam, taurinamide and methylene glycol in a ratio of taurultam 1: taurinamide 7: methylene glycol 1.

Description

Taurolidine Treatment for MYC-expressing Tumors in Mammalian Body

Applicant

Cormedix, Inc.

inventor

Bruce Reidenberg

Robert DiLuccio

References to pending prior patent applications

This patent application is:

(i) Prior pending U.S. patent applications filed on January 11, 2017 by Cormedix, Inc. and DiLucio Roberts for'therapeutic nanoparticles for the treatment of neuroblastoma and other cancers' 15/403,876 (Agency Control No. CORMEDIX-14) as part of the continuing application (CIP), which was submitted by Cormedix, Inc. and DiLucio Roberts to the'Nanoparticle System for the Treatment of Neuroblastoma'. Claiming an interest in prior U.S. Provisional Patent Application No. 62/277,243 (Agent Control Number CORMEDIX-14 PROV) filed on January 11, 2016;

(ii) Cormedix, Inc., Leidenberg Bruce et al. filed a pending prior U.S. provisional patent application on August 31, 2018 for'tauroridine treatment for MYC-expressing tumors in mammals' Claims an interest in No. 62/725,650 (Agent Control Number CORMEDIX-35 PROV).

The three patent applications are incorporated herein by reference.

Field of invention

The present invention relates generally to therapeutic methods and compositions, and more particularly to therapeutic methods and compositions for treating MYC-expressing tumors in mammalian bodies.

Background of the invention

Tauroridine is a well-known antibacterial agent whose mechanism of action and antimicrobial spectrum have been published. Tauroridine is unstable in circulation and has not been successfully developed for systemic infections. Tauroridine has proven efficacy in preventing infection when used topically for peritonitis and as a catheter-locking solution.

Tauroridine has recently been investigated for oncolytic activity and has been shown to have an inhibitory effect on cell lines in culture, either alone or in combination with standard chemotherapy. Despite claims that in vitro inhibitory concentrations are clinically achievable, the only published human pharmacokinetic study found measurable concentrations of tauroridine in healthy volunteers when 5 g of taurolidine was given intravenously as a 20-minute injection. It turns out to be absent. This is believed to be due to the rapid hydrolysis of tauroridine when administered systemically into the mammalian body.

The MYC oncogene has been widely described in solid tumors and lymphoma/leukemia.

Tauroridine has been demonstrated to be effective in treating neuroblastoma in laboratory cell lines. This cell line is known to overexpress the N-myc gene.

Tauroridine has been demonstrated to be effective in treating ovarian cancer in human ovarian cell tumor lines transplanted into mice. This cell line is known to overexpress the C-myc gene.

Tauroridine has been demonstrated to be effective in treating lung cancer in laboratory cell lines. This cell line is known to overexpress the L-myc gene.

There is a need for new methods and compositions that are effective against MYC-expressing tumors in the mammalian body.

According to the present invention, taurolidine and/or the hydrolysis product of taurolidine is used in the mammalian body to treat tumors that overexpress the N-myc gene, the C-myc gene and/or the L-myc gene. Examples of tumors capable of overexpressing the N-myc gene, C-myc gene and/or L-myc gene include, but are not limited to, lymphoma, melanoma, multiple myeloma, neuroblastoma, colon cancer, breast cancer and lung cancer. Includes.

Preferred hydrolysis products of tauroridine may comprise at least one from the group consisting of:

Taurultam;

Taurinamide;

Methylene glycol;

Taurultam and taurinamide in a ratio of taurultam 1: taurinamide 7; And

Taurultam, taurinamide and methylene glycol in a ratio of taurultam 1: taurinamide 7: methylene glycol 1.

Tauroridine is based on individual patient responses from once daily to weekly for the effective period, in the dosage range 5 mg/kg to 280 mg/kg, optimal range 5 mg/kg to 60 mg/kg. Is provided.

Taurinamide is given in a dose range of 5 mg/kg to 280 mg/kg, optimal range of 5 mg/kg to 60 mg/kg, from once daily to weekly for the effective period based on individual patient response.

Taurultam is given in a dose range of 5 mg/kg to 280 mg/kg and an optimal range of 5 mg/kg to 60 mg/kg, from once daily to weekly for the effective period based on individual patient response.

Methylene glycol is given in a dosage range of 2.5 mg/kg to 160 mg/kg, optimal range of 2.5 mg/kg to 30 mg/kg, from once daily to weekly for the effective period based on individual patient response.

Taurultam and taurinamide (ratio of taurultam 1: taurinamide 7) are based on individual patient responses, from once daily to weekly for the expiration date, in the dosage range of taurinamide from 5 mg/kg to 280 mg/kg , In combination with an optimal range of 35 mg/kg to 40 mg/kg, a dosage range of taurultam is provided in the range of 5 mg/kg to 280 mg/kg, and an optimal range of 5 mg/kg to 40 mg/kg.

The taurultam, taurinamide, and methylene glycol (the ratio of taurultam 1: taurinamide 7: methylene glycol 1) are based on individual patient responses, from once a day to a weekly basis during the expiration date, and the dosage range of taurinamide 5 Mg/kg to 280 mg/kg, in combination with the optimal range 35 mg/kg to 40 mg/kg, and further with methylene glycol 2.5 mg/kg to 160 mg/kg, the optimal range 5 mg/kg to 40 mg/kg In combination, a dosage range of taurultam is provided in the range of 5 mg/kg to 280 mg/kg, and in the optimal range of 5 mg/kg to 40 mg/kg.

Taurolidine and/or the hydrolysis product of taurolidine may be provided systemically, preferably intramuscularly or intravenously.

In one preferred form of the present invention, the hydrolysis product of taurolidine and/or taurolidine is a "masked form" so that the hydrolysis product of taurolidine or taurolidine can reach the tumor site without premature degradation. ", so that taurolidine or the hydrolysis product of taurolidine can treat tumors.

More specifically, in one preferred form of the present invention, the hydrolysis product of taurolidine and/or taurolidine can be delivered in the form of nanoparticles, wherein the nanoparticles are A core of degradation products and an outer coating configured to prevent premature exposure of taurolidine and/or hydrolysis products of taurolidine prior to nanoparticles reaching the tumor site. The outer coating is degraded as the nanoparticles migrate from the insertion site to the tumor site, releasing taurolidine and/or the hydrolysis products of tauroridine intact at the tumor site. In one preferred form of the invention, the coating comprises an absorbable polymer or lipid that degrades as the nanoparticles migrate from the site of insertion to the site of the tumor.

In another form of the invention, taurolidine and/or the hydrolysis product of taurolidine (i.e., the active ingredient) can be delivered using a polymer system configured to delay premature degradation of the active ingredient. As a non-limiting example, taurolidine and/or the hydrolysis product of taurolidine may be "pegylated" with polyethylene glycol (PEG) to delay the premature degradation of the active ingredient.

Taurolidine and/or the hydrolysis product of taurolidine can be delivered as a single agent or in combination with other oncolytic agents and/or radiotherapy.

These and other objects and features of the present invention will be more fully disclosed or made apparent by the following detailed description of a preferred embodiment of the present invention considered in conjunction with the accompanying drawings, like numbers refer to like parts, and further here:
1 is a graph showing that leukemia cell lines are more sensitive to the effect 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 reduced viability due to tauroridine when compared to healthy fibroblasts (BJ on the figure) in vitro (not in vivo);
Figures 3 to 6 show that taurolidine provided to CB57 SCID mice with measurable tumors from neuroblastoma cell lines implanted subcutaneously in CB57 SCID mice shows efficacy in IMR5 tumors and in vivo (not in vitro) SK-N-AS Are graphs or photographs showing measurable efficacy in tumors;
7 and 8 show that when tauroridine was administered to treat mice with another cell line derived from neuroblastoma (SK-N-AS), a statistically significant reduction in tumor size was achieved, but overall survival was significantly compared with that of the control group. It is a graph showing no difference;
FIG. 9 is a view of taurolidine (20 mg/mouse/injection) for the development of ip human tumor xenografts in female nude mice after ip administration ^{of 5×10 6 SKOV-3 human ovarian tumor cells.} Chart showing the delayed dosing effect of a single 3 day ip (intraperitoneal) bolus injection regimen.
Figure 10 shows the mechanism for the hydrolysis of tauroridine;
11 is a chart showing the average pharmacokinetic parameters of taurultam;
12 is a chart showing the average pharmacokinetic parameters of taurinamide.

Detailed description of the invention

Tauroridine has been developed as an anti-infective agent, but has been shown to have oncolytic activity against neuroblastoma tumors in laboratory cell lines. This laboratory cell line is known to overexpress the N-myc gene. More specifically, taurolidin has been found to have surprising oncolytic activity in cell cultures of human cancer cells expressing N-myc and in rodent cancer models based on human cancer cell lines currently expressing N-myc.

Leukemia cell lines have been found to be more sensitive to the effects of tauroridine compared to healthy lymphocytes in vitro (not in vivo). See Figure 1.

It has also been found that neuroblastoma cell lines are more sensitive to reduced viability due to tauroridine when compared to healthy fibroblasts in vitro (not in vivo). See Figure 2.

In addition, tauroridine given to CB57 SCID mice with measurable tumors from neuroblastoma cell lines implanted subcutaneously in CB57 SCID mice showed dramatic efficacy in IMR5 tumors and in vivo (not in vitro) SK-N-AS It showed measurable efficacy in tumors. See Figures 3 to 6.

When tauroridine was also administered to treat mice with another cell line derived from neuroblastoma (SK-N-AS), the overall survival rate of tumor-transplanted mice was not statistically different from that of the control group, but statistically in tumor size. Significant reduction was achieved. See Figures 7 and 8.

Tauroridine has also been demonstrated to be effective in treating ovarian cancer in human ovarian cell tumor lines implanted in mice. This cell line is known to overexpress the C-myc gene. A single 3-day ip (intraperitoneal) of tauroridine (20 mg/mouse/injection) for the development of ip human tumor xenografts in female nude mice after ip administration of 5 x 10 ^{6 SKOV-3 human ovarian tumor cells} See FIG. 9 showing the delayed dosing effect of my) bolus injection regimen. In this study, taurolidine therapy was initiated on the day of tumor cell inoculation or until 5 days thereafter. 14 days after the last tauroridine injection, mice from all groups were sacrificed and the presence of tumors in the peritoneal cavity was examined. Each experiment was repeated three times, and the number of animals pooled in each group ranged from 15 to 21 (Cancer Res., 2001 Sep 15; 61 (18): 6816-21, Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic). agent, Calabresi P1, Goulette FA, Darnowski JW).

In addition, tauroridine has been demonstrated to be effective in treating lung cancer in laboratory cell lines. This cell line is known to overexpress the L-myc gene.

According to the present invention, taurolidine and/or the hydrolysis product of taurolidine is used in the mammalian body to treat tumors that overexpress the N-myc gene, the C-myc gene and/or the L-myc gene. Examples of tumors capable of overexpressing the N-myc gene, C-myc gene and/or L-myc gene include, but are not limited to, lymphoma, melanoma, multiple myeloma, neuroblastoma, colon cancer, breast cancer and lung cancer. Includes.

The mechanism of hydrolysis of tauroridine is shown in Figure 10. Preferred hydrolysis products of tauroridine that can be used to treat tumors that overexpress the N-myc gene, C-myc gene and/or L-myc gene in the mammalian body may include one or more from the group consisting of have:

Taurultam;

Taurinamide;

Methylene glycol;

Taurultam and taurinamide in a ratio of taurultam 1: taurinamide 7; And

Taurultam, taurinamide and methylene glycol in a ratio of taurultam 1: taurinamide 7: methylene glycol 1.

Tauroridine is given in a dose range of 5 mg/kg to 280 mg/kg, optimal range of 5 mg/kg to 60 mg/kg, from once daily to weekly for the effective period based on individual patient response.

Taurultam is given in a dose range of 5 mg/kg to 280 mg/kg, optimal range of 5 mg/kg to 60 mg/kg, from once daily to weekly for the effective period based on individual patient response. The average pharmacokinetic parameters of taurultam are shown in Figure 11.

Taurinamide is given in a dose range of 5 mg/kg to 280 mg/kg, optimal range of 5 mg/kg to 60 mg/kg, from once daily to weekly for the effective period based on individual patient response. The average pharmacokinetic parameters of taurinamide are shown in Figure 12.

Methylene glycol is given in a dosage range of 2.5 mg/kg to 160 mg/kg, optimal range of 2.5 mg/kg to 30 mg/kg, from once daily to weekly for the effective period based on individual patient response.

Taurultam and taurinamide (ratio of taurultam 1: taurinamide 7) are based on individual patient responses, from once daily to weekly for the expiration date, in the dosage range of taurinamide from 5 mg/kg to 280 mg/kg , In combination with an optimal range of 35 mg/kg to 40 mg/kg, a dosage range of taurultam is provided in the range of 5 mg/kg to 280 mg/kg, and an optimal range of 5 mg/kg to 40 mg/kg.

Taurultam, taurinamide and methylene glycol (ratio of taurultam 1: taurinamide 7: methylene glycol 1) are based on individual patient responses, ranging from once daily to weekly for the expiration date, the dosage range of taurinamide 5 mg /Kg to 280 mg/kg, in combination with the optimal range 35 mg/kg to 40 mg/kg, and the dosage range of methylene glycol 2.5 mg/kg to 160 mg/kg, the optimal range 5 mg/kg to 40 mg/kg In further combination with, taurultam is provided in a dosage range of 5 mg/kg to 280 mg/kg, and an optimal range of 5 mg/kg to 40 mg/kg.

The dose selection for the hydrolysis product was calculated as follows.

AUC 0-inf taurultam/ AUC 0-inf taurinamide = 42.9/312.7 = 0.14.

Since the molecular weight difference is only in a single methyl group, the use of weight-based AUC does not need to be corrected. Therefore, when providing a combination of taurultam and taurinamide, the target ratio is 0.14 or 1:7. And the target ratio when taurultam, taurinamide, and methylene glycol are used in combination is 1:7:1.

The effective dose was calculated by calculating the human equivalent dose from the effective mouse dose using the following formula.

[Human equivalent dose = mouse mg/kg dose x 1 adult human/12 mice x 25 children BSA ratio/37 adults BSA ratio = children dose in mg/kg (https://www.fda.gov/downloads) /drugs/guidances)/ucmO78932.pdf)].

Taurolidine and/or the hydrolysis product of taurolidine may be provided systemically, preferably intramuscularly or intravenously.

In one preferred form of the present invention, the hydrolysis product of taurolidine and/or taurolidine is delivered systemically in a "shielded form", so that the hydrolysis product of taurolidine and/or taurolidine is prematurely degraded. The tumor site can be reached without it, so that taurolidine and/or the hydrolysis product of taurolidine can treat the tumor.

More particularly, in one preferred form of the present invention, the hydrolysis product of taurolidine and/or taurolidine is delivered in the form of nanoparticles, and the nanoparticles are the hydrolysis product of taurolidine and/or taurolidine. And an outer coating configured to prevent premature exposure of taurolidine and/or a hydrolysis product of taurolidine until the nanoparticles reach the tumor site. The outer coating is degraded as the nanoparticles migrate from the insertion site to the tumor site, so that taurolidine and/or the hydrolysis products of tauroridine at the tumor site are released intact. In one preferred form of the invention, the coating comprises an absorbable polymer or lipid that degrades when the nanoparticles migrate from the site of insertion to the site of the tumor. As a non-limiting example, the coating can be produced from a combination of copolymers and multimers derived from polymers structured from 1-lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate. . The coating can also be associated with a glycol, such as polyethylene glycol (PEG), which can be of a linear or multi-arm structure.

If desired, the nanoparticles may contain excipients (eg, a buffer to provide improved hydrolytic stability of taurolidine and/or hydrolysis products in the nanoparticles).

Additionally, if desired, the nanoparticles may further comprise a coating, wherein the coating is configured to target the nanoparticles to the tumor site to improve the efficacy of taurolidine and/or hydrolysis products for tumor treatment. do. In one preferred form of the invention, the coating comprises a binding molecule configured to target the delivery of the nanoparticles to a specific tissue.

In another form of the present invention, the hydrolysis product of taurolidine and/or taurolidine delays the premature decomposition of taurolidine and/or the hydrolysis product of taurolidine, and/or, taurolidine and/or Alternatively, it may be delivered using a polymer system configured to optimize the release properties of the hydrolysis product of taurolidine. By way of example and not limitation, the hydrolysis product of taurolidine and/or taurolidine is “pegylated” with polyethylene glycol (PEG) to prematurely degrade taurolidine and/or the hydrolysis product of taurolidine. Decomposition can be delayed and/or the release properties of taurolidine and/or the hydrolysis products of taurolidine can be optimized.

Tauroridine (and/or the hydrolysis product of taurolidine) can be delivered systemically as 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 hydrolysis products of taurolidine for systemic delivery include platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan). , Topoisomerase II inhibitors), vinca alkaloids (vincristine), and topoisomerase I inhibitors (topotecan and irinotecan).

transform

Although the present invention has been described with respect to certain preferred embodiments, those skilled in the art will not limit the invention to this, and while including within the scope of the present invention, many additions, deletions, and additions to the preferred embodiments described above. It will be easy to understand and recognize that transformation can be made.

Claims (31)

As a method of treating cancer that overexpresses the N-myc gene, the C-myc gene and/or the L-myc gene in a mammalian body,
The method comprises administering the composition into the mammalian body,
The composition,
Tauroridine;
Taurultam;
Taurinamide;
Methylene glycol;
Taurultam and taurinamide in a 7 ratio of taurultam 1: taurinamide; And
Taurutam 1: Taurinamide 7: Methylene glycol 1 ratio of taurutam, taurinamide and methylene glycol
The method comprising at least one from the group consisting of. The method of claim 1,
Wherein the composition comprises tauroridine. The method of claim 2,
The method, wherein the dosage range is from 5 mg/kg to 280 mg/kg from once daily to weekly for the effective period based on individual patient response. The method of claim 3,
The method, wherein the dosage range is from 5 mg/kg to 60 mg/kg from once a day to weekly units for an effective period based on individual patient responses. The method of claim 2,
The method, wherein the composition is administered in combination with an oncolytic agent and/or radiotherapy. The method of claim 1,
Wherein the composition comprises taurultam. The method of claim 6,
The method, wherein the dosage range is from 5 mg/kg to 280 mg/kg from once daily to weekly for the effective period based on individual patient response. The method of claim 7,
The method, wherein the dosage range is from 5 mg/kg to 60 mg/kg from once a day to weekly units for an effective period based on individual patient responses. The method of claim 6,
The method, wherein the composition is administered in combination with an oncolytic agent and/or radiotherapy. The method of claim 1,
Wherein the composition comprises taurinamide. The method of claim 10,
The method, wherein the dosage range is from 5 mg/kg to 280 mg/kg from once daily to weekly for the effective period based on individual patient response. The method of claim 11,
The method, wherein the dosage range is optimally from 5 mg/kg to 60 mg/kg from once a day to weekly units for an effective period based on individual patient response. The method of claim 10,
The method, wherein the composition is administered in combination with an oncolytic agent and/or radiotherapy. The method of claim 1,
The method, wherein the composition is made of methylene glycol. The method of claim 14,
The method, wherein the dosage range is from 2.5 mg/kg to 160 mg/kg from once daily to weekly for the period of validity based on individual patient response. The method of claim 15,
The method, wherein the dosage range is from 2.5 mg/kg to 30 mg/kg from once daily to weekly for the effective period based on individual patient response. The method of claim 14,
The method, wherein the composition is administered in combination with an oncolytic agent and/or radiotherapy. The method of claim 1,
The method of claim 1, wherein the composition is composed of taurultam and taurinamide in a ratio of taurultam 1: taurinamide 7. The method of claim 18,
The dosage range of the taurultam is 5 mg/kg in combination with the dosage range of taurinamide from once a day to a weekly basis during the effective period based on individual patient responses, and in combination with the dosage range of taurinamide from 5 mg/kg to 280 mg/kg. 280 mg/kg, the method. The method of claim 19,
The dosage range of the taurultam is 5 mg/kg in combination with the dosage range of taurinamide from once a day to weekly units for an effective period based on individual patient responses, from 35 mg/kg to 40 mg/kg of taurinamide 40 mg/kg, method. The method of claim 18,
The method, wherein the composition is administered with an oncolytic agent. The method of claim 1,
The method, wherein the composition is composed of taurultam, taurinamide and methylene glycol in a ratio of taurultam 1: taurinamide 7: methylene glycol 1. The method of claim 22,
The dosage range of the taurultam is in combination with a dosage range of 5 mg/kg to 280 mg/kg of taurinamide, from once a day to a weekly basis for an effective period based on individual patient responses, and a dosage of methylene glycol 5 mg/kg to 280 mg/kg in further combination with the range 2.5 mg/kg to 160 mg/kg. The method of claim 23,
The dosage range of the taurultam is in combination with a dosage range of 35 mg/kg to 40 mg/kg of taurinamide for an effective period from once a day to a weekly basis for an effective period based on individual patient responses, and the dosage of methylene glycol In further combination with the range 5 mg/kg to 40 mg/kg, which is optimally 5 mg/kg to 40 mg/kg. The method of claim 22,
The method, wherein the composition is administered in combination with an oncolytic agent and/or radiotherapy. The method of claim 1,
The method, wherein the composition is delivered to the patient using one from the group consisting of parenteral delivery, intramuscular delivery and intravenous delivery. The method of claim 1,
Wherein the composition is included in the nanoparticles, and the nanoparticles are further configured to delay exposure of the composition until the nanoparticles reach the tumor site. The method of claim 27,
Wherein the nanoparticles comprise a core and an outer coating of the composition, and the outer coating is configured to prevent exposure of the composition until the nanoparticles reach the tumor site. The method of claim 28,
The method, wherein the outer coating comprises an absorbable polymer or lipid that degrades when the nanoparticles move from the insertion site to the tumor site. The method of claim 1,
The method, wherein the composition is delivered using a polymer system configured to delay premature degradation of the composition. The method of claim 30,
Wherein the composition is "pegylated" with polyethylene glycol (PEG) to delay premature degradation of the composition.

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