Taurolidine treatment of myc-expressing tumors in mammalian body

Abstract

To provide methods for treating cancers that overexpress any of the N-myc genes, C-myc genes and / or L-myc genes in a mammalian body.SOLUTION: Provided is a method comprising administering to a mammalian body a composition comprising at least one from the group consisting of: taurolidine; taurultam; taurinamide; methylene glycol; taurultam and taurinamide in a ration of 1 taurultam:7 taurinamide; and taurultam, taurinamide and methylene glycol in a ratio of 1 taurultam:7 taurinamide:1 methylene glycol.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] Applicant CorMedix Inc. Inventor Bruce Reidenberg Robert DiLuccio Reference to prior pending patent applications This patent application is filed (i) a continuation-in-part of pending prior U.S. patent application Ser. No. 15 / 403,876, filed January 11, 2017, by CorMedix Inc. and Robert DiLuccio, entitled "THERAPEUTIC NANOPARTICLES FOR THE TREATMENT OF NEUROBLASTOMA AND OTHER CANCERS" (Docket No. CORMEDIX-14), which claims the benefit of prior U.S. provisional patent application Ser. No. 62 / 277,243, filed January 11, 2016, by CorMedix Inc. and Robert DiLuccio, entitled "NANOPARTICLE SYSTEM FOR THE TREATMENT OF NEUROBLASTOMA" (Docket No. CORMEDIX-14 PROV); (ii) "TAUROLIDINE TREATMENT FOR MYC-EXPRESSING TUMORS IN MAMMALIAN BODIES" (Docket No. CORMEDIX-35 This application claims the benefit of pending prior U.S. Provisional Patent Application No. 62 / 725,650, filed August 31, 2018, by CorMedix Inc. and Bruce Reidenberg et al. for PROV.

[0002] The three above-identified patent applications are incorporated herein by reference. Technical Field The present invention relates generally to therapeutic methods and compositions, and more particularly to therapeutic methods and compositions for the treatment of MYC-expressing tumors in the mammalian body. [Background technology]

[0003] Taurolidine is a well-known antibacterial drug with a published mechanism of action and antibacterial spectrum. Taurolidine is unstable in the circulation, and therefore has not been successfully developed for systemic infections. Taurolidine has shown efficacy in topical application for peritonitis and in preventing infections when used as a catheter lock solution.

[0004] Taurolidine has recently been studied for its oncolytic activity and has been found to have inhibitory effects on cultured cell lines, either alone or in combination with standard chemotherapy. Despite claims that in vitro inhibitory concentrations are clinically achievable, the only published human pharmacokinetic study failed to demonstrate measurable concentrations of taurolidine in healthy volunteers when 5 grams of taurolidine was administered intravenously via a 20-minute infusion. This is thought to be due to the rapid hydrolysis of taurolidine when administered systemically to the mammalian body.

[0005] The MYC oncogene has been extensively described in solid tumors and lymphoma / leukemia. Taurolidine has shown efficacy in treating neuroblastoma in experimental cell lines known to overexpress the N-myc gene.

[0006] Taurolidine has shown efficacy in treating ovarian cancer in a human ovarian cell tumor line implanted in mice, which is known to overexpress the c-myc gene. Summary of the Invention [Problem to be solved by the invention]

[0007] Taurolidine has shown efficacy in treating lung cancer in experimental cell lines known to overexpress the L-myc gene. There is a need for new methods and compositions that are effective against MYC-overexpressing tumors in the mammalian body. [Means for solving the problem]

[0008] According to the present invention, taurolidine and / or taurolidine hydrolysate are used to treat tumors that overexpress the N-myc gene, the C-myc gene and / or the L-myc gene in mammalian bodies. Examples of tumors that may overexpress the N-myc gene, the C-myc gene and / or the L-myc gene include, but are not limited to, lymphoma, malignant melanoma, multiple myeloma, neuroblastoma, colon cancer, breast cancer and lung cancer.

[0009] Preferred hydrolysis products of taurolidine are: Taurultum; Taurinamide; Methylene glycol; Taurultam and taurinamide in a ratio of 1:7 taurultam:taurinamide; and Taurultam, taurinamide, and methylene glycol in a 1:7:1 ratio of taurultam:taurinamide:methylene glycol It may comprise at least one from the group consisting of:

[0010] Taurolidine is given at a dosage range of 5 mg / kg to 280 mg / kg, with an optimal range of 5 mg / kg to 60 mg / kg, once daily to once weekly for an effective duration based on individual patient response.

[0011] Taurultam is given in a dosage range of 5 mg / kg to 280 mg / kg, with an optimal range of 5 mg / kg to 60 mg / kg, once daily to once weekly for an effective duration based on individual patient response.

[0012] Taurinamide is given at a dosage range of 5 mg / kg to 280 mg / kg, with an optimal range of 5 mg / kg to 60 mg / kg, once daily to once weekly for an effective duration based on individual patient response.

[0013] Methylene glycol is given at a dosage range of 2.5 mg / kg to 160 mg / kg, with an optimal range of 2.5 mg / kg to 30 mg / kg, once daily to once weekly for an effective duration based on individual patient response.

[0014] Taurultam and taurinamide (in a ratio of 1 taurultam:7 taurinamide) were administered in dose ranges of 5 mg / kg to 280 mg / kg for taurultam and 5 mg / kg to 40 mg / kg for taurinamide. kg, in combination with taurinamide in a dose range of 5 mg / kg to 280 mg / kg, with an optimum range of 35 mg / kg to 40 mg / kg, given once daily to once weekly for an effective duration based on individual patient response.

[0015] Taurultam, taurinamide, and methylene glycol (taurultam:taurinamide:methylene glycol in a 1:7:1 ratio) is given once daily to once weekly for an effective duration based on individual patient response, with taurultam in a dosage range of 5 mg / kg to 280 mg / kg, with an optimal range of 5 mg / kg to 40 mg / kg, in combination with taurinamide in a dosage range of 5 mg / kg to 280 mg / kg, with an optimal range of 35 mg / kg to 40 mg / kg, and with methylene glycol in a dosage range of 2.5 mg / kg to 160 mg / kg, with an optimal range of 5 mg / kg to 40 mg / kg.

[0016] Taurolidine, and / or the hydrolysis products of taurolidine, can be given systemically, preferably intramuscularly or intravenously. In one preferred form of the invention, taurolidine and / or the hydrolysis products of taurolidine are delivered systemically in a "shielded form" so that the taurolidine or the hydrolysis products of taurolidine can treat the tumor as soon as it can reach the tumor site without premature degradation.

[0017] More specifically, in one preferred form of the invention, taurolidine and / or taurolidine hydrolysates may be delivered in the form of nanoparticles comprising a core of taurolidine and / or taurolidine hydrolysates and an outer coating configured to prevent premature exposure of the taurolidine and / or taurolidine hydrolysates before the nanoparticles reach the tumor site. degrades as the nanoparticles travel from the insertion site to the tumor site, so as to release taurolidine and / or hydrolysis products of taurolidine 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 travel from the insertion site to the tumor site.

[0018] In another form of the invention, taurolidine and / or hydrolysis products of taurolidine (i.e., the active ingredient) may be delivered using a polymer system configured to retard premature degradation of the active ingredient. By way of non-limiting example, taurolidine and / or hydrolysis products of taurolidine may be "pegylated" using polyethylene glycol (PEG) to retard premature degradation of the active ingredient.

[0019] Taurolidine and / or its hydrolysis products are used either as single agents or in combination with other oncolytic agents and / or radiation therapy. can be delivered.

[0020] These and other objects and features of the present invention will be more fully disclosed or made apparent by the following detailed description of preferred embodiments of the invention, which is to be considered in conjunction with the accompanying drawings in which like numerals refer to like parts and in which: [Brief explanation of the drawings]

[0021] [Figure 1] FIG. 1 is a graph showing that leukemia cell lines appear to be more sensitive to the effects of Taurolidine compared to healthy lymphocytes in vitro (but not in vivo). [Figure 2] FIG. 2 is a graph showing that neuroblastoma cell lines are more sensitive to the loss of viability by Taurolidine when compared to healthy fibroblasts in vitro (but not in vivo) (graph BJ). [Figure 3] FIG. 3 is a graph or photograph showing that Taurolidine given to CB57 SCID mice bearing measurable tumors derived from a neuroblastoma cell line implanted subcutaneously in the CB57 SCID mice has efficacy in IMR5 tumors in vivo (but not in vitro), and measurable efficacy in SK-N-AS tumors. [Figure 4] FIG. 4 is a graph or photograph showing that Taurolidine given to CB57 SCID mice bearing measurable tumors derived from a neuroblastoma cell line implanted subcutaneously in the CB57 SCID mice has efficacy in IMR5 tumors in vivo (but not in vitro), and measurable efficacy in SK-N-AS tumors. [Figure 5] FIG. 5 is a graph or photograph showing that Taurolidine given to CB57 SCID mice bearing measurable tumors derived from a neuroblastoma cell line implanted subcutaneously in the CB57 SCID mice has efficacy in IMR5 tumors in vivo (but not in vitro), and measurable efficacy in SK-N-AS tumors. [Figure 6]FIG. 6 is a graph or photograph showing that Taurolidine given to CB57 SCID mice bearing measurable tumors derived from a neuroblastoma cell line implanted subcutaneously in the CB57 SCID mice has efficacy in IMR5 tumors in vivo (but not in vitro), and measurable efficacy in SK-N-AS tumors. [Figure 7] FIG. 7 is a graph showing that when Taurolidine was administered to treat mice bearing a different cell line (SK-N-AS), also derived from neuroblastoma, a statistically significant reduction in tumor size was achieved, but overall survival was not significantly different from controls. [Figure 8] FIG. 8 is a graph showing that when Taurolidine was administered to treat mice bearing a different cell line (SK-N-AS), also derived from neuroblastoma, a statistically significant reduction in tumor size was achieved, but overall survival was not significantly different from controls. [Figure 9] FIG. 9 shows the effect of delayed administration of a single 3-day ip (intraperitoneal) bolus injection regimen of Taurolidine (20 mg / mouse / injection) on the development of ip human tumor xenografts in female nude mice following ip administration of 5×10 SKOV-3 human ovarian tumor cells. [Figure 10] FIG. 10 is a diagram illustrating the mechanism of hydrolysis of taurolidine. [Figure 11] FIG. 11 is a table showing the mean pharmacokinetic parameters of taurultam. [Figure 12] FIG. 12 is a table showing the mean pharmacokinetic parameters of taurinamide. DETAILED DESCRIPTION OF THE INVENTION

[0022] Taurolidine was developed as an anti-infective drug, but has been found to have oncolytic activity against neuroblastoma tumors in experimental cell lines. These cell lines are known to overexpress the N-myc gene. More specifically, taurolidine has been found to have surprising oncolytic activity in cell cultures of human cancer cells expressing N-myc, and now in rodent cancer models based on N-myc-expressing human cancer cell lines.

[0023] It has been found that compared to healthy lymphocytes in vitro (but not in vivo), leukemia cell lines appear to be more sensitive to the effects of Taurolidine. See Figure 1.

[0024] Neuroblastoma cell lines have also been found to be more sensitive to the loss of viability by Taurolidine when compared to healthy fibroblasts in vitro (but not in vivo). See Figure 2.

[0025] Furthermore, Taurolidine given to CB57 SCID mice bearing measurable tumors derived from a neuroblastoma cell line implanted subcutaneously in the CB57 SCID mice showed dramatic efficacy in IMR5 tumors in vivo (but not in vitro) and in SK-N-AS tumors. The results showed measurable efficacy in the treatment of rheumatoid arthritis. See Figures 3-6.

[0026] A statistically significant reduction in tumor size was achieved when Taurolidine was administered to treat mice bearing a different cell line (SK-N-AS) also derived from neuroblastoma, but the overall survival of the tumor-implanted mice was not statistically different from controls. See Figures 7 and 8.

[0027] Taurolidine has also shown efficacy in treating ovarian cancer in a human ovarian cell tumor line implanted in mice. This cell line is known to overexpress the c-myc gene. 5 × 10 6See Figure 9, which shows the effect of delayed administration of a single 3-day intraperitoneal (ip) bolus injection regimen of taurolidine (20 mg / mouse / injection) on the development of ip human tumor xenografts in female nude mice following ip administration of SKOV-3 human ovarian tumor cells. In this study, taurolidine therapy was initiated on the day of tumor cell inoculation or up to 5 days thereafter. 14 days after the final taurolidine injection, mice from all groups were sacrificed, and the peritoneal cavities were examined for the presence of tumors. Each experiment was repeated three times, with pooled numbers of animals in each group ranging from 15 to 21 (Calabresi PI, Goulette FA, Darnowski JW, Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic agent, Cancer Res., 2001 Sep 15;61(18):6816-21).

[0028] Taurolidine has also shown efficacy in treating lung cancer in experimental cell lines known to overexpress the L-myc gene. According to the present invention, taurolidine and / or taurolidine hydrolysate are used to treat tumors that overexpress the N-myc gene, the C-myc gene and / or the L-myc gene in mammalian bodies. Examples of tumors that may overexpress the N-myc gene, the C-myc gene and / or the L-myc gene include, but are not limited to, lymphoma, malignant melanoma, multiple myeloma, neuroblastoma, colon cancer, breast cancer and lung cancer.

[0029] The mechanism of hydrolysis of taurolidine is shown in Figure 10. Preferred hydrolysis products of taurolidine that can be used to treat tumors that overexpress the N-myc, C-myc and / or L-myc genes in the mammalian body are: Taurultum; Taurinamide; Methylene glycol; Taurultam and taurinamide in a ratio of 1:7 taurultam:taurinamide; and Taurultam, taurinamide, and methylene glycol in a 1:7:1 ratio of taurultam:taurinamide:methylene glycol It may comprise at least one from the group consisting of:

[0030] Taurolidine is given at a dosage range of 5 mg / kg to 280 mg / kg, with an optimal range of 5 mg / kg to 60 mg / kg, once daily to once weekly for an effective duration based on individual patient response.

[0031] Taurultam is given once daily to once weekly at a dose range of 5 mg / kg to 280 mg / kg, with an optimal range of 5 mg / kg to 60 mg / kg, for an effective duration based on individual patient response. Mean pharmacokinetic parameters for taurultam are shown in Figure 11.

[0032] Taurinamide is given once daily to once weekly at a dose range of 5 mg / kg to 280 mg / kg, with an optimal range of 5 mg / kg to 60 mg / kg, for an effective duration based on individual patient response. Mean pharmacokinetic parameters for taurinamide are shown in Figure 12.

[0033] Methylene glycol is given at a dosage range of 2.5 mg / kg to 160 mg / kg, with an optimal range of 2.5 mg / kg to 30 mg / kg, once daily to once weekly for an effective duration based on individual patient response.

[0034] Taurultam and taurinamide (1:7 taurultam:taurinamide ratio) in combination with taurultam at a dose range of 5 mg / kg to 280 mg / kg, with an optimal range of 5 mg / kg to 40 mg / kg, and taurinamide at a dose range of 5 mg / kg to 280 mg / kg, with an optimal range of 35 mg / kg to 40 mg / kg, given once daily to once weekly for an effective duration based on individual patient response.

[0035] Taurultam, taurinamide, and methylene glycol (1:7:1 taurultam:taurinamide:methylene glycol) are given once daily to once weekly in a dose range of 5 mg / kg to 280 mg / kg, with an optimal range of 5 mg / kg to 40 mg / kg, in combination with taurinamide at a dose range of 5 mg / kg to 280 mg / kg, with an optimal range of 35 mg / kg to 40 mg / kg, and in combination with methylene glycol at a dose range of 2.5 mg / kg to 160 mg / kg, with an optimal range of 5 mg / kg to 40 mg / kg, for a duration effective based on individual patient response.

[0036] The dose selection for the hydrolysis products of taurolidine was calculated as follows: AUC 0-inf taurultam / AUC 0-inf taurinamide = 42.9 / 312.7 =0.14 Because the molecular weight difference is only one methyl group, the use of weight-based AUC does not need to be corrected. Therefore, when taurultam and taurinamide are given in combination, the target ratio is 0.14 or 1:7. And when taurultam, taurinamide, and methylene glycol are given in combination, the target ratio is 1:7:1.

[0037] The effective dose is of the formula: [Human equivalent dose = mouse mg / kg dose x 1 adult / 12 mouse x 25 pediatric BSA ratio / 37 adult BSA ratio = pediatric dose mg / kg (https: / / www.fda.gov / downloads / drugs / guidances / ucm078932.pdf)] The human equivalent dose was calculated from the effective mouse dose using the formula:

[0038] Taurolidine, and / or the hydrolysis products of taurolidine, can be given systemically, preferably intramuscularly or intravenously. In one preferred form of the invention, taurolidine and / or the hydrolysis products of taurolidine are delivered systemically in a "shielded form" so that the taurolidine or the hydrolysis products of taurolidine can treat the tumor as soon as it can reach the tumor site without premature degradation.

[0039] More specifically, in one preferred form of the invention, taurolidine and / or hydrolysis products of taurolidine are delivered in the form of nanoparticles, which contain taurolidine and The nanoparticles comprise a core containing taurolidine and / or hydrolysis products of taurolidine, and an outer coating configured to prevent premature exposure of taurolidine and / or hydrolysis products of taurolidine before the nanoparticles reach the tumor site. The outer coating degrades as the nanoparticles move from the insertion site to the tumor site, releasing the taurolidine and / or hydrolysis products of taurolidine intact at the tumor site. In one preferred form of the present invention, the coating comprises an absorbable polymer or lipid that degrades as the nanoparticles move from the insertion site to the tumor site. By way of example and not limitation, the coating can be made from a combination of copolymers and multimers derived from polymers constructed from l-lactide, glycolide, e-caprolactone, p-dioxanone, and trimethylene carbonate. The coating can also be combined with a glycol, such as polyethylene glycol (PEG), which can be either linear or branched.

[0040] If desired, the nanoparticles may include an excipient (eg, a buffer that enhances the hydrolytic stability of the taurolidine and / or hydrolysis products within the nanoparticles). Furthermore, if desired, the nanoparticles can further comprise a coating configured to target the nanoparticles to tumor sites to improve the efficacy of Taurolidine and / or hydrolysates for treating tumors. In one preferred form of the invention, the coating comprises binding molecules configured to target delivery of the nanoparticles to specific tissues.

[0041] In another form of the invention, taurolidine and / or taurolidine hydrolysates may be delivered using a polymer system configured to delay premature degradation of taurolidine and / or taurolidine hydrolysates and / or optimize the release characteristics of taurolidine and / or taurolidine hydrolysates. By way of non-limiting example, taurolidine and / or taurolidine hydrolysates may be "pegylated" using polyethylene glycol (PEG) to delay premature degradation of taurolidine and / or taurolidine hydrolysates and / or optimize the release characteristics of taurolidine and / or taurolidine hydrolysates.

[0042] Taurolidine (and / or its hydrolysis products) can be delivered either as a single agent or in combination with other oncolytic agents and / or radiation therapy. Examples of oncolytic agents that can be combined with taurolidine and / or its hydrolysis products for systemic delivery are platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan, topoisomerase II inhibitors), vinca alkaloids (vincristine), and topoisomerase I inhibitors (topotecan and irinotecan).

[0043] change While the present invention has been described in terms of certain exemplary preferred embodiments, those skilled in the art will readily understand and appreciate that the invention is not so limited and that many additions, deletions and modifications to the preferred embodiments discussed above may be made within the scope of the present invention.

Claims

1. 1. A method of treating a cancer that overexpresses any of the N-myc gene, the C-myc gene and / or the L-myc gene in a mammalian body, comprising: Taurolidine; Taurultum; Taurinamide; Methylene glycol; Taurultam and taurinamide in a ratio of 1:7 taurultam:taurinamide; and Taurultam, taurinamide, and methylene glycol in a ratio of 1:7:1 taurultam:taurinamide:methylene glycol 20. A method comprising administering to a mammalian body a composition comprising at least one from the group consisting of:

2. 10. The method of claim 1, wherein the composition comprises taurolidine.

3. 3. The method of claim 2, wherein the dosage range is 5 mg / kg to 280 mg / kg once daily to once weekly for an effective period based on individual patient response.

4. 4. The method of claim 3, wherein the dosage range is 5 mg / kg to 60 mg / kg once daily to once weekly for an effective period based on individual patient response.

5. 3. The method of claim 2, wherein the composition is administered in combination with an oncolytic agent and / or radiation therapy.

6. 10. The method of claim 1, wherein the composition comprises taurultam.

7. 7. The method of claim 6, wherein the dosage range is 5 mg / kg to 280 mg / kg once daily to once weekly for an effective period based on individual patient response.

8. 8. The method of claim 7, wherein the dosage range is 5 mg / kg to 60 mg / kg once daily to once weekly for an effective period based on individual patient response.

9. 7. The method of claim 6, wherein the composition is administered in combination with an oncolytic agent and / or radiation therapy.

10. 10. The method of claim 1, wherein the composition comprises taurinamide.

11. 11. The method of claim 10, wherein the dosage range is 5 mg / kg to 280 mg / kg once daily to once weekly for an effective period based on individual patient response.

12. 12. The method of claim 11, wherein the dosage range is 5 mg / kg to 60 mg / kg once daily to once weekly for an effective period based on individual patient response.

13. 11. The method of claim 10, wherein the composition is administered in combination with an oncolytic agent and / or radiation therapy.

14. The method of claim 1 wherein the composition consists of methylene glycol.

15. 15. The method of claim 14, wherein the dosage range is 2.5 mg / kg to 160 mg / kg once daily to once weekly for an effective period based on individual patient response.

16. 16. The method of claim 15, wherein the dosage range is 2.5 mg / kg to 30 mg / kg once daily to once weekly for an effective period based on individual patient response.

17. 15. The method of claim 14, wherein the composition is administered in combination with an oncolytic agent and / or radiation therapy.

18. 2. The method of claim 1, wherein the composition consists of taurultam and taurinamide in a ratio of taurultam:taurinamide of 1:

7.

19. 19. The method of claim 18, wherein the dosage range of taurultam is 5 mg / kg to 280 mg / kg once daily to once weekly for an effective period based on individual patient response in combination with taurinamide at a dosage range of 5 mg / kg to 280 mg / kg.

20. 20. The method of claim 19, wherein the dosage range of taurultam is 5 mg / kg to 40 mg / kg once daily to once weekly for an effective period based on individual patient response in combination with taurinamide at a dosage range of 35 mg / kg to 40 mg / kg.

21. 20. The method of claim 18, wherein the composition is administered in combination with an oncolytic agent.

22. 2. The method of claim 1, wherein the composition consists of taurultam, taurinamide, and methylene glycol in a ratio of taurultam:taurinamide:methylene glycol of 1:7:

1.

23. 23. The method of claim 22, wherein the dosage range of taurultam is 5 mg / kg to 280 mg / kg once daily to once weekly in combination with taurinamide in a dosage range of 5 mg / kg to 280 mg / kg, in combination with methylene glycol in a dosage range of 2.5 mg / kg to 160 mg / kg, for an effective period based on individual patient response.

24. 24. The method of claim 23, wherein the dosage range of taurultam is once daily to once weekly, optimally 5 mg / kg to 40 mg / kg, in combination with taurinamide in the dosage range of 35 mg / kg to 40 mg / kg, in combination with methylene glycol in the dosage range of 5 mg / kg to 40, for an effective period based on individual patient response.

25. 23. The method of claim 22, wherein the composition is administered in combination with an oncolytic agent and / or radiation therapy.

26. 10. The method of claim 1, wherein the composition is delivered to the patient using one from the group consisting of parenteral delivery, intramuscular delivery, and intravenous delivery.

27. 10. The method of claim 1, wherein the composition is contained in nanoparticles, and the nanoparticles are configured to delay exposure of the composition until the nanoparticles reach a tumor site.

28. The nanoparticles comprise a core of the composition and an outer coating configured to prevent exposure of the composition before the nanoparticles reach a tumor site.

28. The method of claim 27.

29. 30. The method of claim 28, wherein the outer coating comprises an absorbable polymer or lipid that degrades as the nanoparticles travel from the insertion site to the tumor site.

30. The method of claim 1 , wherein the composition is delivered using a polymer system configured to retard premature degradation of the composition.

31. 31. The method of claim 30, wherein the composition is "pegylated" using polyethylene glycol (PEG) to retard premature degradation of the composition.

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