NZ615005B2

NZ615005B2 - Combinations comprising macitentan for the treatment of glioblastoma multiforme

Info

Publication number: NZ615005B2
Application number: NZ615005A
Authority: NZ
Inventors: Urs Regenass
Original assignee: Actelion Pharmaceuticals Ltd
Filing date: 2012-02-03
Publication date: 2016-02-02

Abstract

Disclosed herein is the use of macitentan (N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N'-propylsulfamide) in combination with temozolomide or paclitaxel and/or with radiotherapy, in the manufacture of a medicament for the treatment of malignant glioma, in particular glioblastoma multiforme. glioblastoma multiforme.

Description

COMBINATIONS COMPRISING MACITENTAN FOR THE TREATMENT OF GLIOBLASTOMA MULIFORME The present invention concerns the combination of macitentan, i.e. the compound of formula I S Br N NH O Br with a chemotherapeutic agent such as temozolomide or paclitaxel, with radiotherapy or with both a chemotherapeutic agent and radiotherapy, for therapeutic use, simultaneously, separately or over a period of time, in the treatment of malignant glioma, in particular glioblastoma multiforme.

Malignant glioma and glioblastoma multiforme constitute rare cancer forms for which there are currently no satisfactory treatments. Even with the best available therapy, the prognosis for the patients remains poor (see e.g. M. Khasraw and A.B. Lassman, Curr.

Oncol. Rep. (2010), 12, 26-33).

PCT publication WO 02/053557 describes endothelin receptor antagonists including the compound of formula (I) (the International Nonproprietary Name of which is macitentan) and the use of said endothelin receptor antagonists in the treatment of various diseases, including cancer in general.

Besides, PCT publication discloses that the combination of macitentan and paclitaxel has a synergistic effect in the treatment of ovarian cancer.

Temozolomide (the active principle of a medicament sold under the trademarks Temodar in the United States) is an oral alkylating agent. This compound is currently approved in the European Union and the United States for, among others, the treatment of glioblastoma multiforme.

The potential role of endothelins, in particular endothelin-1 (ET-1), in malignant glioma and in glioblastoma multiforme is known from literature and endothelin receptor antagonists in general have been mentioned as potential therapeutic agents for treating glioblastoma multiforme.

For example, G. Egidy et al (Lab. Invest. (2000), 80, 1681-1689) teach that “[in] human glioblastoma cell lines, the ET-1 system was not involved in tumor proliferation, but ET-1 was a survival factor (...)”.

Besides, M. Paolillo et al (Pharmacol. Res. (2010), 61, 306-315) teach that “in glioma cell lines ETB antagonists reduce proliferation and induce apoptosis”. However the authors then admit that “(f)uture studies (...) are required to confirm the reliability of ETB antagonists as a promising pharmacological tool in glioma treatment”.

On the other hand, the endothelin receptor antagonist atrasentan has been studied in patients having recurrent malignant glioma in phase I clinical studies, as reported by Phuphanich et al (J Neurooncol. (2008). 10(4), 617-623). However the development of this compound in this indication has not been continued to date.

The applicant has now found that macitentan, which is both an endothelin receptor A (ET R) and an endothelin receptor B (ET R) antagonist, produces exceptionally high effects in an in vivo model of glioblastoma when combined with a cytotoxic chemotherapy agent such as temozolomide or paclitaxel. As a result, macitentan in combination with a cytotoxic chemotherapy agent such as temozolomide or paclitaxel may be used for the preparation of a medicament, and is suitable, for the treatment of malignant glioma, in particular glioblastoma multiforme.

Summary of the Invention In one aspect, the invention provides a use of macitentan, or a pharmaceutically acceptable salt of this compound, for the manufacture of a medicament for the treatment of malignant glioma, wherein the medicament is for administration in combination with a cytotoxic therapy agent, with radiotherapy or with both a cytotoxic therapy agent and radiotherapy, wherein said cytotoxic therapy agent is temozolomide or a pharmaceutically acceptable salt thereof or paclitaxel or a pharmaceutically acceptable salt thereof.

Various disclosures are presented hereafter: 1) Herein described is a product containing macitentan, or a pharmaceutically acceptable salt of this compound, for use in the treatment of malignant glioma in combination with a cytotoxic chemotherapy agent, with radiotherapy or with both a cytotoxic therapy agent and radiotherapy. The components of the combination may be administered simultaneously, separately or over a period of time.

The following paragraphs provide definitions of the various terms used in the present patent application and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader or narrower definition.

The term "pharmaceutically acceptable salt" refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J.

Pharm. (1986), 33, 201-217.

The term “cytotoxic chemotherapy agent” as used herein refers to a substance inducing apoptosis or necrotic cell death. Examples of cytotoxic chemotherapy agents which may be used in combination with ERAs in accordance to the present invention include: alkylating agents (for example mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa or altretamine); platinum drugs (for example cisplatin, carboplatin or oxaliplatin); antimetabolite drugs (for example 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine or pemetrexed); anti-tumor antibiotics (for example daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C or mitoxantrone); and mitotic inhibitors (for example paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine or estramustine); and topoisomerase inhibitors (for example etoposide, teniposide, topotecan, irinotecan, diflomotecan or elomotecan).

“Simultaneously” or “simultaneous”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients by the same route and at the same time.

“Separately” or “separate”, when referring to an administration type, means in the present application that the administration type concerned consists in the administration of two or more active ingredients at approximately the same time by at least two different routes.

By administration “over a period of time” is meant in the present application the administration of two or more active ingredients at different times, and in particular an administration method according to which the entire administration of one of the active ingredients is completed before the administration of the other or others begins. In this way it is possible to administer one of the active ingredients for several months before administering the other active ingredient or ingredients. In this case, no simultaneous administration occurs. Administration “over a period of time” also encompasses situations wherein the active ingredients are not given with the same periodicity (e.g. wherein one active ingredient is given once a day and another is given once a week).

The term 'comprising' as used in this specification and claims means 'consisting at least in part of'. When interpreting statements in this specification and claims which include the term 'comprising', other features besides the features prefaced by this term in each statement can also be present. Related terms such as 'comprise' and 'comprised' are to be interpreted in similar manner.2) In particular, the malignant glioma of disclosure 1) will be glioblastoma multiforme. 3) Preferably, the product of disclosure 1) or 2) will be combined with a cytotoxic therapy agent or both a cytotoxic therapy agent and radiotherapy, said cytotoxic therapy agent being selected from alkylating agents and mitotic inhibitors. 4) According to one variant of disclosure 3), the cytotoxic therapy agent will be an alkylating agent (notably an alkylating agent selected from mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa, altretamine and pharmaceutically acceptable salts of these compounds).

) In particular, the alkylating agent of disclosure 4) will be temozolomide or a pharmaceutically acceptable salt thereof. 6) According to another variant of disclosure 3), the cytotoxic therapy agent will be a mitotic inhibitor (and notably a mitotic inhibitor selected from paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, estramustine and pharmaceutically acceptable salts of these compounds). 7) In particular, the mitotic inhibitor of disclosure 6) will be paclitaxel or a pharmaceutically acceptable salt thereof. 8) According to one variant of disclosures 1) to 7), macitentan or its pharmaceutically acceptable salt will be intended to be administered by oral route. 9) According to another variant of disclosures 1) to 7), macitentan or its pharmaceutically acceptable salt will be intended to be administered by intravenous or intraperitoneal route (and notably by intravenous route).

) In one particular sub-disclosure, the product according to one of disclosures 1) to 9) will be such that the cytotoxic therapy agent is intended to be administered by oral route. 11) In another particular sub-disclosure, the product according to one of disclosures 1) to 4) will be such that the cytotoxic therapy agent is intended to be administered by intravenous or intraperitoneal route (and notably by intravenous route). 12) Also described is a pharmaceutical composition containing, as active principles, macitentan, or a pharmaceutically acceptable salt of this compound, in combination with a cytotoxic therapy agent, as well as at least one non-toxic excipient, for use, optionally in combination with radiotherapy, in the treatment of malignant glioma. 13) In particular, the pharmaceutical composition of disclosure 12) will be for use in the treatment of glioblastoma multiforme. 14) Preferably, the cytotoxic therapy agent of disclosure 12) or 13) will be selected from alkylating agents and mitotic inhibitors. 15) According to one variant of disclosure 14), the cytotoxic therapy agent will be an alkylating agent (notably an alkylating agent selected from mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa, altretamine and pharmaceutically acceptable salts of these compounds). 16) In particular, the alkylating agent of disclosure 15) will be temozolomide or a pharmaceutically acceptable salt thereof. 17) According to another variant of disclosure 14), the cytotoxic therapy agent will be a mitotic inhibitor (and notably a mitotic inhibitor selected from paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, estramustine and pharmaceutically acceptable salts of these compounds). 18) In particular, the mitotic inhibitor of disclosure 17) will be paclitaxel or a pharmaceutically acceptable salt thereof. 19) In one preferred sub-disclosure, the pharmaceutical composition according to one of disclosures 12) to 18) will be in a liquid form suitable for intravenous administration. 20) The pharmaceutical composition of disclosure 19) may for example contain macitentan or a pharmaceutically acceptable salt of this compound and temozolomide or a pharmaceutically acceptable salt thereof, in a water solution containing mannitol, L-threonine, polysorbate 80, sodium citrate and hydrochloric acid (such water solution being for example obtained by mixing commercial TEMODAR for injection with water for injection and adding macitentan or a pharmaceutically acceptable salt thereof). 21) The pharmaceutical composition of disclosure 19) may also contain macitentan or a pharmaceutically acceptable salt of this compound and temozolomide or a pharmaceutically acceptable salt thereof, in a water solution containing methylcellulose, polysorbate 80, glucose, polyoxyethylated castor oil (e.g. Cremophor EL) and ethanol. 22) In another preferred sub-disclosure, the pharmaceutical composition according to one of disclosures 12) to 18) will be in a solid form suitable for oral administration. 23) In an alternative disclosure, macitentan may be formulated as a tablet as described in , whereas the cytotoxic therapy agent may be in one of its commercial formulations (preferably an oral formulation if available), the combination being intended for therapeutic use, simultaneously, separately or over a period of time, in the treatment of malignant glioma, in particular glioblastoma multiforme.

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, “Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. 24) Also described is the use of macitentan, or a pharmaceutically acceptable salt of this compound, in combination with a cytotoxic therapy agent, for the manufacture of a medicament intended to be used, optionally in combination with radiotherapy, in the treatment of malignant glioma.

) In particular, the malignant glioma of disclosure 24) will be glioblastoma multiforme. 26) Preferably, the cytotoxic therapy agent of disclosure 24) or 25) will be selected from alkylating agents and mitotic inhibitors. 27) According to one variant of disclosure 26), the cytotoxic therapy agent will be an alkylating agent (notably an alkylating agent selected from mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa, altretamine and pharmaceutically acceptable salts of these compounds). 28) In particular, the alkylating agent of disclosure 27) will be temozolomide, or a pharmaceutically acceptable salt thereof. 29) According to another variant of disclosure 26), the cytotoxic therapy agent will be a mitotic inhibitor (and notably a mitotic inhibitor selected from paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, estramustine and pharmaceutically acceptable salts of these compounds).

) In particular, the mitotic inhibitor of disclosure 29) will be paclitaxel or a pharmaceutically acceptable salt thereof. 31) Also described is the use of macitentan, or a pharmaceutically acceptable salt of this compound, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament intended to be used in combination with radiotherapy with the treatment malignant glioma. 32) In particular, the malignant glioma of disclosure 31) will be glioblastoma multiforme. 33) Also described is a method of treating a patient having malignant glioma by administering to said patient a combination of macitentan or a pharmaceutically acceptable salt of this compound, with a cytotoxic therapy agent, with radiotherapy, or with both a cytotoxic therapy agent and radiotherapy. 34) In particular, the malignant glioma of disclosure 33) will be glioblastoma multiforme.

) Preferably, the cytotoxic therapy agent of disclosure 33) or 34) will be selected from alkylating agents and mitotic inhibitors. 36) According to one variant of disclosure 35), the cytotoxic therapy agent will be an alkylating agent (notably an alkylating agent selected from mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide, streptozocin, carmustine, lomustine, melphalan, busulfan, dacarbazine, temozolomide, thiotepa, altretamine and pharmaceutically acceptable salts of these compounds). 37) In particular, the alkylating agent of disclosure 36) will be temozolomide, or a pharmaceutically acceptable salt thereof. 38) According to another variant of disclosure 35), the cytotoxic therapy agent will be a mitotic inhibitor (and notably a mitotic inhibitor selected from paclitaxel, docetaxel, ixabepilone, vinblastine, vincristine, vinorelbine, vindesine, estramustine and pharmaceutically acceptable salts of these compounds). 39) In particular, the mitotic inhibitor of disclosure 38) will be paclitaxel or a pharmaceutically acceptable salt thereof.

Besides, preferences indicated for the product according to this invention of course apply mutatis mutandis to the pharmaceutical compositions, uses and methods according to this invention.

Though the exact administration doses of the active principle(s) of a product according to this invention will have to be determined by the treating physician, it is expected that a dose of 0.01 to 10 mg (and preferably 0.1 to 5 mg and more preferably 0.1 to 1 mg) of macitentan per kg of patient body weight per day optionally combined with, for example, a dose of 1 to 20 mg (and preferably 2 to 15 mg) of temozolomide per kg of patient body weight per day, or a dose of 0.1 to 10 mg (and preferably 1 to 3 mg) of paclitaxel per kg of patient body weight per day, will be appropriate.

In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

In the description in this specification reference may be made to subject matter that is not within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.

Examples showing the usefulness of the invention are described in the following section, which serves to illustrate the invention in more detail without limiting its scope in any way.

Pharmacological properties of the invention product Examples 1 to 3: LN229 human glioblastoma cells stereotactically injected into nude mice brain: Materials Vehicle for macitentan: The vehicle for macitentan consisted in 0.5% methylcellulose and 0.05% Tween 80.

Tween 80 was added to the appropriate volume of sterile 0.5% methylcellulose solution before each preparation of macitentan. Macitentan was weighed and homogenised with vehicle for one hour at room temperature to obtain a fine and homogeneous suspension at 2 mg/ml. The working solutions of macitentan were prepared every week. Seven aliquots were prepared for each day of treatment, stored at 4°C and protected from light. After each use, remaining solution was not kept for another use and was destroyed.

Vehicle for temozolomide: Temozolomide (100 mg) was prepared first in Cremophor EL/Ethanol (2:1 w/w). After complete dilution, temozolomide was diluted in glucose 5% (Aguettant, France) to reach the concentration of 0.25 mg/ml. The working solutions of temozolomide was prepared prior to each administration to mice and not kept for another use.

Administration routes Administration route for macitentan: Macitentan was administered by oral gavage via a canula at 5 ml/kg. The administration volumes were adapted according to the most recent individual body weight of mice.

Administration route for temozolomide: Temozolomide was administered by oral gavage via a canula at 10 ml/kg. The administration volume was adapted according to the most recent individual body weight of mice.

Animals Forty-eight (48) female Swiss Nude mice were obtained from Charles River (France).

Animals were observed for 7 days in a specific-pathogen-free animal care unit before treatment during the acclimatization period. Animal experiments were performed according to the European ethical guidelines of animal experimentation.

General method used for stereotactic injections of human glioblastoma LN229 cells into nude mice brain Cultured human glioblastoma LN229 cells were harvested by a brief exposure to ++ ++ 0.02%EDTA-0.25%Trypsin and re-suspended in Mg /Ca free Hank’s Balanced Salt Solution (adjusted to 1x10 cells in 10μl). Nude mice were anesthetized by the intraperitoneal injection of Nembutal (0.5 mg/g body weight, Abbott Laboratories, North Chicago, IL) for stereotactic intrathecal injection of 1x10 LN229 cells/mouse. In brief, a single incision was made from the anterior pole of the skull to the posterior ridge to expose the scalp. A hole was drilled over the target area and LN229 cells were injected using the following stereotactic coordinates, all relative to the bregma: 1.5 mm rostral, 1.5 mm anterioa and 4 mm below the pial surface. An automated micro-pump (Stoelting Instruments, Wood Dale, IL) was used to dispense 1x10 cells in 10 μl suspension over a 5 minute period. After the injection, the hole was plugged with bone wax and skin was closed with skin staples.

Example 1: treatment with macitentan and temozolomide: Two weeks after the stereotactic intrathecal injection of tumor cells (using the general method described hereabove), the mice were randomized into 4 treatment groups: - a group of 13 mice (“CONTROL group”) which received no treatment; - a group of 12 mice (“TMZ group”) which received one oral administration of temozolomide per day at 7.5 mg/kg for a week, then no treatment for two weeks, then again one oral administration of temozolomide per day at 7.5 mg/kg for a week, then again no treatment for two weeks, and so on; - a group of 12 mice (“MCTNT group”) which received one oral administration of macitentan at 10 mg/kg every day; and - a group of 13 mice (“TMZ + MCTNT group”) which received both temozolomide and macitentan according to the same doses, administration routes and schedules as for the two previous groups.

The mice were monitored daily and euthanized when they developed neurologic symptoms or became moribund. Days of survival were recorded and brain tissues were harvested and processed for histologic examinations. The experiment was terminated on day 100.

Results: The respective survival results obtained for the four groups of mice are shown in Figure 1.

As can be noticed, after 100 days, the survival rate of the CONTROL group was below % and the survival of either the TMZ group or the MCTNT group was about 40%; in contrast, the survival of the TMZ + MCTNT group was 100%. Besides, all mice treated with macitentan plus temozolomide were alive at day 100 with no evidence of tumor in the brain.

Example 2: treatment with macitentan and paclitaxel: Experimental methods: Two weeks after the stereotactic intrathecal injection of tumor cells (using the general method described hereabove), the mice were randomized into 4 treatment groups: - a group of 8 mice (“CONTROL group”) which received no treatment; - a group of 8 mice (“PTL group”) which received one intraperitoneal administration of paclitaxel per week at 8.5 mg/kg; - a group of 8 mice (“MCTNT group”) which received one oral administration of macitentan at 10 mg/kg every day; and - a group of 8 mice (“PTL + MCTNT group”) which received both paclitaxel and macitentan according to the same doses, administration routes and schedules as for the two previous groups.

The treatment was continued for 70 days, after which the experiment was terminated.

Moribund mice were euthanized.

Results: The respective survival results obtained for the four groups of mice are shown in Figure 2.

As can be noticed, after 70 days, in the CONTROL group, the PTL group or the MCTNT group about 60% of the animals were still alive; in contrast, at the time of termination, the survival rate of the PTL + MCTNT group was 100% without any signs of disease.

Example 3: comparison of treatments involving endothelin receptor antagonists in combination with temozolomide: Experimental methods: 21 days after the stereotactic intrathecal injection of luciferase labeled LN229 glioblastoma cells (using the general method described here above) (day 0), the mice were randomized into 7 treatment groups: - a group of 10 mice (“Control group”) which received no treatment; - a group of 10 mice (“TMZ group”) which received one oral administration of temozolomide per day at 7.5 mg/kg for a week, then no treatment for two weeks, then again one oral administration of temozolomide per day at 7.5 mg/kg for a week, then again no treatment for two weeks, and so on; - a group of 10 mice (“Macitentan + TMZ group”) which received, on the one hand, one oral administration of macitentan at 10 mg/kg every day and, on the other hand, temozolomide according to the same dose, administration route and schedule as for the TMZ group; - a group of 10 mice (“Atrasentan group”) which received intraperitoneal administration of atrasentan at 10 mg/kg every day; - a group of 10 mice (“Atrasentan + TMZ group”) which received both atrasentan and temozolomide according to the same doses, administration routes and schedules as for the Atrasentan group and the TMZ group respectively; - a group of 10 mice (“Zibotentan group”) which received oral administration of zibotentan at 20 mg/kg every day; and - a group of 10 mice (“Zibotentan + TMZ group”) which received both zibotentan and temozolomide according to the same doses, administration routes and schedules as for the Zibotentan group and the TMZ group respectively.

The treatment was continued for 120 days, after which the experiment was terminated.

Moribund mice were euthanized.

Results: The respective survival results obtained for the seven groups of mice are shown in Figure 3. As can be noticed all mice from the Control group, the Atrasentan group or the Zibotentan group became moribund during the first 50-80 days of the study and had to be euthanized. Animals of the TMZ group, the Atrasentan + TMZ group or the Zibotentan + TMZ group survived longer but at termination of the study all animals were moribund and had to be euthanized; in contrast, at termination of the study at 120 days after tumor cell injection, all mice of the Macitentan + TMZ group were alive without any signs of disease.

IVIS Bioluminescence imaging, after treating animals with luciferine, confirmed the minimal residual disease in animals treated with the macitentan + TMZ combination.

Immunohistochemistry of tumors from Examples 1 and 2 using antibodies directed against phosphorylated AKT and MAPK demonstrated strong reduction of both proteins in animals treated with macitentan. The reduction of these proteins which indicate highly active survival and proliferation pathways is much less prominent in tumors of animals treated with atrasentan or zibotentan (this example). Suppression of survival and proliferation pathways sensitizes cells to chemotherapy and could be the reason for the high effectiveness of macitentan in combination with chemotherapy.

Claims

1. Use of macitentan, or a pharmaceutically acceptable salt of this compound, for the manufacture of a medicament for the treatment of malignant glioma, wherein the medicament is for administration in combination with a cytotoxic therapy agent, with 5 radiotherapy or with both a cytotoxic therapy agent and radiotherapy, wherein said cytotoxic therapy agent is temozolomide or a pharmaceutically acceptable salt thereof or paclitaxel or a pharmaceutically acceptable salt thereof.

2. Use according to claim 1, wherein the malignant glioma are glioblastoma multiforme.

3. Use according to claim 1 or 2, wherein the cytotoxic therapy agent is temozolomide or a 10 pharmaceutically acceptable salt thereof.

4. Use according to claim 1 or 2, wherein the cytotoxic therapy agent is paclitaxel or a pharmaceutically acceptable salt thereof.

5. Use according to claim 1 to 4, wherein the medicament is for administration by oral route. 15

6. Use according to claim 1 to 4, wherein the medicament is for administration by intravenous or intraperitoneal route.

7. A use of claim 1, substantially has herein described with reference to any example thereof.