RU2772287C1 - Aqueous composition containing 1-(4-{[4-(dimethylamino)piperidine-1-yl]carbonyl} phenyl)-3-[4-(4,6- dimorpholine-4-yl-1,3,5-triazine-2-yl)phenyl]urea - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, in particular, to oncology, and is intended for treating cancer. The pharmaceutical aqueous composition contains a compound of 1-(4-{[4-(dimethylamino)piperidine-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4-yl-1,3,5-triazine-2-yl)phenyl]urea, or a pharmacologically acceptable salt thereof with an organic or inorganic acid, a pharmacologically acceptable organic or inorganic acid, pharmacologically acceptable beta- or gamma-cyclodextrins and water, and is in the form of a transparent solution. The group of inventions also relates to a lyophilised composition of the compound; to a pharmaceutical composition in the form of an aqueous solution, containing the lyophilised composition; and to an application of the composition for treating cancer.

EFFECT: implementation of the invention allows for production of a chemically and physically stable pharmaceutical composition of 1-(4-{[4-(dimethylamino)piperidine-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4-yl-1,3,5-triazine-2-yl)phenyl]urea at 25°C with a relative humidity of 60%, and also provides a possibility of facilitating effective intravenous or parenteral administration by creating a more convenient dosage form, namely a vial containing a single dosage of the composition.

34 cl, 1 dwg, 4 tbl, 6 ex

Description

COMPOUND

The present invention relates to a pharmaceutical composition containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3 ,5-triazin-2-yl)phenyl]urea, or a pharmaceutically acceptable salt thereof with an organic or inorganic acid. More specifically, the present invention relates to a pharmaceutical aqueous formulation containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or a pharmaceutically acceptable salt thereof with an organic or inorganic acid, which is a clear solution. Such a formulation is particularly suitable for intravenous or parenteral administration to a patient.

State of the art invention

1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl )phenyl]urea and preparations based on it are disclosed in WO2009/143313. This compound is an inhibitor of PI3 kinase and mTOR, which is useful in the treatment of cancer.

The crystalline form of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2 -yl)phenyl]urea and its preparation are disclosed in WO2010/096619.

WO2016/097949 describes an aqueous solution pharmaceutical formulation suitable for intravenous administration, comprising (i) 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4 ,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea or its salt with lactic acid, lactic acid and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in solution at a concentration of less than 6 mg / ml, and lactic acid is present in sufficient quantity to provide a clear solution; or (ii) 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazine -2-yl)phenyl]urea or its salt with phosphoric acid, phosphoric acid and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-( 4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in solution at a concentration of less than 4 mg/mL, and phosphoric acid is present in sufficient quantity to provide a clear solution. Lyophilization of such formulations is also described. Of the many acids tested (i.e., from citric acid, succinic acid, acetic acid, glycine, tartaric acid, maleic acid, malic acid, hydrochloric acid, lactic acid, and orthophosphoric acid), only lactic acid and orthophosphoric acid have been found to be able to provide a clear solution at a concentration of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- triazin-2-yl)phenyl]urea 3 mg/ml or higher.

1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl )phenyl]urea, also known as gedatolisib, has the following chemical structure:

1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl )phenyl]urea can be obtained in crystalline form and is chemically and physically stable at 25° C. and 60% relative humidity (RH) for up to 3 years in this form. However, this free base is not sufficiently soluble in water to provide an aqueous solution formulation suitable for intravenous or parenteral administration at the required therapeutic dosage levels.

There is a need to develop a pharmaceutically acceptable formulation of an aqueous solution of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1, 3,5-triazin-2-yl)phenyl]urea, which is preferably (a) chemically stable on storage (e.g. at 25° C. and 60% RH), (b) which will facilitate effective intravenous (or parenteral) ) administering the drug to a mammal, including a human being, and (c) preferably to give a concentration of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4- (4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea in solution, which is at least 6 mg/ml.

The essence of the invention

Concentration of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2- yl)phenyl]urea in solution that is at least 6 mg/mL is desirable to allow dosing to subjects using a single dose in a commercial drug product vial. A lyophilized drug product (for reconstitution) providing a solution of less than 6 mg/mL drug product will require multiple vials to deliver the required therapeutic dose. The multi-dose delivery vial approach is not desirable, given current regulatory requirements, for these types of products.

Preferably, the formulation is suitable for intravenous or parenteral administration of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1, 3,5-triazin-2-yl)phenyl]urea in terms of specific pharmacokinetic and bioavailability characteristics of this drug.

It is imperative that the intravenous formulation of any drug is a solution, which facilitates safe and effective administration to the patient. It must be free of particles and must not form a gel or suspension. A clear aqueous solution is preferred.

A "clear solution" is defined herein as a visually clear solution that can undergo turbidity (opalescence) that is substantially free of any visible particles that can be seen upon visual inspection. In general, if any particulate matter is noted, the formulation is not suitable for intravenous administration and should not be used as occlusion of the blood vessel may occur. Therefore, in view of the qualitative nature of the visual test, the term "substantially free of any visible particles" is generally used when no visible particulate matter is noted.

Particulate matter can be defined as follows:

visible inclusion - a single particle whose shape cannot be determined without magnification,

smoke or swirl streaks fine particles that look like smoke or tornadoes and usually originate from the bottom of the sample vial and swirl upwards as the vial is rotated,

flaky material - loosely aggregated particles or soft flakes,

particles with a particular shape or characteristic that can be described as being glassy, looking like metal, etc.

Visual inspection can be carried out in accordance with the method that is defined in the European Pharmacopoeia, Method 2.9.20, entitled "Particulate contamination: visible particles" (see Figure 1). This method allows you to determine the contamination of injection and infusion drugs with foreign, moving, undissolved particles, with the exception of gas bubbles that may be present in solutions. The test is intended to provide a simple procedure for visually evaluating the quality of parenteral solutions with respect to visible particles.

This method states: “Remove any attached labels from the container and rinse and dry outside. Carefully rotate or invert the container, ensuring that no air bubbles enter it, and observe for approximately 5 seconds against the white panel. Repeat the procedure on the black panel background. Record the presence of any particles."

A suitable method according to the Method of the European Pharmacopoeia 2.9.20, which was used for the present invention, is described in Example 1(i).

Other validated methods may also be used to determine the presence of any visible particles. Such methods include Optical Polarization Microscopy ("OPM"). A suitable OPM method that is used for the present invention is described in Example 1(ii).

Without wishing to be bound by any theory, it is believed that the matte tint may be caused by the formation of chromonic liquid crystals. Chromonic liquid crystals are formed as a result of the formation of aromatic regions of the molecule stacked one above the other according to the position of the pi-pi bond to form a column similar to stacks of dimers, trimers and oligomers of low molecular weight of these molecules. The resulting stacks, which can be shown using OPM, are non-crystalline microstructures associated with a chromonic liquid crystal. Non-crystalline microstructures exhibit interactions that are not constant and there is movement that keeps the system in free energy equilibrium. The turbidity of the solution results from a change in the refractive index of the solution due to the formation of these stacks. An Optical Polarizing Microscope (OPM) micrograph of solutions will show that no crystalline material is present and instead a chromonic liquid crystal phase exists. The presence of the liquid crystal phase results in a solution with opacity and/or haze due to the difference in refractive index within the resulting solution. For a discussion of material on liquid crystal formation, see "Optical Properties of Condensed Matter and Applications", Jai Singh (Editor), ISBN: 978-0-470-02193-4, Wiley, October 2006.

It has now surprisingly been found that by using a pharmaceutically acceptable beta- or gamma-cyclodextrin, pharmaceutical aqueous formulations can be obtained as a clear solution containing (a) 1-(4-{[4-(dimethylamino)piperidine-1- and (b) one of the acids selected from a number of pharmaceutically acceptable organic or inorganic acids.

Description of Drawings

Figure 1 reproduces Figure 2.9.20.-1 from the publication "European Pharmacopoeia Method 2.9.20" and describes an apparatus consisting of a viewing unit including: a black matte panel (1) of appropriate size, held in a vertical position; an appropriately sized non-shiny white panel (2) held in a vertical position next to a black panel; a suitably sized non-shiny white panel (3) held in a horizontal position at the base of the vertical panels; and an adjustable lamp holder (4) equipped with a suitable, covered white light source and a suitable light diffuser (a suitable viewing illumination device containing two 13-watt fluorescent tubes, each 525 mm in length). The illumination intensity at the viewing point is maintained at a level between 2000 lux and 3750 lux, although higher values are preferred for colored glass and plastic containers.

Detailed description

In accordance with the above, the present invention relates to a pharmaceutical aqueous composition containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4 -yl-1,3,5-triazin-2-yl)phenyl]urea, or a pharmaceutically acceptable organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin, and water, which is a clear solution, with the proviso that the organic or inorganic acid (including its salt) is not a sulfonic acid (hereinafter referred to as "the composition of the invention").

More specifically, the present invention relates to a pharmaceutical aqueous formulation containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or a pharmaceutically acceptable organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin, and water, where sufficient amounts are pharmaceutically an acceptable organic or inorganic acid and a pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including its salt) is not a sulfonic acid.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein sufficient amounts of a pharmaceutically acceptable organic or inorganic acid and a pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including its salt) is not a sulfonic acid.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising the pharmaceutically acceptable salt 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine- 4-yl-1,3,5-triazin-2-yl)phenyl]urea with an organic or inorganic acid, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where sufficient amounts of a pharmaceutically acceptable organic or an inorganic acid and a pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including its salt) is not a sulfonic acid.

In such embodiments, where applicable, the acid forming a pharmaceutically acceptable salt with an organic or inorganic acid and the pharmaceutically acceptable organic or inorganic acid are preferably the same.

Preferably, the pharmaceutically acceptable organic acid used (including the acid for its salt) is lactic acid, tartaric acid, malic acid, citric acid, succinic acid, acetic acid or maleic acid. This acid may be used in its racemic form, or as a single stereoisomeric form (or as mixtures thereof), where applicable.

Preferably, the pharmaceutically acceptable inorganic acid used (including the acid for its salt) is hydrochloric acid or phosphoric acid.

Examples of pharmaceutically acceptable beta-cyclodextrin are 2-hydroxyropyl-beta-cyclodextrin and sulfobutylether-β-cyclodextrin (SBECD). Examples of such pharmaceutically acceptable gamma-cyclodextrin are gamma-cyclodextrin and 2-hydroxypropyl-gamma-cyclodextrin. Preferably, hydroxypropyl-beta-cyclodextrin is used in the compositions of the invention. By using a pharmaceutically acceptable beta- or gamma-cyclodextrin, it has been found that clear solutions can be obtained without any presence of turbidity and/or containing higher concentrations of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl }phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]ureas than those obtained in the absence of the cyclodextrin component.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or a pharmaceutically acceptable salt thereof with an organic or inorganic acid, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-( 4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl] urea is present in a concentration of at least 6 mg/ml of solution, and where sufficient amounts of a pharmaceutically acceptable organic or inorganic acid and a pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic the acid (including its salt) is not a sulfonic acid.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of at least 6 mg/ml solution, and where sufficient amounts of a pharmaceutically acceptable organic or inorganic acid and a pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including its salt) is not a sulfonic acid.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising the pharmaceutically acceptable salt 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine- 4-yl-1,3,5-triazin-2-yl)phenyl]urea with an organic or inorganic acid, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{ [4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in concentration of at least 6 mg/ml of solution, and where sufficient amounts of a pharmaceutically acceptable organic or inorganic acid and a pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution, provided that the organic or inorganic acid (including its salt) is not a sulfonic acid.

Compounds with lactic acid

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or a lactic acid salt thereof, lactic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 30 mg/ml or from 6 to less than 35 mg/ml solution, and where sufficient amounts of lactic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, lactic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 6 to 30 mg/ml or 6 to less than 35 mg/ml solution, and where sufficient amounts of lactic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with lactic acid, lactic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 6 to 30 mg/ml or from 6 to less than 35 mg/ml of solution, and wherein sufficient amounts of lactic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or a lactic acid salt thereof, lactic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 25 , 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution, and where sufficient lactic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, lactic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of from 6 to 25, from 6 to 20, from 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution, and where sufficient lactic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with lactic acid, lactic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 6 to 25, from 6 up to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/ml solution, and where sufficient lactic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

Preferably, for the aforementioned lactic acid-containing embodiments, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with lactic acid, lactic acid, sulfobutylether-β-cyclodextrin (SBECD) and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 25 mg/ml or from 6 to less than 30 mg/ml solution, and where sufficient amounts of lactic acid and sulfobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with lactic acid, lactic acid, 2-hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino) piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 30 mg /ml or from 6 to less than 35 mg/ml solution, and where sufficient amounts of lactic acid and 2-hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with lactic acid, lactic acid, 2-hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino) piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 30, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/ml solution, and where sufficient lactic acid and 2-hydroxypropyl-beta-cyclodextrin are present providing a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with lactic acid, lactic acid, 2-hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino) piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 30, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution, and where the concentration of lactic acid is 10 to 100, 15 to 100 or from 30 to 100 mm, and the concentration of 2-hydroxypropyl-beta-cyclodextrin is from 15 to 120, from 20 to 120 or from 35 to 120 mg/ml, which provides a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, lactic acid, 2-hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl }phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 10 to 30 or 10 to 20 mg/mL solution, and, where the concentration of lactic acid is from 20 to 100 or from 30 to 100 mm, and the concentration of 2-hydroxypropyl-beta-cyclodextrin is from 35 to 120 mg/ml, which provides a clear solution.

In such lactic acid formulations, DL-lactic acid or L-lactic acid, or any combination thereof, may be used. Preferably, DL-lactic acid is used.

Compounds with acetic acid

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or an acetic acid salt thereof, acetic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 15 mg/ml or from 3 to less than 20 mg/ml solution, and where sufficient amounts of acetic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, acetic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 15 mg/ml or 3 to less than 20 mg/ml solution, and where sufficient amounts of acetic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with acetic acid, acetic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 15 mg/ml or from 3 to less than 20 mg/ml of solution, and wherein sufficient amounts of acetic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or an acetic acid salt thereof, acetic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 15 , 8 to 15 or 10 to 15 mg/ml solution, and wherein sufficient amounts of acetic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, acetic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 15, 8 to 15, or 10 to 15 mg/ml solution, and where sufficient amounts of acetic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with acetic acid, acetic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 6 to 15, from 8 up to 15 or 10 to 15 mg/ml solution, and wherein sufficient amounts of acetic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

Preferably, for the above acetic acid-containing embodiments, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin (SBECD).

Formulations with maleic acid

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with maleic acid, maleic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 30 mg/ml or from 3 to less than 35 mg/ml solution, and where sufficient amounts of maleic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, maleic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 30 mg/ml or 3 to less than 35 mg/ml solution, and where sufficient amounts of maleic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with maleic acid, maleic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 30 mg/mL or from 3 to less than 35 mg/ml of solution, and wherein sufficient amounts of maleic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with maleic acid, maleic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25 , 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution, and, where sufficient amounts maleic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, maleic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25, 4 to 20, from 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/ml solution, and where sufficient amounts of maleic acid and pharmaceutically acceptable beta- or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with maleic acid, maleic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 4 to 25, from 4 up to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25 or 10 to 20 mg/ml solution, and where sufficient amounts of maleic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

Preferably, for the above maleic acid-containing embodiments, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with maleic acid, maleic acid, hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 20 mg/mL or from 3 to less than 25 mg/ml of solution, and where sufficient amounts of maleic acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with maleic acid, maleic acid, gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 15 mg/ml or from 3 to less than 20 mg/ml solution, and where sufficient amounts of maleic acid and gamma-cyclodextrin are present to provide a clear solution.

Compositions with succinic acid

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with succinic acid, succinic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 65 mg/ml or from 3 to less than 70 mg/ml solution, and where sufficient amounts of succinic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, succinic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 65 mg/ml or 3 to less than 70 mg/ml solution, and where sufficient amounts of succinic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with succinic acid, succinic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 65 mg/mL or from 3 to less than 70 mg/ml of solution, and wherein sufficient amounts of succinic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with succinic acid, succinic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25 , 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution, and, where sufficient amounts succinic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, succinic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25, 4 to 20, from 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/ml solution, and where sufficient amounts of succinic acid and pharmaceutically acceptable beta- or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with succinic acid, succinic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 4 to 25, from 4 up to 20, from 4 to 15, from 6 to 25, from 6 to 20, from 6 to 15, from 10 to 30, from 10 to 25 or from 10 to 20 mg / ml of solution, and, where sufficient amounts of succinic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

Preferably, for the above succinic acid-containing embodiments, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with succinic acid, succinic acid, hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 25 mg/mL or from 3 to less than 30 mg/ml of solution, and where sufficient amounts of succinic acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with succinic acid, succinic acid, sulfobutylether-β-cyclodextrin (SBECD) and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 20 mg/ml or from 3 to less than 25 mg/ml solution, and where sufficient amounts of succinic acid and sulfobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution.

Compositions with citric acid

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or a citric acid salt thereof, citric acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 55 mg/ml or from 3 to less than 60 mg/ml solution, and where sufficient amounts of citric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, citric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 55 mg/ml or 3 to less than 60 mg/ml solution, and where sufficient amounts of citric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with citric acid, citric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 55 mg/mL or from 3 to less than 60 mg/ml of solution, and wherein sufficient amounts of citric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or a citric acid salt thereof, citric acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25 , 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20 mg/ml solution, and where sufficient amounts of citric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, citric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25, 4 to 20, from 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25 or 10 to 20 mg/ml solution, and, wherein sufficient amounts of citric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with citric acid, citric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 4 to 25, from 4 up to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution, and wherein sufficient amounts of citric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

Preferably, for the above citric acid-containing embodiments, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with citric acid, citric acid, hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 25 mg/mL or from 3 to less than 30 mg/ml of solution, and where sufficient amounts of citric acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its citric acid salt, citric acid, sulfobutylether-β-cyclodextrin (SBECD) and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 20 mg/ml or from 3 to less than 25 mg/ml solution, and where sufficient amounts of citric acid and sulfobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution.

Compositions with malic acid

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with malic acid, malic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 65 mg/ml or from 3 to less than 70 mg/ml solution, and where sufficient amounts of malic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, malic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 65 mg/ml or 3 to less than 70 mg/ml solution, and where sufficient amounts of malic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with malic acid, malic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 65 mg/mL or from 3 to less than 70 mg/ml of solution, and wherein sufficient amounts of malic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with malic acid, malic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25 , 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20 mg/ml solution, and where sufficient amounts of malic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, malic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25, 4 to 20, from 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25 or 10 to 20 mg/ml solution, and, wherein sufficient amounts of malic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with malic acid, malic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 4 to 25, from 4 up to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution, and wherein sufficient amounts of malic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

Preferably, for the aforementioned malic acid-containing embodiments, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with malic acid, malic acid, hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 30 mg/mL or from 3 to less than 35 mg/ml of solution, and where sufficient amounts of malic acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with malic acid, malic acid, sulfobutylether-β-cyclodextrin (SBECD) and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 25 mg/ml or from 3 to less than 30 mg/ml solution, and where sufficient amounts of malic acid and sulfobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution.

Compositions with tartaric acid

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or a tartaric acid salt thereof, tartaric acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 65 mg/ml or from 3 to less than 70 mg/ml solution, and where sufficient amounts of tartaric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, tartaric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 65 mg/mL or 3 to less than 70 mg/ml solution, and where sufficient amounts of tartaric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with tartaric acid, tartaric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 65 mg/mL or from 3 to less than 70 mg/ml of solution, and wherein sufficient amounts of tartaric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or a tartaric acid salt thereof, tartaric acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25 , 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20 mg/ml solution, and where sufficient amounts of tartaric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, tartaric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25, 4 to 20, from 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25 or 10 to 20 mg/ml solution, and, wherein sufficient amounts of tartaric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with tartaric acid, tartaric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 4 to 25, from 4 up to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution, and where sufficient amounts of tartaric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

Preferably, for the above tartaric acid-containing embodiments, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with tartaric acid, tartaric acid, hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 30 mg/mL or from 3 to less than 35 mg/ml of solution, and where sufficient amounts of tartaric acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or a salt thereof with tartaric acid, tartaric acid, sulfobutylether-β-cyclodextrin (SBECD) and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 25 mg/ml or from 3 to less than 30 mg/ml solution, and where sufficient amounts of tartaric acid and sulfobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution.

Compounds with hydrochloric acid

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with hydrochloric acid, hydrochloric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 60 mg/ml or from 3 to less than 65 mg/ml solution, and where sufficient amounts of hydrochloric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, hydrochloric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 60 mg/ml or 3 to less than 65 mg/ml solution, and where sufficient amounts of hydrochloric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with hydrochloric acid, hydrochloric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 60 mg/mL or from 3 to less than 65 mg/ml of solution, and where sufficient amounts of hydrochloric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with hydrochloric acid, hydrochloric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25 , 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 35, 10 to 25 or 10 to 20 mg/ml solution, and wherein sufficient amounts of hydrochloric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, hydrochloric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25, 4 to 20, from 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 35, 10 to 25, or 10 to 20 mg/day ml of solution, and where sufficient amounts of hydrochloric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with hydrochloric acid, hydrochloric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 4 to 25, from 4 up to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 35, 10 to 25 or 10 up to 20 mg/ml solution, and where sufficient amounts of hydrochloric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

Preferably, for the above hydrochloric acid-containing embodiments, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with hydrochloric acid, hydrochloric acid, hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 3 to 35 mg/mL or from 3 to less than 40 mg/ml solution, and where sufficient amounts of hydrochloric acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with hydrochloric acid, hydrochloric acid, sulfobutylether-β-cyclodextrin (SBECD) and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 30 mg/ml or from 3 to less than 35 mg/ml solution, and where sufficient amounts of hydrochloric acid and sulfobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution.

Compositions with phosphoric acid

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with orthophosphoric acid, orthophosphoric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 50 mg/ml or 4 to less than 55 mg/ml solution, and where sufficient amounts of phosphoric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 4 to 50 mg/ml or 4 to less than 55 mg/ml solution, and where sufficient amounts of phosphoric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with orthophosphoric acid, orthophosphoric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 4 to 50 mg/ml or from 4 to less than 55 mg/ml of solution, and wherein sufficient amounts of orthophosphoric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with orthophosphoric acid, orthophosphoric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25 , 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 35, 10 to 25 or 10 to 20 mg/ml solution, and wherein sufficient amounts of orthophosphoric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 25, 4 to 20, from 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 35, 10 to 25, or 10 to 20 mg/day ml of solution, and where sufficient amounts of phosphoric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea with orthophosphoric acid, orthophosphoric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 4 to 25, from 4 up to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 35, 10 to 25 or 10 up to 20 mg/ml solution, and where sufficient amounts of phosphoric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

Preferably, for the aforementioned phosphoric acid-containing embodiments, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with orthophosphoric acid, orthophosphoric acid, hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 4 to 35 mg/ml or from 4 to less than 40 mg/ml solution, and, where sufficient amounts of phosphoric acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment, a pharmaceutical aqueous formulation is provided comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea, or its salt with orthophosphoric acid, orthophosphoric acid, sulfobutylether-β-cyclodextrin (SBECD) and water, where 1-(4-{[4-(dimethylamino )piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 30 mg/ml or from 4 to less than 35 mg/ml solution, and where sufficient amounts of phosphoric acid and sulfobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution.

The "concentration in solution" values referred to herein refer to the concentration of the free base 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea in the composition of the invention.

The compositions of the invention may be administered directly to the patient (to avoid degradation), intravenously or parenterally, preferably with the addition of a tonicity regulator. Alternatively, if administered to a patient after some time has elapsed, such formulation, optionally containing a bulking agent and/or tonicity regulator, may first be freeze-dried to form a freeze-dried solid composition that is chemically shelf-stable (preferably at least 2 years). ), and where the lyophilized solid composition can then be reconstituted, or reconstituted, to provide a clear aqueous solution, preferably with the addition of a tonicity regulator, if necessary, immediately before administration to the patient by the intravenous (or parenteral) route. The reconstituted or reconstituted solution may be injected into an infusion bag prior to administration to a patient.

The preferred concentration of a pharmaceutically acceptable organic or inorganic acid for use in the composition of the invention is 10 to 200 mM, or 50 to 200 mM, and is preferably about 50 mM, about 100 mM, or about 150 mM. Preferably, the concentration of the pharmaceutically acceptable organic or inorganic acid is about 100 mM.

The preferred amount of pharmaceutically acceptable beta- or gamma-cyclodextrin for use in the formulation of the invention is 2 to 30% w/v, 5 to 20% w/v, or 15 to 30% w/v, and preferably is approximately 20% wt./volume or approximately 25% wt./volume. Preferably, the amount of pharmaceutically acceptable beta- or gamma-cyclodextrin to be used in the formulation of the invention is about 20% w/v.

If the formulation of the invention is to be lyophilized to provide a lyophilized solid composition, a bulking agent may be added to the formulation before the lyophilization process begins. The main function of the bulking agent is to provide a lyophilized solid having non-collapsed structural integrity that will allow for rapid resolubility upon reconstitution of the aqueous formulation prior to administration, and should also facilitate efficient lyophilization. Bulking agents are usually used when the total mass of dissolved substances in the composition is less than 2 g/100 ml. Bulking agents may also be added to achieve isotonicity with blood. The bulking agent may be selected from a saccharide, sugar alcohol, amino acid, or polymer, or may be a mixture of any two or more of these. Preferably, the bulking agent is a sugar or a sugar alcohol, or a mixture thereof. Preferably, the sugar is sucrose. Preferably, the sugar alcohol is mannitol.

Preferably, if present, 5 to 10% w/v bulking agent is used.

Redissolution of the lyophilized solid composition can be achieved by adding the required amount of water, which was present prior to lyophilization, to obtain a clear solution. A tonicity regulator may then be added prior to use.

Dissolution of the lyophilized solid composition can be achieved with an appropriate amount of water and/or an aqueous solution of a suitable tonicity regulator to ensure a clear solution is obtained.

The tonicity regulator may be present prior to intravenous or parenteral administration of the formulation to a patient by injection, to avoid jagged or hemolytic red blood cells, and to alleviate or eliminate pain and discomfort in the patient. This requires that the composition to be administered to the patient has an effective osmotic pressure that approximates the effective osmotic pressure of the patient's blood.

Suitable tonicity regulators are non-ionic tonicity regulators such as glycerol, sorbitol, mannitol, sucrose, propylene glycol or dextrose, or a mixture of any two or more of these. Preferably, the non-ionic tonicity regulator is dextrose, sucrose, or mannitol, or a mixture thereof, consisting of any two or more of these.

Preferably, 1 to 5% w/v tonicity regulator is used.

Aqueous pharmaceutical formulations of the invention that are suitable for intravenous administration typically have a pH of 3 to 9. However, lower pH values are acceptable in some treatment regimens. Preferably the pH is 3 to 8 or 4 to 8.

The composition of the invention can be used for the treatment, palliative care or prevention of cancer in a mammal, including a human. The cancer to be treated may be selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, stomach cancer and brain cancer.

Weekly dose of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2 -yl)phenyl]urea to be administered intravenously for the treatment of cancer using the formulations disclosed herein is preferably in the range of 100 to 400 mg per week.

The following examples describe the preparation of the compositions of the invention.

EXAMPLE 1

Preparation of a pharmaceutical composition in the form of an aqueous solution containing 35 mg/ml 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea, 20% w/v 2-hydroxypropyl-beta-cyclodextrin and hydrochloric acid

Hydrochloric acid (1M aqueous solution) (10 ml, 100 mm) is diluted with water for irrigation (80 ml). 2-Hydroxypropyl-beta-cyclodextrin (adjusted 93% w/w) (21.57 g, 147.2 mmol) is added and the solution is stirred until a particle-free solution is obtained. 1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin- 2-yl)phenyl]urea (3500 mg, 56.9 mmol) and stirred until a particle-free solution is obtained. Irrigation water is added with stirring to give a target volume of 100 ml.

visual analysis

A sample of the formulation is analyzed according to the visual method defined in European Pharmacopeia Method 2.9.20 (using a camera with Verivide (trademark) light and a photometer reading 3250 lux against a matte black panel and a white panel) to determine the presence of crystallites or particles. The sample is tested in this way both when the solution has just been prepared and again after 24 hours.

(ii) OPM analysis

A sample of the composition is placed on a clean glass slide for microscopy and covered with a protective coverslip. It is then analyzed by OPM using both unpolarized and cross-polarized light, under a Nikon LV 100POL (trade mark) microscope with 10x magnification lenses and a 10x magnification eye, to establish the presence of crystallites or particles. The image is recorded using a DFK 23UP031 TIS USB 3.0 CMOS (trademark) 5MP 1/2.5” technical color camera and video image capture software. The procedure is also repeated using a sample of the composition in a glass capillary tube. The sample is tested in this way when the solution has just been prepared and again after 4 and 24 hours.

EXAMPLE 2

Preparation of a pharmaceutical composition in the form of an aqueous solution containing 30 mg/ml 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea, 20% w/v sulfobutylether-beta-cyclodextrin (SBECD) and tartaric acid

Tartaric acid (racemic) (content 99% w/w) (1.5 g, 100 mmol) is diluted with water for irrigation (80 ml). Sulfobutylether-beta-cyclodextrin (adjusted 90% w/w) (22.18 g, 195 mmol) is added and the solution is stirred until a particle-free solution is obtained. 1-(4-{[4-(Dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin- 2-yl)phenyl]urea (3000 mg, 48.7 mmol) and stirred until a particle-free solution is obtained. Irrigation water is added with stirring to give a target volume of 100 ml.

Samples of the composition are analyzed in accordance with the methods of Example 1.

EXAMPLE 3

Preparation of a pharmaceutical composition in the form of an aqueous solution containing 45 mg/ml 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea, 20% w/v gamma-cyclodextrin and phosphoric acid

Orthophosphoric acid (tolerance 99% w/w) (979 mg, 100 mmol) is diluted with water for irrigation (80 ml). Gamma-cyclodextrin (tolerance 100% w/w) (20 g, 154 mmol) is added and the solution is stirred until a particle-free solution is obtained. To this solution is added 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazine -2-yl)phenyl]urea (4500 mg, 73.1 mmol) and stirred until a particle-free solution is obtained. Irrigation water is added with stirring to give a target volume of 100 ml.

Samples of the composition are analyzed in accordance with the methods of Example 1.

EXAMPLE 4

Obtaining a lyophilized composition based on a pharmaceutical composition in the form of an aqueous solution according to the invention

The aqueous solution pharmaceutical composition of the invention (eg, prepared in accordance with any of Examples 1-3) is filled into 10 ml vials to a target volume of 3 ml. The vials are loosely stoppered (not sealed) using a Gray Lyo D777-1 V10-F597W FluroTec (trade mark) siliconized stopper 20 mm thick. The vials are loaded into stainless steel trays and inserted into an LSL1000 (trademark) lyophilizer. The temperature on the shelf is set at 5°C. The lyophilization cycle is then carried out according to standard procedures.

At the end of the lyophilization cycle, the lyophilizer is refilled with sterile filtered nitrogen to a setpoint of 500 Torr (approximately 666 mbar or 66600 Pascal) and the vials are tightly closed with stoppers. The lyophilizer is then depressurized to atmospheric pressure using sterile filtered air and the vials are discharged from the lyophilizer.

Each vial contains the freeze-dried (lyophilized) formulation as a solid.

EXAMPLE 5

Redissolution of a pharmaceutical composition in the form of an aqueous solution according to the invention from a lyophilized solid composition according to the invention

The vial with the lyophilized solid composition obtained in Example 4 is reconstituted as follows. Irrigation water (3 ml) is injected with a syringe into the vial containing the lyophilized composition obtained in Example 4. The mixture is stirred by rotating the vial until a particle-free solution is obtained.

EXAMPLE 6

Obtaining a lyophilized composition based on a pharmaceutical composition in the form of an aqueous solution containing 10 mg/ml 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, 5% w/v 2-hydroxypropyl-beta-cyclodextrin and lactic acid

DL-lactic acid (4.505 g, 30 mmol) is diluted with water for irrigation (1275 ml). 2-Hydroxypropyl-beta-cyclodextrin (adjusted 92.85% w/w) (80.775 g, 35.7 mmol) is added and the solution is stirred until a particle-free solution is obtained. To this solution is added 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazine -2-yl)phenyl]urea (15.00 g, 16.24 mmol) and stirred until a particle-free solution was obtained. Irrigation water is added with stirring to give a target volume of 1500 ml.

The aqueous solution pharmaceutical formulation of the invention (above) is filled into 20 ml vials to a target volume of 7 ml. The vials are loosely stoppered (not sealed) using a Gray Lyo D777-1 V10-F597W FluroTec (trade mark) siliconized stopper 20 mm thick. The vials are loaded into stainless steel trays and inserted into an LSL1000 (trademark) lyophilizer. The lyophilization cycle is then carried out according to standard procedures.

At the end of the lyophilization cycle, the lyophilizer is refilled with sterile filtered nitrogen to a setpoint of 500 Torr (approximately 666 mbar or 66600 Pascal) and the vials are tightly closed with stoppers. The lyophilizer is then depressurized to atmospheric pressure using sterile filtered air and the vials are discharged from the lyophilizer.

Each vial contains the freeze-dried (lyophilized) formulation as a solid.

ADDITIONAL EXAMPLES for preparing pharmaceutical formulations in aqueous solution containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea, beta- or gamma-cyclodextrin and a pharmaceutically acceptable organic or inorganic acid

Subsequent tabulated samples of the Examples (indicated by a check mark or a cross) (target volume=100 ml) were prepared by methods analogous to those of Examples 1-3 using the ingredient specification shown in the table below.

These samples of the Examples are analyzed by the visual control method defined in EP Method 2.9.20 and by the OPM method, both of which are described in Example 1. These results are also summarized in the table below.

In this Table, "particle-free" means that the formulation is visually clear and free of visible crystallites or particles and meets the required definition of "clear solution" as previously described.

Abbreviations

API =1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazine-2 -yl)phenyl]urea

*=acid used in racemic form;

HPBCD =2-hydroxypropyl-beta-cyclodextrin;

SBECD =sulfobutylether-β-cyclodextrin;

GammaCD =gamma cyclodextrin;

AlphaCD = alpha cyclodextrin;

(1) = Free from particles (and non-opalescent). All of these Examples studied are free of visible crystalline or particulate matter and meet the required definition of "clear solution" as described previously;

(2) = particulate suspension.

Chemical stability of the lyophilized solid composition according to the invention

A sample of the lyophilized composition according to the invention is prepared in accordance with Example 6 ("Sample A").

Each individual portion of Sample A is placed in a 20 ml clear vial and one is stored at 25°C/60% Relative Humidity ("RH") for 6 months and the other is stored at 40°C/75% -noy RH for 6 months.

After 6 months of storage under the above conditions, each individual Sample is tested for chemical purity by Ultra High Performance Liquid Chromatography (UHPLC) using the methodology below, measuring any chemical degradation during the test period.

UHPLC Method

Solutions, samples, standards and the UHPLC method are as follows:

Reference Standard Solution : 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazine -2-yl)phenyl]urea with a known content value.

Diluent: Acetonitrile/Water/Trifluoroacetic acid (v/v/v 750:250:1)

Mobile Phase A: Acetonitrile/Water/Trifluoroacetic acid (v/v/v 97:3:1)

Mobile Phase B: Acetonitrile/Trifluoroacetic acid (v/v 1000:1)

(Note: larger or smaller volumes of solutions can be obtained using the appropriate ratio of components).

Standard solution and Control solution:

Carefully prepare two solutions that are a Reference Standard containing approximately 0.2 mg/mL (+/- 10%) 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3 -[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea in Diluent and record the exact concentrations of both. These solutions are the Standard Solution and the Control Solution.

Solution for determining the sensitivity of the system:

Accurately dilute the Standard Solution to approximately 0.1 micrograms/mL with 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4- yl-1,3,5-triazin-2-yl)phenyl]urea using a Diluent.

Sample solution preparation:

Reconstitute Sample A after storage by adding 7.0 ml of water to each 20 ml vial, shake the vial until the solid dissolves and wait for the bubbles to disappear. Transfer 1.0 ml of this solution to a 50 ml volumetric flask. Dilute to the prescribed volume with Thinner.

Conditions for chromatography:

Liquid Chromatography System - Agilent 1290 Infinity II™ with 380 µl Jet Weaver™ Multilayer Mixing System

Column: Waters BEH C18™ 15 cm × 2.1 mm, 1.7 µm or equivalent

Column temperature: 20°C

Injection volume: 2 µl

Flow rate: 0.25 ml/min

Flow cell: G4212-60008, layer thickness 10 mm, 1.0 µl

Detection: UV at 240 nm / slit width 4 nm

Chromatogram recording time: 77 minutes

Mobile Phase A

Mobile Phase B

Needle wash solution: Water/Acetonitrile (v/v 95:5), multiple washes 20 sec

Sealant Wash Solution: Water/Propan-2-ol (90:10 v/v)

Linear gradient elution table

Time (minutes) Mobile Phase A % Mobile phase in % 0 95 5 5.0 95 5 31.4 78 22 42.3 78 22 65.0 5 95 67.0 5 95 67.1 95 5 77.0 95 5

Explanatory notes

Before starting the analysis, the UHPLC system is subjected to mobile phase treatment.

Before analyzing samples with samples, verify that the system is fit for use by introducing a diluent blank, a system sensitivity solution, and a standard solution using the above chromatographic conditions.

The following criteria must be met during the initial preparation of the system for UHPLC or after any major change to the system. It is recommended to inject at least one conditioning blank before testing the suitability of the chromatographic system.

Trial No. of injected samples Solution Criteria blank test one Diluent Free from interfering peaks Signal/Noise one System Sensitivity Solution European Pharmacopoeia (EP) / United States Pharmacopeia (USP) Signal/Noise ≥ 10 Reproducibility 5 Standard solution Relative Standard Deviation ≤2.0% retention time one* 38-44 minutes Efficiency (Theoretical plate)** Number of theoretical plates for peak 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5- triazin-2-yl)phenyl]urea ≥10000 Peak asymmetry (T)** 0.9≤T≤2.0 for peak 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea Permission one Peak-to-Peak Resolution 2-yl)phenyl]urea and Decomposition product 2 [((4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)-l2-azaneyl)((4-(4-( methyl-l2-azaneyl)piperidine-1-carbonyl)phenyl)-l2-azaneyl)methanone] ≥ 1.0

*Take the average of all input samples to assess system suitability (reproducibility),

**Refer to the formulas for calculating Efficiency and Peak Skewness given in the United States Pharmacopeia (USP).

Introduce the control solution in accordance with the chromatography conditions above. The response factor (calculated from area, standard weight, dilution factor, and standard purity factor) for a given control solution must be within ±2% of the standard solution.

After the suitability of the system is confirmed, inject the blank, standard, and prepared test samples, followed by injecting the standard in accordance with the chromatography conditions described above. It is recommended to inject no more than 6 test specimens between injections of the standard solution. For each input (standard and sample), the retention time and peak area of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4.6 -dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea. For each sample injection, also determine the retention time and peak area for any peaks present at the sample injection and not present at the blank injection. If there are artifacts that originate from the gradient, they are not integrated. To determine which peaks in a sample are due to blank and gradient artifacts, compare the chromatograms from blank injection to sample injection. Calculate % (w/w) of degradation products and indicate individual peaks of degradation products constituting or greater than 0.05% w/w. Unknown degradation products should be listed separately with their relative retention times. Known degradation products should be listed separately with their name.

These results are summarized in the table below.

Abbreviations

NMT - no more

RRT - relative retention time

Decomposition product 1

Decomposition products 2, 3 and 4

Each of them is characterized only by the value of the relative retention time (RRT).

Results for Sample A

25°C/60%RH 40°C/75%RH Decomposition product Eligibility Criteria Initially 6 months 6 months Decomposition product 1 (RRT ~0.72) NMT 0.5% 0.10% 0.12% 0.14% Decomposition product 2 (RRT ~0.98) NMT 1.1% NMT 0.05% NMT 0.05% 0.10% Decomposition product 3 (RRT ~1.07) NMT 0.5% NMT 0.05% NMT 0.05% 0.13% Decomposition product 4 (RRT ~1.17) NMT 0.5% 0.06% NMT 0.05% NMT 0.05% Total Decomposition Products NMT 3.0% 0.16% 0.12% 0.37%

Conclusion

The results show that Sample A is chemically stable for at least 6 months at 25°C/60% RH and for at least 6 months at 40°C/75% RH.

Claims (44)

1. Pharmaceutical aqueous composition containing the compound 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3 ,5-triazin-2-yl)-phenyl]-urea or a pharmaceutically acceptable salt thereof with an organic or inorganic acid, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein sufficient amounts of a pharmaceutically acceptable organic or inorganic acid are present. acid and pharmaceutically acceptable beta- or gamma-cyclodextrin, which provide a clear solution, where the compound or its pharmaceutically acceptable organic or inorganic acid salt and the pharmaceutically acceptable organic or inorganic acid are selected from the group consisting of: (i) a compound or its lactate salt and lactic acid, wherein the compound is present in solution at a concentration of 6 mg/mL to 30 mg/mL; (ii) a compound or an acetate salt thereof and acetic acid, wherein the compound is present in solution at a concentration of 3 mg/mL to about 15 mg/mL; (iii) a compound or its maleate salt and maleic acid, where the compound is present in solution at a concentration of 3 mg/mL to 30 mg/mL; (iv) a compound or its succinate salt and succinic acid, wherein the compound is present in solution at a concentration of 3 mg/mL to 65 mg/mL; (v) a compound or its citrate salt and citric acid, wherein the compound is present in solution at a concentration of 3 mg/mL to 55 mg/mL; (vi) a compound or its malate salt and malic acid, wherein the compound is present in solution at a concentration of 3 mg/mL to 65 mg/mL; (vii) a compound or its tartrate salt and tartaric acid, wherein the compound is present in solution at a concentration of 3 mg/mL to 65 mg/mL; (viii) a compound or its hydrochloride salt and hydrochloric acid, wherein the compound is present in solution at a concentration of 3 mg/mL to 45 mg/mL; and (ix) a compound or its phosphate salt and phosphoric acid, wherein the compound is present in solution at a concentration of 4 mg/mL to 45 mg/mL. 2. Pharmaceutical aqueous composition according to claim 1, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or a salt thereof with lactic acid, lactic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 30 mg/ ml of solution and where sufficient amounts of lactic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 3. Pharmaceutical aqueous composition according to claim 2, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea, lactic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl }phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 6 to 30 mg/ml solution and where sufficient amounts lactic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 4. Pharmaceutical aqueous composition according to claim 2, containing salt 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea with lactic acid, lactic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 6 to 30 mg/ml solution and wherein sufficient amounts of lactic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 5. Pharmaceutical aqueous composition according to claim 2, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or a salt thereof with lactic acid, lactic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 25, from 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/ml solution and wherein sufficient lactic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 6. Pharmaceutical aqueous composition according to claim 2, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea, lactic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl }phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 25, 6 to 20, 6 up to 15, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution, and wherein sufficient lactic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution. 7. Pharmaceutical aqueous composition according to claim 2, containing salt 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl -1,3,5-triazin-2-yl)phenyl]urea with lactic acid, lactic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution, and wherein sufficient lactic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution. 8. Pharmaceutical aqueous composition according to any one of paragraphs. 2-7, wherein the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulfobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. 9. A pharmaceutical aqueous composition according to claim 8, wherein the pharmaceutically acceptable beta- or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin. 10. Pharmaceutical aqueous composition according to claim 2, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or its salt with lactic acid, lactic acid, sulfobutylether-β-cyclodextrin (SBECD) and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 6 to 25 mg/ ml or from 6 to less than 30 mg/ml of solution and where sufficient amounts of lactic acid and sulfobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution. 11. Pharmaceutical aqueous composition according to claim 2, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or its salt with lactic acid, lactic acid, 2-hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 6 to 30 mg/ml solution and where sufficient amounts of lactic acid and 2-hydroxypropyl-beta-cyclodextrin are present to provide a clear solution. 12. Pharmaceutical aqueous composition according to claim 2, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or its salt with lactic acid, lactic acid, 2-hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 6 to 30, from 6 up to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20 mg/mL solution and where sufficient lactic acid and 2-hydroxypropyl-beta-cyclodextrin are present to provide a clear solution . 13. Pharmaceutical aqueous composition according to claim 2, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or its salt with lactic acid, lactic acid, 2-hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine- 1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 6 to 30, from 6 up to 25, from 6 to 20, from 6 to 15, from 10 to 30, from 10 to 25 or from 10 to 20 mg / ml of solution and where the concentration of lactic acid is from 10 to 100, from 15 to 100 or from 30 to 100 mm and the concentration of 2-hydroxypropyl-beta-cyclodextrin is from 15 to 120, from 20 to 120 or from 35 to 120 mg/ml, which provides a clear solution. 14. Pharmaceutical aqueous composition according to claim 2, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea, lactic acid, 2-hydroxypropyl-beta-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl} phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a concentration of 10 to 30 or 10 to 20 mg/ml solution and where the concentration of lactic acid is from 20 to 100 or from 30 to 100 mm and the concentration of 2-hydroxypropyl-beta-cyclodextrin is from 35 to 120 mg/ml, which provides a clear solution. 15. Pharmaceutical aqueous composition according to claim 1, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or its salt with acetic acid, acetic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 15 mg/ ml of solution and wherein sufficient amounts of acetic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 16. Pharmaceutical aqueous composition according to claim 1, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or its salt with maleic acid, maleic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 30 mg/ ml of solution and wherein sufficient amounts of maleic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 17. Pharmaceutical aqueous composition according to claim 1, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or its salt with succinic acid, succinic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 65 mg/ ml of solution and wherein sufficient amounts of succinic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 18. Pharmaceutical aqueous composition according to claim 1, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or a citric acid salt thereof, citric acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, wherein 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 55 mg/ ml of solution and wherein sufficient amounts of citric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 19. Pharmaceutical aqueous composition according to claim 1, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or its salt with malic acid, malic acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 65 mg/ ml of solution and where sufficient amounts of malic acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 20. Pharmaceutical aqueous composition according to claim 1, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or a tartaric acid salt thereof, tartaric acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 65 mg/ ml of solution and wherein sufficient amounts of tartaric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 21. Pharmaceutical aqueous composition according to claim 1, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or its salt with hydrochloric acid, hydrochloric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 3 to 45 mg/ ml of solution and where sufficient amounts of hydrochloric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 22. Pharmaceutical aqueous composition according to claim 1, containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1,3,5-triazin-2-yl)phenyl]urea or its salt with orthophosphoric acid, orthophosphoric acid, pharmaceutically acceptable beta- or gamma-cyclodextrin and water, where 1-(4-{[4-(dimethylamino)piperidine -1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a concentration of 4 to 45 mg/ ml of solution and wherein sufficient amounts of phosphoric acid and pharmaceutically acceptable beta or gamma cyclodextrin are present to provide a clear solution. 23. Composition according to any one of paragraphs. 1-12 or 15-22, where 10 to 200 mM or 50 to 200 mM of a pharmaceutically acceptable organic or inorganic acid is used. 24. Composition according to any one of paragraphs. 1-12 or 15-23, where 2 to 30% w/v, 5 to 20% w/v, or 15 to 30% w/v cyclodextrin are used. 25. Freeze-dried lyophilized composition containing the composition according to any one of paragraphs. 1-24. 26. Freeze-dried lyophilized formulation according to claim 25 containing a bulking agent. 27. The freeze-dried lyophilized formulation of claim 26, wherein the bulking agent is mannitol. 28. Pharmaceutical composition in the form of an aqueous solution containing a lyophilized composition according to any one of paragraphs. 25-27, where the specified solution is a clear solution obtained by re-dissolving or restoring the lyophilized composition according to any one of paragraphs. 25-27 using water or an aqueous solution containing a tonicity regulator. 29. A pharmaceutical composition in the form of an aqueous solution according to claim 28, where the tonicity regulator is dextrose, sucrose or mannitol, or a mixture thereof, consisting of any two or more of these substances. 30. Pharmaceutical composition in the form of an aqueous solution according to any one of paragraphs. 1-24, or 28, or 29, which is adjusted, if necessary, so as to have a pH suitable for intravenous or parenteral administration. 31. Composition according to any one of paragraphs. 1-30 for use as a drug. 32. Composition according to any one of paragraphs. 1-30 for use in the treatment of cancer. 33. The use of the composition according to any one of paragraphs. 1-30 for cancer treatment. 34. Use according to claim 33, wherein the cancer is selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, pancreatic cancer, kidney cancer, stomach cancer and brain cancer.

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