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

Abstract

The present invention relates to an aqueous pharmaceutical preparation comprising 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 a pharmaceutically acceptable organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin and water, which is a clear solution, provided that the organic or inorganic acid (including its salt) is not a sulfonic acid. Such preparations are particularly suitable for intravenous or parenteral administration to patients.

Description

[0001] preparation

[0002] The present invention relates to a pharmaceutical formulation 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 organic or inorganic acid salt thereof. More specifically, the present invention relates to an aqueous pharmaceutical formulation 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 organic or inorganic acid salt thereof, which is a clear solution. Such formulations are particularly suitable for intravenous or parenteral administration to patients. Background Art

[0003] 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 WO2009 / 143313. The compound is an inhibitor of PI3 kinase and mTOR and is useful for treating cancer.

[0004] 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 the preparation method thereof are disclosed in WO2010 / 096619.

[0005] WO2016 / 097949 describes a pharmaceutical aqueous solution 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 a lactate thereof, lactic acid 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 at a solution concentration of less than 6 mg / ml, and sufficient lactic acid is present to provide 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-triazin-2-yl)phenyl]urea or a phosphate thereof, orthophosphoric acid, 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 at a solution concentration of less than 4 mg / mL and sufficient orthophosphoric acid is present to provide a clear solution. Lyophilization of such formulations is also described. Of the various acids tested (i.e., 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 were found to be able to produce clear solutions 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 at concentrations of 3 mg / ml or higher.

[0006] 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 also known as gedatolisib, which has the following chemical structure:

[0007]

[0008] 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

[0009] 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 prepared in crystalline form and remains chemically and physically stable in this form for up to 3 years at 25°C and 60% relative humidity (RH). However, the free base is not sufficiently water soluble to prepare an aqueous solution formulation suitable for intravenous or parenteral administration at the desired therapeutic dose levels.

[0010] There is a need to develop pharmaceutically acceptable aqueous solution formulations 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 that preferably (a) remain chemically stable upon storage (e.g., at 25°C and 60% RH), (b) facilitate effective intravenous (or parenteral) administration of the drug to mammals (including humans), and (c) preferably achieve a solution 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 of ​​at least 6 mg / ml. SUMMARY OF THE INVENTION

[0012] In order to achieve dosing to an individual using a single vial presentation of a commercially available drug product, a solution concentration of at least 6 mg / ml 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 is required. Lyophilized drug products (for reconstitution) containing less than 6 mg / ml of drug solution would require multiple vials to deliver the desired therapeutic dose. Given current regulatory expectations for these product types, the approach of dose delivery using multiple vials is not ideal.

[0013] 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 view of the specific pharmacokinetic and bioavailability characteristics of this drug.

[0014] The intravenous formulation of any drug must be a solution that facilitates safe and effective administration to patients. It must be particle-free and not form a gel or suspension. Clear aqueous solutions are preferred.

[0015] A "clear solution" herein is defined as a visually clear solution, which may have a solution opalescence, which is substantially free of any visible particles that can be observed upon visual inspection. Generally speaking, if any particulate matter is observed, the formulation is not suitable for intravenous administration and should not be used because vascular occlusion may occur. Accordingly, given the qualitative nature of the visual test, the term "substantially free of any visible particles" is generally applicable when no visible particulate matter is observed.

[0016] Particulate matter can be defined as follows:

[0017] Spots - dispersed particles whose shape cannot be determined without magnification

[0018] Puffs or swirls - fine particles that look like smoke or a tornado and usually originate from the bottom of the sample vial and swirl upward when the vial is turned

[0019] · Flocculent material - loosely aggregated particles or flakes

[0020] Particles that have a definite shape or features that can be described as glassy, ​​looking metallic, etc.

[0021] Visual inspection can be carried out according to the method defined in European Pharmacopoeia Method 2.9.20 entitled "Particulate contamination: visible particles" (see Figure 1 ). This method determines the particulate contamination of injections and infusions caused by foreign, mobile, undissolved particles other than air bubbles that may be present in the solution. The test is intended to provide a simple procedure for visually assessing the quality of parenteral solutions in terms of visible particles.

[0022] The method states: "Remove any adhered labels from the container and wash and dry the outside of the container. Gently turn or invert the container, making sure not to introduce air bubbles, and observe in front of a white panel for approximately 5 seconds. Repeat in front of a black panel. Record the presence of any particles."

[0023] A suitable method according to Ph. Eur. method 2.9.20 for use in the present invention is described in Example 1(i).

[0024] Other validated methods may also be used to determine the presence or absence of visible particles. Such methods include Optical Polarised Microscopy ("OPM"). A suitable OPM method for use in the present invention is described in Example 1(ii).

[0025] Without wishing to be bound by theory, any milky white hue may be caused by the formation of chromonic liquid crystals. Chromophoric liquid crystals are formed by forming π-π stacked aromatic portions of the molecule, which form columnar stacks of dimers, trimers, and low molecular weight oligomers of the molecule. The stacks formed can be confirmed by OPM as amorphous microstructures associated with chromonic liquid crystals. The amorphous microstructures exhibit non-permanent interactions, and there is motion to keep the system in free energy balance. The milky white color of the solution is caused by changes in the refractive index of the solution due to the formation of these stacks. OPM micrographs of the solution will confirm that there is no crystalline material, but rather a chromonic liquid crystal phase. The presence of a liquid crystal phase causes the solution to be opaque or milky white due to the presence of a refractive index difference in the solution formed. For a discussion of liquid crystal formation, see "Optical Properties of Condensed Matter and Applications", Jai Singh (ed.), ISBN: 978-0-470-02193-4, Wiley, October 2006.

[0026] Surprisingly, it has been found that by using pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin, an aqueous pharmaceutical formulation in the form of a clear solution can be prepared, which comprises (a) a 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, whose solution concentration is significantly higher than 6 mg / ml, and (b) one of a series of pharmaceutically acceptable organic or inorganic acids. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 Figure 2.9.20.-1 of the publication "European Pharmacopoeia Method 2.9.20" is reproduced and describes an apparatus consisting of an inspection table comprising: a matt black panel of suitable size held in a vertical position (1); a glare-free white panel of suitable size held in a vertical position next to the black panel (2); a glare-free white panel of suitable size held in a horizontal position at the bottom of the vertical panel (3); and an adjustable lamp holder (4) provided with a suitable light-shielded white light source and provided with a suitable diffuser (an inspection luminaire containing two 13 Watt fluorescent tubes, each 525 mm long, is suitable). The illumination intensity at the inspection point is maintained at 2000 to 3750 lux, but higher values ​​are preferably used for colored glass and plastic containers. DETAILED DESCRIPTION OF THE INVENTION

[0029] Therefore, the present invention relates to an aqueous pharmaceutical formulation 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 organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin and water, which is a clear solution, provided that the organic or inorganic acid (including its salt) is not a sulfonic acid (hereinafter referred to as the "preparation of the present invention").

[0030] More particularly, the present invention relates to an aqueous pharmaceutical formulation 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 organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin, and water, wherein sufficient pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution, provided that the organic or inorganic acid (including its salt) is not a sulfonic acid.

[0031] In one embodiment of the present invention, an aqueous pharmaceutical 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 β-cyclodextrin or γ-cyclodextrin, and water, wherein there is sufficient pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution, provided that the organic or inorganic acid (including its salts) is not a sulfonic acid.

[0032] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising a pharmaceutically acceptable organic or inorganic acid salt 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, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin, and water, wherein there is sufficient pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution, provided that the organic or inorganic acid (including its salt) is not a sulfonic acid.

[0033] In such embodiments, where applicable, the acid forming the pharmaceutically acceptable organic or inorganic acid salt is preferably the same as the pharmaceutically acceptable organic or inorganic acid.

[0034] Preferably, the pharmaceutically acceptable organic acid used (including the acid used for its salt) is lactic acid, tartaric acid, malic acid, citric acid, succinic acid, acetic acid or maleic acid. When applicable, the acid can be used in its racemic form or in a single stereoisomer form (or a mixture thereof).

[0035] Preferably, the pharmaceutically acceptable inorganic acid used (including the acid for its salts) is hydrochloric acid or orthophosphoric acid.

[0036] Examples of pharmaceutically acceptable β-cyclodextrins are 2-hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin (SBECD). Examples of such pharmaceutically acceptable γ-cyclodextrins are γ-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin. Preferably, hydroxypropyl-β-cyclodextrin is used in the formulation of the present invention. It has been found that by using pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin, a clear solution can be obtained that does not have a milky white color and / or contains a higher concentration of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazine-2-yl)phenyl]urea than can be obtained in the absence of a cyclodextrin component.

[0037] In one embodiment of the present invention, an aqueous pharmaceutical 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 organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of at least 6 mg / ml, and wherein there is sufficient pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution, provided that the organic or inorganic acid (including its salt) is not a sulfonic acid.

[0038] In one embodiment of the present invention, an aqueous pharmaceutical 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 β-cyclodextrin or γ-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 at a solution concentration of at least 6 mg / ml, and wherein there is sufficient pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution, provided that the organic or inorganic acid (including its salts) is not a sulfonic acid.

[0039] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising a pharmaceutically acceptable organic or inorganic acid salt 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, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of at least 6 mg / ml, and wherein there is sufficient pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution, provided that the organic or inorganic acid (including its salt) is not a sulfonic acid.

[0040] Lactic acid preparations

[0041] In one embodiment of the present invention, an aqueous pharmaceutical 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 lactate thereof, lactic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 30 mg / ml or 6 mg / ml to less than 35 mg / ml, and wherein sufficient lactic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0042] In one embodiment of the present invention, an aqueous pharmaceutical 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 β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 30 mg / ml or 6 mg / ml to less than 35 mg / ml, and wherein sufficient lactic acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0043] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising a lactate salt 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, lactic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 30 mg / ml or 6 mg / ml to less than 35 mg / ml, and wherein sufficient lactic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0044] In one embodiment of the present invention, an aqueous pharmaceutical preparation is provided, which comprises 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 lactate, lactic acid, pharmaceutically acceptable β-cyclodextrin or γ-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 or its lactate, lactic acid, pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin and water. -dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein there is sufficient lactic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

[0045] In one embodiment of the present invention, an aqueous pharmaceutical preparation is provided, which comprises 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 β-cyclodextrin or γ-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

[0045] The invention relates to a method for preparing an aqueous solution of 4-hydroxy-1,4-dextrin-4-yl-1,3,5-triazin-2-yl)phenyl]urea in a solution concentration of 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein sufficient lactic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0046] In one embodiment of the present invention, an aqueous pharmaceutical preparation is provided, which comprises a lactate 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, lactic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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

[0045] The invention relates to a method for preparing an aqueous solution of 4-nitro-2-nitro-1,4-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea in a solution concentration of 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein sufficient lactic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0047] Preferably, for the above embodiments of the present invention containing lactic acid, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin. More preferably, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin.

[0048] In one embodiment of the present invention, an aqueous pharmaceutical 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 lactate thereof, lactic acid, sulfobutyl ether-β-cyclodextrin (SBECD) 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 at a solution concentration of 6 mg / ml to 25 mg / ml or 6 mg / ml to less than 30 mg / ml, and wherein sufficient lactic acid and sulfobutyl ether-β-cyclodextrin (SBECD) are present to provide a clear solution.

[0049] In one embodiment of the present invention, an aqueous pharmaceutical 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 lactate thereof, lactic acid, 2-hydroxypropyl-β-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 at a solution concentration of 6 mg / ml to 30 mg / ml or 6 mg / ml to less than 35 mg / ml, and wherein sufficient lactic acid and 2-hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

[0050] In one embodiment of the present invention, an aqueous pharmaceutical preparation is provided, which comprises 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 lactate, lactic acid, 2-hydroxypropyl-β-cyclodextrin and water, wherein 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 lactate, lactic acid, 2-hydroxypropyl-β-cyclodextrin and water. -1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of 6 mg / ml to 30 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml, or 10 mg / ml to 20 mg / ml, and wherein sufficient lactic acid and 2-hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

[0051] In one embodiment of the present invention, an aqueous pharmaceutical preparation 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 lactate, lactic acid, 2-hydroxypropyl-β-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 added in an amount of 6 mg / ml to 30 mg / ml, 6 mg / ml to 10 mg / ml, and 2-hydroxypropyl-β-cyclodextrin is added in an amount of ... A solution concentration of 10 to 25 mg / ml, 6 to 20 mg / ml, 6 to 15 mg / ml, 10 to 30 mg / ml, 10 to 25 mg / ml or 10 to 20 mg / ml is present and wherein the lactic acid concentration is 10 to 100 mM, 15 to 100 mM or 30 to 100 mM and the 2-hydroxypropyl-β-cyclodextrin concentration is 15 to 120 mg / ml, 20 to 120 mg / ml or 35 to 120 mg / ml to provide a clear solution.

[0052] In one embodiment of the present invention, an aqueous pharmaceutical 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-β-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 at a solution concentration of 10 mg / ml to 30 mg / ml or 10 mg / ml to 20 mg / ml, and wherein the lactic acid concentration is 20 mM to 100 mM or 30 mM to 100 mM and the 2-hydroxypropyl-β-cyclodextrin concentration is 35 mg / ml to 120 mg / ml to provide a clear solution.

[0053] In such lactic acid preparations, DL-lactic acid, D-lactic acid or L-lactic acid or any combination thereof may be used. DL-lactic acid is preferably used.

[0054] Acetic acid preparation

[0055] In one embodiment of the present invention, an aqueous pharmaceutical 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 acetate, acetic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 15 mg / ml or 3 mg / ml to less than 20 mg / ml, and wherein sufficient acetic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0056] In one embodiment of the present invention, an aqueous pharmaceutical 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, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 15 mg / ml or 3 mg / ml to less than 20 mg / ml, and wherein sufficient acetic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0057] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising the acetate salt 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, acetic acid, a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin, and water, wherein the 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 solution concentration of 3 mg / ml to 15 mg / ml or 3 mg / ml to less than 20 mg / ml, and wherein sufficient acetic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0058] In one embodiment of the present invention, an aqueous pharmaceutical 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 acetate, acetic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 15 mg / ml, 8 mg / ml to 15 mg / ml, or 10 mg / ml to 15 mg / ml, and wherein sufficient acetic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0059] In one embodiment of the present invention, an aqueous pharmaceutical 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, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 15 mg / ml, 8 mg / ml to 15 mg / ml, or 10 mg / ml to 15 mg / ml, and wherein sufficient acetic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0060] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising the acetate salt 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, acetic acid, a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin, and water, wherein the 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 solution concentration of 6 mg / ml to 15 mg / ml, 8 mg / ml to 15 mg / ml, or 10 mg / ml to 15 mg / ml, and wherein sufficient acetic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0061] Preferably, for the above embodiments of the present invention containing acetic acid, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin. More preferably, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin or sulfobutyl ether-β-cyclodextrin (SBECD).

[0062] Maleic acid preparations

[0063] In one embodiment of the present invention, an aqueous pharmaceutical 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 maleate, maleic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 30 mg / ml or 3 mg / ml to less than 35 mg / ml, and wherein sufficient maleic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0064] In one embodiment of the present invention, an aqueous pharmaceutical 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, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 30 mg / ml or 3 mg / ml to less than 35 mg / ml, and wherein sufficient maleic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0065] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising a maleate salt 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, maleic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 30 mg / ml or 3 mg / ml to less than 35 mg / ml, and wherein sufficient maleic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0066] In one embodiment of the present invention, an aqueous pharmaceutical preparation is provided, which comprises 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 maleate, maleic acid, pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin and water, wherein 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 maleate, maleic acid, pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin and water. )phenyl]urea is present in a solution concentration of 4 mg / ml to 25 mg / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml and wherein sufficient maleic acid and a pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

[0067] In one embodiment of the present invention, an aqueous pharmaceutical preparation is provided, which comprises 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 β-cyclodextrin or γ-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 Urea is present at a solution concentration of 4 mg / ml to 25 mg / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml, or 10 mg / ml to 20 mg / ml, and there is sufficient maleic acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

[0068] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising maleate 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, maleic acid, pharmaceutically acceptable β-cyclodextrin or γ-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 [phenyl] urea is present in a solution concentration of 4 mg / ml to 25 mg / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein sufficient maleic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0069] Preferably, for the above embodiments of the present invention containing maleic acid, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin. More preferably, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin.

[0070] In one embodiment of the present invention, an aqueous pharmaceutical 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 maleate, maleic acid, hydroxypropyl-β-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 at a solution concentration of 3 mg / ml to 20 mg / ml or 3 mg / ml to less than 25 mg / ml, and wherein sufficient maleic acid and hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

[0071] In one embodiment of the present invention, an aqueous pharmaceutical 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 maleate, maleic acid, γ-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 at a solution concentration of 3 mg / ml to 15 mg / ml or 3 mg / ml to less than 20 mg / ml, and wherein sufficient maleic acid and γ-cyclodextrin are present to provide a clear solution.

[0072] Succinic acid preparations

[0073] In one embodiment of the present invention, an aqueous pharmaceutical 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 succinate, succinic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 65 mg / ml or 3 mg / ml to less than 70 mg / ml, and wherein sufficient succinic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0074] In one embodiment of the present invention, an aqueous pharmaceutical 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, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 65 mg / ml or 3 mg / ml to less than 70 mg / ml, and wherein sufficient succinic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0075] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising a succinate salt 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, succinic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 65 mg / ml or 3 mg / ml to less than 70 mg / ml, and wherein sufficient succinic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0076] In one embodiment of the present invention, an aqueous pharmaceutical preparation 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 succinate, succinic acid, pharmaceutically acceptable β-cyclodextrin or γ-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 or its succinate, succinic acid, pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin and water. [phenyl] urea is present in a solution concentration of 4 mg / ml to 25 mg / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein sufficient succinic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0077] In one embodiment of the present invention, an aqueous pharmaceutical preparation is provided, which comprises 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 β-cyclodextrin or γ-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 Urea is present at a solution concentration of 4 mg / ml to 25 mg / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml, or 10 mg / ml to 20 mg / ml, and there is sufficient succinic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

[0078] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, which comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea succinate, succinic acid, pharmaceutically acceptable β-cyclodextrin or γ-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 succinate, succinic acid, pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin and water.

[0043] urea is present in a solution concentration of 4 mg / ml to 25 mg / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein sufficient succinic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0079] Preferably, for the above embodiments of the present invention containing succinic acid, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin. More preferably, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin.

[0080] In one embodiment of the present invention, an aqueous pharmaceutical 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 succinate thereof, succinic acid, hydroxypropyl-β-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 at a solution concentration of 3 mg / ml to 25 mg / ml or 3 mg / ml to less than 30 mg / ml, and wherein sufficient succinic acid and hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

[0081] In one embodiment of the present invention, an aqueous pharmaceutical 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 succinate thereof, succinic acid, sulfobutyl ether-β-cyclodextrin (SBECD), 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 at a solution concentration of 3 mg / ml to 20 mg / ml or 3 mg / ml to less than 25 mg / ml, and wherein sufficient succinic acid and sulfobutyl ether-β-cyclodextrin (SBECD) are present to provide a clear solution.

[0082] Citric acid preparations

[0083] In one embodiment of the present invention, an aqueous pharmaceutical 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 citrate, citric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 55 mg / ml or 3 mg / ml to less than 60 mg / ml, and wherein sufficient citric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0084] In one embodiment of the present invention, an aqueous pharmaceutical 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, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 55 mg / ml or 3 mg / ml to less than 60 mg / ml, and wherein sufficient citric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0085] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising a citrate salt 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, citric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 55 mg / ml or 3 mg / ml to less than 60 mg / ml, and wherein sufficient citric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0086] In one embodiment of the present invention, an aqueous pharmaceutical 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 citrate, citric acid, pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml. g / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and there is sufficient citric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

[0087] In one embodiment of the present invention, an aqueous pharmaceutical 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 β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml. 1, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and there is sufficient citric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

[0088] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising a citrate 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, citric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml. / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and there is sufficient citric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

[0089] Preferably, for the above embodiments of the present invention containing citric acid, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin. More preferably, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin.

[0090] In one embodiment of the present invention, an aqueous pharmaceutical 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 citrate salt, citric acid, hydroxypropyl-β-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 at a solution concentration of 3 mg / ml to 25 mg / ml or 3 mg / ml to less than 30 mg / ml, and wherein sufficient citric acid and hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

[0091] In one embodiment of the present invention, an aqueous pharmaceutical 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 citrate salt, citric acid, sulfobutyl ether-β-cyclodextrin (SBECD) 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 at a solution concentration of 3 mg / ml to 20 mg / ml or 3 mg / ml to less than 25 mg / ml, and wherein sufficient citric acid and sulfobutyl ether-β-cyclodextrin (SBECD) are present to provide a clear solution.

[0092] Malic acid preparations

[0093] In one embodiment of the present invention, an aqueous pharmaceutical 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 malate, malic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 65 mg / ml or 3 mg / ml to less than 70 mg / ml, and wherein sufficient malic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0094] In one embodiment of the present invention, an aqueous pharmaceutical 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, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 65 mg / ml or 3 mg / ml to less than 70 mg / ml, and wherein sufficient malic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0095] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising malate salt 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, malic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 65 mg / ml or 3 mg / ml to less than 70 mg / ml, and wherein sufficient malic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0096] In one embodiment of the present invention, an aqueous pharmaceutical preparation 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 malate, malic acid, pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml. g / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein sufficient malic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0097] In one embodiment of the present invention, an aqueous pharmaceutical 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 β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml. 1, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein sufficient malic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0098] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising malate 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, malic acid, pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml. / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and there is sufficient malic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

[0099] Preferably, for the above embodiments of the present invention containing malic acid, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin. More preferably, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin.

[0100] In one embodiment of the present invention, an aqueous pharmaceutical 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 malate salt, malic acid, hydroxypropyl-β-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 at a solution concentration of 3 mg / ml to 30 mg / ml or 3 mg / ml to less than 35 mg / ml, and wherein sufficient malic acid and hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

[0101] In one embodiment of the present invention, an aqueous pharmaceutical 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 malate salt, malic acid, sulfobutyl ether-β-cyclodextrin (SBECD) 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 at a solution concentration of 3 mg / ml to 25 mg / ml or 3 mg / ml to less than 30 mg / ml, and wherein sufficient malic acid and sulfobutyl ether-β-cyclodextrin (SBECD) are present to provide a clear solution.

[0102] Tartaric acid preparations

[0103] In one embodiment of the present invention, an aqueous pharmaceutical 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 tartrate, tartaric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 65 mg / ml or 3 mg / ml to less than 70 mg / ml, and wherein sufficient tartaric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0104] In one embodiment of the present invention, an aqueous pharmaceutical 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, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 65 mg / ml or 3 mg / ml to less than 70 mg / ml, and wherein sufficient tartaric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0105] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising a tartaric acid salt 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, tartaric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 65 mg / ml or 3 mg / ml to less than 70 mg / ml, and wherein sufficient tartaric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0106] In one embodiment of the present invention, an aqueous pharmaceutical preparation 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 tartrate, tartaric acid, pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml. g / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and there is sufficient tartaric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

[0107] In one embodiment of the present invention, an aqueous pharmaceutical 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 β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml. 1, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and there is sufficient tartaric acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

[0108] In one embodiment of the present invention, an aqueous pharmaceutical 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, tartaric acid, pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml. / ml, 4 mg / ml to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and there is sufficient tartaric acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

[0109] Preferably, for the above embodiments of the present invention containing tartaric acid, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin. More preferably, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin.

[0110] In one embodiment of the present invention, an aqueous pharmaceutical 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 tartrate, tartaric acid, hydroxypropyl-β-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 at a solution concentration of 3 mg / ml to 30 mg / ml or 3 mg / ml to less than 35 mg / ml, and wherein sufficient tartaric acid and hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

[0111] In one embodiment of the present invention, an aqueous pharmaceutical 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 tartrate, tartaric acid, sulfobutyl ether-β-cyclodextrin (SBECD) 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 at a solution concentration of 3 mg / ml to 25 mg / ml or 3 mg / ml to less than 30 mg / ml, and wherein sufficient tartaric acid and sulfobutyl ether-β-cyclodextrin (SBECD) are present to provide a clear solution.

[0112] Hydrochloric acid preparation

[0113] In one embodiment of the present invention, an aqueous pharmaceutical 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 hydrochloride, hydrochloric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 60 mg / ml or 3 mg / ml to less than 65 mg / ml, and wherein sufficient hydrochloric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0114] In one embodiment of the present invention, an aqueous pharmaceutical 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 β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 60 mg / ml or 3 mg / ml to less than 65 mg / ml, and wherein sufficient hydrochloric acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0115] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising the hydrochloride salt 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, hydrochloric acid, pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 3 mg / ml to 60 mg / ml or 3 mg / ml to less than 65 mg / ml, and wherein sufficient hydrochloric acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0116] In one embodiment of the present invention, an aqueous pharmaceutical preparation 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 hydrochloride, hydrochloric acid, pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml, 4 mg / ml to 50 mg / ml. or 10 mg / ml to 20 mg / ml, and wherein sufficient hydrochloric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0117] In one embodiment of the present invention, an aqueous pharmaceutical 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 β-cyclodextrin or γ-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 added at 4 mg / ml to 25 mg / ml, 4 mg / ml to 50 mg / ml. to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 35 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein sufficient hydrochloric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0118] In one embodiment of the present invention, an aqueous pharmaceutical preparation is provided, which comprises the hydrochloride 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, hydrochloric acid, pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml, 4 mg / ml to 50 mg / ml. or 10 mg / ml to 20 mg / ml, and wherein sufficient hydrochloric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0119] Preferably, for the above embodiments of the present invention containing hydrochloric acid, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin. More preferably, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin.

[0120] In one embodiment of the present invention, an aqueous pharmaceutical 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 hydrochloride, hydrochloric acid, hydroxypropyl-β-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 at a solution concentration of 3 mg / ml to 35 mg / ml or 3 mg / ml to less than 40 mg / ml, and wherein sufficient hydrochloric acid and hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

[0121] In one embodiment of the present invention, an aqueous pharmaceutical 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 hydrochloride, hydrochloric acid, sulfobutyl ether-β-cyclodextrin (SBECD) 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 at a solution concentration of 3 mg / ml to 30 mg / ml or 3 mg / ml to less than 35 mg / ml, and wherein sufficient hydrochloric acid and sulfobutyl ether-β-cyclodextrin (SBECD) are present to provide a clear solution.

[0122] Orthophosphoric acid preparation

[0123] In one embodiment of the present invention, an aqueous pharmaceutical 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 phosphate thereof, orthophosphoric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 4 mg / ml to 50 mg / ml or 4 mg / ml to less than 55 mg / ml, and wherein sufficient orthophosphoric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0124] In one embodiment of the present invention, an aqueous pharmaceutical 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 β-cyclodextrin or γ-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 at a solution concentration of 4 mg / ml to 50 mg / ml or 4 mg / ml to less than 55 mg / ml, and wherein sufficient orthophosphoric acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0125] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising a phosphate salt 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, orthophosphoric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 4 mg / ml to 50 mg / ml or 4 mg / ml to less than 55 mg / ml, and wherein sufficient orthophosphoric acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0126] In one embodiment of the present invention, an aqueous pharmaceutical 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 phosphate thereof, orthophosphoric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml, 4 mg / ml to 50 mg / ml. or 10 mg / ml to 20 mg / ml, and wherein sufficient orthophosphoric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0127] In one embodiment of the present invention, an aqueous pharmaceutical 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 β-cyclodextrin or γ-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 added at 4 mg / ml to 25 mg / ml, 4 mg / ml to 50 mg / ml. to 20 mg / ml, 4 mg / ml to 15 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 4 mg / ml to 30 mg / ml, 6 mg / ml to 30 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 35 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein sufficient orthophosphoric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0128] In one embodiment of the present invention, an aqueous pharmaceutical formulation is provided, comprising a phosphate 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, orthophosphoric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 4 mg / ml to 25 mg / ml, 4 mg / ml to 50 mg / ml. or 10 mg / ml to 20 mg / ml, and wherein sufficient orthophosphoric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

[0129] Preferably, for the above embodiments of the present invention containing orthophosphoric acid, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin. More preferably, the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin.

[0130] In one embodiment of the present invention, an aqueous pharmaceutical 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 phosphate thereof, orthophosphoric acid, hydroxypropyl-β-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 at a solution concentration of 4 mg / ml to 35 mg / ml or 4 mg / ml to less than 40 mg / ml, and wherein sufficient orthophosphoric acid and hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

[0131] In one embodiment of the present invention, an aqueous pharmaceutical 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 phosphate thereof, orthophosphoric acid, sulfobutyl ether-β-cyclodextrin (SBECD) 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 at a solution concentration of 4 mg / ml to 30 mg / ml or 4 mg / ml to less than 35 mg / ml, and wherein sufficient orthophosphoric acid and sulfobutyl ether-β-cyclodextrin (SBECD) are present to provide a clear solution.

[0132] The "solution concentration" values ​​referred to herein relate to the concentration of the free base 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 the formulations of the present invention.

[0133] The preparations of the present invention can be directly administered to the patient intravenously or parenterally (to avoid degradation), preferably with the addition of an osmotic regulator. Alternatively, in order to be administered to the patient at a later date, such preparations (optionally containing an extender and / or an osmotic regulator) can first be freeze-dried to prepare a freeze-dried solid composition that remains chemically stable (preferably at least 2 years) during storage, and then the freeze-dried solid composition can be immediately formulated (constituted) or reconstituted to obtain a clear aqueous solution before administration to the patient by an intravenous (or parenteral) route, preferably with the addition of an osmotic regulator if necessary. The reconstituted or formulated solution can be added to an infusion bag before administration to the patient.

[0134] The concentration of the pharmaceutically acceptable organic or inorganic acid used in the formulation of the present invention is preferably 10 mM to 200 mM or 50 mM to 200 mM, 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.

[0135] The amount of pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used in the formulation of the present invention is preferably 2% w / v to 30% w / v, 5% w / v to 20% w / v or 15% w / v to 30% w / v, preferably about 20% w / v or about 25% w / v. Preferably, the amount of pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used in the formulation of the present invention is about 20% w / v.

[0136] If the preparation of the present invention is freeze-dried to produce a lyophilized solid composition, then an extender can be added to the preparation before the freeze drying process begins. The main function of the extender is to make the freeze-dried solid have a structural integrity that will not collapse, which can achieve rapid recovery or preparation of an aqueous preparation before administration, and it should also contribute to effective lyophilization. Extenders are usually used when the total mass of the solute in the preparation is less than 2g / 100ml. Extenders can also be added to achieve isotonicity with blood. Extenders can be selected from sugar, sugar alcohol, amino acid or polymer, or a mixture of any two or more thereof. Preferably, the extender is sugar or sugar alcohol or its mixture. Preferably, sugar is sucrose. Preferably, sugar alcohol is mannitol.

[0137] Preferably, if present, a bulking agent is used at 5 to 10% w / v.

[0138] Reconstitution of the lyophilized solid composition can be achieved by adding the necessary amount of water present prior to lyophilization to obtain a clear solution. Any osmotic regulator may be added prior to use.

[0139] Formulation of the lyophilized solid composition may be achieved by using an appropriate amount of water and / or an aqueous solution of a suitable osmotic regulator to ensure that a clear solution is obtained.

[0140] Before the formulation is administered intravenously or parenterally to a patient via injection, an osmotic regulator may be present to avoid shrinkage or lysis of red blood cells and to reduce or avoid pain and discomfort in the patient. This requires that the formulation to be administered to a patient has an effective osmotic pressure that is approximately the same as that of the patient's blood.

[0141] Suitable osmotic regulators are nonionic osmotic regulators, such as glycerol, sorbitol, mannitol, sucrose, propylene glycol or dextrose or a mixture of any two or more thereof. Preferably, the nonionic osmotic regulator is dextrose, sucrose or mannitol or a mixture of any two or more thereof.

[0142] Preferably, 1% w / v to 5% w / v of osmotic regulator is used.

[0143] Aqueous pharmaceutical formulations of the invention suitable for intravenous administration typically have a pH of 3 to 9. However, lower pHs are tolerated in certain circumstances. Preferably, the pH is 3 to 8 or 4 to 8.

[0144] The preparation of the present invention can be used for curative, palliative or preventive treatment of cancer in mammals (including humans). The cancer to be treated can be selected from: 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.

[0145] Using the formulations disclosed herein, the weekly dosage 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 administered by the intravenous route for the treatment of cancer is preferably 100 mg to 400 mg per week.

[0146] The following examples describe the preparation of formulations of the invention.

[0147] Example 1

[0148] Preparation of an aqueous pharmaceutical formulation containing 35 mg / ml 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, 20% w / v 2-hydroxypropyl-β-cyclodextrin and hydrochloric acid

[0149] Dilute hydrochloric acid (1M aqueous solution) (10 ml, 100 mM) with perfusion water (80 ml). Add 2-hydroxypropyl-β-cyclodextrin (93% w / w adjusted titer) (21.57 g, 147.2 mM) and stir the solution until a particle-free solution is obtained. To this solution, add 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4-yl-1,3,5-triazine-2-yl)phenyl]urea (3500 mg, 56.9 mM) and stir until a particle-free solution is obtained. Add perfusion water under stirring to reach a target volume of 100 ml.

[0150] (i) Visual analysis

[0151] The formulation samples were analyzed to determine the presence of crystallites or particles according to the visual method defined in European Pharmacopoeia method 2.9.20 (using a Verivide (trade mark) light cabinet against a matt black panel and a white panel and a light meter with a reading of 3250 lux). The samples were tested by this method immediately after the solution was made and then after 24 hours.

[0152] (ii) OPM analysis

[0153] The formulation sample was placed on a clean microscope slide and covered with a cover slip. The formulation sample was then analyzed by OPM using both non-polarized and cross-polarized light under a Nikon LV 100POL (trademark) microscope, using a 10× magnification lens and a 10× magnification eyepiece to determine if crystallites or particles were present. Images were recorded using a DFK 23UP031 TIS USB 3.0CMOS (trademark) color industrial camera 5MP 1 / 2,5″ and image capture software. The operation was also repeated in a glass capillary using the formulation sample. The samples were tested by this method when the solution was just made and then after 4 hours and 24 hours.

[0154] Example 2

[0155] Preparation of an aqueous pharmaceutical formulation containing 30 mg / ml 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, 20% w / v sulfobutyl ether-β-cyclodextrin (SBECD) and tartaric acid

[0156] Tartaric acid (racemic) (99% w / w potency) (1.5 g, 100 mM) was diluted with perfusion water (80 ml). Sulfonbutyl ether-β-cyclodextrin (90% w / w adjusted potency) (22.18 g, 195 mM) was added and the solution was stirred until a particle-free solution was obtained. To this solution was 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 (3000 mg, 48.7 mM) and stirred until a particle-free solution was obtained. Perfusion water was added under stirring to reach a target volume of 100 ml.

[0157] The formulation samples were analyzed according to the method of Example 1.

[0158] Example 3

[0159] Preparation of an aqueous pharmaceutical formulation containing 45 mg / ml 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, 20% w / v γ-cyclodextrin and orthophosphoric acid

[0160] Orthophosphoric acid (99% w / w assumed potency) (979 mg, 100 mM) was diluted with perfusion water (80 ml). γ-cyclodextrin (assumed 100% potency) (20 g, 154 mM) was added and the solution was stirred until a particle-free solution was obtained. To this solution was added 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4-yl-1,3,5-triazine-2-yl)phenyl]urea (4500 mg, 73.1 mM) and stirred until a particle-free solution was obtained. Perfusion water was added under stirring to reach a target volume of 100 ml.

[0161] The formulation samples were analyzed according to the method of Example 1.

[0162] Example 4

[0163] Preparation of lyophilized composition of aqueous solution pharmaceutical preparation of the present invention

[0164] The aqueous pharmaceutical formulation of the invention (e.g., prepared according to any one of Examples 1 to 3) is filled into 10 mL vials to a target volume of 3 ml. The vials are partially stoppered (non-sealed) with 20 mm Gray Lyo D777-1 V10-F597W FluroTec Siliconised (trademark) stoppers. The vials are loaded into a stainless steel tray and inserted into a LSL1000 (trademark) freeze dryer. The shelf temperature is set to 5°C. A freeze drying cycle is then performed according to conventional procedures.

[0165] After the freeze drying cycle is complete, the freeze dryer is backfilled with sterile filtered nitrogen to a setting of 500 Torr (approximately 666 mbar or 66,600 Pascals) and the vials are completely closed using stoppers. The freeze dryer is then vented to atmospheric pressure using sterile filtered air and the vials are removed from the freeze dryer.

[0166] Each vial contains the freeze-dried (lyophilized) formulation in solid form.

[0167] Example 5

[0168] Reconstitution of the aqueous solution pharmaceutical preparation of the present invention from the freeze-dried solid composition of the present invention

[0169] The lyophilized solid composition prepared in Example 4 in a vial was reconstituted as follows.

[0170] Perfusion water (3 ml) was injected using a syringe into the vial containing the lyophilized composition prepared in Example 4. The mixture was vortexed until a particle-free solution was obtained.

[0171] Example 6

[0172] Preparation of a lyophilized composition of an aqueous pharmaceutical formulation comprising 10 mg / ml 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, 5% w / v 2-hydroxypropyl-β-cyclodextrin and lactic acid

[0173] DL-lactic acid (4.505 g, 30 mM) was diluted with perfusion water (1275 mL). 2-Hydroxypropyl-β-cyclodextrin (92.85% w / w adjusted titer) (80.775 g, 35.7 mM) was added and the solution was stirred until a particle-free solution was obtained. 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine-4-yl-1,3,5-triazine-2-yl)phenyl]urea (15.00 g, 16.24 mM) was added to the solution and stirred until a particle-free solution was obtained. Perfusion water was added under stirring to reach a target volume of 1500 mL.

[0174] The aqueous pharmaceutical formulation of the invention (described above) was filled into 20 mL vials to a target volume of 7 ml. The vials were partially stoppered (non-sealed) with 20 mm Gray Lyo D777-1 V10-F597W FluroTec Siliconised (trademark) stoppers. The vials were loaded into a stainless steel tray and inserted into a LSL1000 (trademark) freeze dryer. A freeze drying cycle was then performed according to conventional procedures.

[0175] After the freeze drying cycle is complete, the freeze dryer is backfilled with sterile filtered nitrogen to a setting of 500 Torr (approximately 666 mbar or 66,600 Pascals) and the vials are completely closed using stoppers. The freeze dryer is then vented to atmospheric pressure using sterile filtered air and the vials are removed from the freeze dryer.

[0176] Each vial contains the freeze-dried (lyophilized) formulation in solid form.

[0177] Other Examples of Preparing an Aqueous Pharmaceutical 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, β-cyclodextrin or γ-cyclodextrin, and a Pharmaceutically Acceptable Organic or Inorganic Acid

[0178] The examples listed below were prepared using a method similar to that of Examples 1 to 3 using the ingredient specifications listed below (indicated by a tick or cross) (target volume = 100 ml).

[0179] These examples were analyzed by both the visual method defined in European Pharmacopoeia method 2.9.20 and the OPM method as described in Example 1. The results are also tabulated below.

[0180] In this table, "particulate-free" means that the formulation is visually clear and contains no visible crystallites or particles, and meets the definition of the desired "clear solution" as previously described.

[0181]

[0182]

[0183]

[0184] Keywords

[0185] API = 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea

[0186] * = acid used in racemic form

[0187] HPBCD = 2-hydroxypropyl-β-cyclodextrin

[0188] SBECD = sulfobutyl ether-β-cyclodextrin

[0189] γCD=γ-cyclodextrin

[0190] αCD=α-cyclodextrin

[0191] (1) = No particles (and not milky). All of the Examples studied contained no visible crystallites or particulate matter and met the definition of the desired "clear solution" as previously described.

[0192] (2) = Particle suspension

[0193] Chemical stability of the freeze-dried solid preparation of the present invention

[0194] A sample of the lyophilized formulation of the present invention was prepared according to Example 6 ("Sample A").

[0195] Separate portions of Sample A were each contained in a 20 mL transparent vial, and one portion was stored at 25° C. / 60% relative humidity (“RH”) for 6 months and the other portion was stored at 40° C. / 75% RH for 6 months.

[0196] After 6 months storage as above, each individual sample was tested for chemical purity using ultra high performance liquid chromatography (UHPLC) using the following method to measure any chemical degradation during the testing period.

[0197] UHPLC Methods

[0198] Solutions, samples, standards, and UHPLC methods are as follows:

[0199] Reference Standard: 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 known potency.

[0200] Diluent: acetonitrile / water / trifluoroacetic acid (750:250:1 v / v / v)

[0201] Mobile phase A: acetonitrile / water / trifluoroacetic acid (97:3:1 v / v / v)

[0202] Mobile phase B: acetonitrile / trifluoroacetic acid (1000:1 v / v).

[0203] (Note: Larger or smaller volumes of solution can be prepared by using appropriate ratios of components)

[0204] Standard preparations and test standard preparations:

[0205] Prepare two solutions of the 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea reference standard in diluent at a concentration of approximately 0.2 mg / mL (+ / - 10%) and record the concentrations of both accurately. These are the standard preparation and the check standard preparation.

[0206] Sensitive solution:

[0207] • Use diluent to accurately dilute the standard preparation to a concentration of about 0.1 μg / mL 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.

[0208] Sample preparation:

[0209] • Reconstitute Sample A after storage as follows: Add 7.0 ml of water to each sample in a 20 ml vial, shake the vial to dissolve the solids and wait for the bubbles to disappear. Transfer 1.0 ml of this solution to a 50 ml volumetric flask. Dilute to set volume with diluent.

[0210] Chromatographic conditions:

[0211] Liquid chromatography system - with 380μl Jet Weaver TM Agilent 1290 Infinity IITM

[0212] ·Column: Waters BEH C18 TM 15cm×2.1mm, 1.7μm or equivalent

[0213] Column temperature: 20℃

[0214] Injection volume: 2μL

[0215] Flow rate: 0.25mL / min

[0216] Flow cell: G4212-60008, 10 mm path length, 1.0 μL

[0217] Detection: UV at 240nm / 4nm slit width

[0218] Running time: 77 minutes

[0219] Mobile phase A

[0220] Mobile phase B

[0221] Needle wash solution: water / acetonitrile (95:5 v / v), multiple washes, 20 s.

[0222] Seal wash solution: water / propan-2-ol (90:10 v / v)

[0223] Linear gradient table:

[0224] Time (minutes) % Mobile phase A % Mobile phase B 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

[0225] Explanatory notes

[0226] Before starting the analysis, condition the UHPLC system with the mobile phase.

[0227] Prior to running samples, ensure that the system is suitable for use by injecting blank diluents, sensitive solutions, and standard preparations using the chromatographic conditions described above.

[0228] The following guidelines must be met during initial UHPLC setup or after any significant changes to the system. It is recommended to inject at least one conditioning blank before testing system suitability.

[0229]

[0230]

[0231] *Average of all system suitability (repeatability) injections used.

[0232] ** Refers to the United States Pharmacopeia (USP) calculation equations for efficiency and peak asymmetry.

[0233] The test standard preparation is injected according to the above chromatographic conditions. The response factor of this test standard preparation (calculated by the area, standard weight, dilution factor and purity factor of the standard) must be within ±2% of the standard preparation.

[0234] After confirming system suitability, inject the blank solution, standard preparation, and prepared test samples according to the above chromatographic conditions, followed by the standard preparation. It is recommended that no more than 6 test sample injections be made between standard preparation injections. For each injection (standard and sample), measure the retention time and area of ​​the 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea peak in each chromatogram. For each sample injection, also measure the retention time and peak area of ​​any peaks present in the sample injection that do not appear in the blank injection. Do not integrate gradient artifacts (if present). Compare the blank injection chromatogram to the sample chromatogram to determine which peaks in the sample are related to the blank and gradient artifact peaks. Calculate the % w / w of the degradation products and report each degradation product peak that is equal to or greater than 0.05% w / w. Unknown degradation products should be reported individually according to their relative retention times. Known degradation products should be reported individually by name.

[0235] The results are summarized in the table below.

[0236] Keywords

[0237] NMT = not more than.

[0238] RRT = relative retention time

[0239] Degradation product 1

[0240]

[0241] Degradation products 2, 3 and 4

[0242] Each of these degradation products is characterized only by its RRT.

[0243] Sample A results

[0244]

[0245] in conclusion

[0246] The results show that Sample A remains chemically stable for at least 6 months at 25°C / 60%RH and remains chemically stable for at least 6 months at 40°C / 75%RH.

Claims

1. An aqueous pharmaceutical formulation 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 organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 solution concentration of at least 6 mg / ml, and wherein the drug is present in a sufficient amount to A pharmaceutically acceptable organic or inorganic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution, wherein the pharmaceutically acceptable organic or inorganic acid is lactic acid, acetic acid, maleic acid, succinic acid, citric acid, malic acid, tartaric acid, hydrochloric acid or orthophosphoric acid, and wherein the pharmaceutically acceptable organic or inorganic acid is present in a solution concentration of 50 mM to 100 mM; wherein the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin, and wherein the amount of the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin is 20% w / v.

2. The aqueous pharmaceutical formulation of claim 1, 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 acetate salt, acetic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 15 mg / ml or 6 mg / ml to less than 20 mg / ml, and wherein sufficient acetic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

3. The aqueous pharmaceutical formulation of claim 1, 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 maleate salt, maleic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 30 mg / ml or 6 mg / ml to less than 35 mg / ml, and wherein sufficient maleic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

4. The aqueous pharmaceutical formulation of claim 1, 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 succinate thereof, succinic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 65 mg / ml or 6 mg / ml to less than 70 mg / ml, and wherein sufficient succinic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

5. The aqueous pharmaceutical formulation of claim 1, 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 citrate salt, citric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 55 mg / ml or 6 mg / ml to less than 60 mg / ml, and wherein sufficient citric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

6. The aqueous pharmaceutical formulation of claim 1 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 malate salt, malic acid, a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin, and water, wherein the 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 solution concentration of 6 mg / ml to 65 mg / ml or 6 mg / ml to less than 70 mg / ml, and wherein sufficient malic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

7. The aqueous pharmaceutical formulation of claim 1, 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 tartrate salt, tartaric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 65 mg / ml or 6 mg / ml to less than 70 mg / ml, and wherein sufficient tartaric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

8. The aqueous pharmaceutical formulation of claim 1, 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 hydrochloride, hydrochloric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 60 mg / ml or 6 mg / ml to less than 65 mg / ml, and wherein sufficient hydrochloric acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

9. The aqueous pharmaceutical formulation of claim 1, 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 phosphate thereof, orthophosphoric acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 50 mg / ml or 6 mg / ml to less than 55 mg / ml, and wherein sufficient orthophosphoric acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

10. An aqueous pharmaceutical preparation 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 lactate thereof, lactic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 added in an amount of 6 mg / ml to 30 ml. g / ml or 6 mg / ml to less than 35 mg / ml solution concentration, and wherein there is sufficient lactic acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution, and wherein the lactic acid is present at a solution concentration of 30 mM to 150 mM; wherein the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin is 2-hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin (SBECD) or γ-cyclodextrin, and wherein the amount of the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin is 20% w / v.

11. The aqueous pharmaceutical formulation of claim 10, 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, a pharmaceutically acceptable β-cyclodextrin or γ-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 at a solution concentration of 6 mg / ml to 30 mg / ml or 6 mg / ml to less than 35 mg / ml, and wherein sufficient lactic acid and pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

12. The aqueous pharmaceutical formulation of claim 10, comprising a lactate salt 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, lactic acid, a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin, and water, wherein the 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 solution concentration of 6 mg / ml to 30 mg / ml or 6 mg / ml to less than 35 mg / ml, and wherein sufficient lactic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin are present to provide a clear solution.

13. The aqueous pharmaceutical formulation of claim 10, 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 lactate thereof, lactic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 -4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a solution concentration of 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein there is sufficient lactic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

14. The aqueous pharmaceutical formulation of claim 10, 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, a pharmaceutically acceptable β-cyclodextrin or γ-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 -yl-1,3,5-triazin-2-yl)phenyl]urea is present in a solution concentration of 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein there is sufficient lactic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

15. The aqueous pharmaceutical formulation of claim 10, comprising a lactate salt 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, lactic acid, a pharmaceutically acceptable β-cyclodextrin or γ-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 -4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in a solution concentration of 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml, and wherein there is sufficient lactic acid and a pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin to provide a clear solution.

16. The aqueous pharmaceutical preparation of claim 10, wherein the pharmaceutically acceptable β-cyclodextrin or γ-cyclodextrin used is 2-hydroxypropyl-β-cyclodextrin or γ-cyclodextrin.

17. The aqueous pharmaceutical formulation of claim 10, 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 lactate salt thereof, lactic acid, sulfobutyl ether-β-cyclodextrin (SBECD), 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 at a solution concentration of 6 mg / ml to 25 mg / ml or 6 mg / ml to less than 30 mg / ml, and wherein sufficient lactic acid and sulfobutyl ether-β-cyclodextrin (SBECD) are present to provide a clear solution.

18. The aqueous pharmaceutical formulation of claim 10, 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 lactate thereof, lactic acid, 2-hydroxypropyl-β-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 at a solution concentration of 6 mg / ml to 30 mg / ml or 6 mg / ml to less than 35 mg / ml, and wherein sufficient lactic acid and 2-hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

19. The aqueous pharmaceutical formulation of claim 10, 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 lactate thereof, lactic acid, 2-hydroxypropyl-β-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 or a lactate thereof, lactic acid, 2-hydroxypropyl-β-cyclodextrin and water. 3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of 6 mg / ml to 30 mg / ml, 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml, or 10 mg / ml to 20 mg / ml, and wherein sufficient lactic acid and 2-hydroxypropyl-β-cyclodextrin are present to provide a clear solution.

20. The aqueous pharmaceutical formulation of claim 10, 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 lactate thereof, lactic acid, 2-hydroxypropyl-β-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 added in an amount of 6 mg / ml to 30 mg / ml, A solution concentration of 6 mg / ml to 25 mg / ml, 6 mg / ml to 20 mg / ml, 6 mg / ml to 15 mg / ml, 10 mg / ml to 30 mg / ml, 10 mg / ml to 25 mg / ml or 10 mg / ml to 20 mg / ml is present and wherein the lactic acid concentration is 30 mM to 100 mM and the 2-hydroxypropyl-β-cyclodextrin concentration is 15 mg / ml to 120 mg / ml, 20 mg / ml to 120 mg / ml or 35 mg / ml to 120 mg / ml to provide a clear solution.

21. The aqueous pharmaceutical formulation of claim 10, 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-β-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 at a solution concentration of 10 mg / ml to 30 mg / ml or 10 mg / ml to 20 mg / ml, and wherein the lactic acid concentration is 30 mM to 100 mM and the 2-hydroxypropyl-β-cyclodextrin concentration is 35 mg / ml to 120 mg / ml to provide a clear solution.

22. A lyophilized preparation obtainable by freeze-drying the preparation according to any one of claims 1 to 21.

23. The lyophilized formulation of claim 22, further comprising a bulking agent.

24. The lyophilized formulation of claim 23, wherein the bulking agent is mannitol.

25. An aqueous pharmaceutical formulation obtainable in the form of a clear solution by reconstituting or formulating the lyophilized formulation according to any one of claims 22 to 24 with water or an aqueous solution comprising an osmotic regulator.

26. The aqueous solution pharmaceutical formulation of claim 25, wherein the osmotic regulator is dextrose, sucrose or mannitol, or a mixture of any two or more thereof.

27. The aqueous pharmaceutical formulation of claim 1, which is adjusted, if necessary, to have a pH suitable for intravenous or parenteral administration.

28. The formulation of claim 1 for use as a medicament.

29. The formulation of claim 1 for use in treating cancer.

30. Use of an effective amount of the formulation of claim 1 in the preparation of a medicament for treating cancer in a mammal.

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