HK40041654A - Aqueous 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 - Google Patents

Description

Aqueous 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

Preparation

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 (pharmaceutical aqueous 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 a patient.

Background

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 WO 2009/143313. The compounds are inhibitors of PI3 kinase and mTOR, and are useful for the treatment of cancer.

Crystalline forms 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 methods for their preparation are disclosed in WO 2010/096619.

WO2016/097949 describes an aqueous pharmaceutical formulation (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 salt 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 in a solution concentration of less than 6mg/ml, and sufficient lactic acid is present 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 4mg/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 with a concentration of 1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea of 3mg/ml or more.

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

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

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 ℃ and 60% Relative Humidity (RH). However, the water solubility of the free base is insufficient to prepare aqueous solution formulations suitable for intravenous or parenteral administration at the desired therapeutic dosage levels.

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 ℃ and 60% RH), (b) facilitate effective intravenous (or parenteral) administration of the drug to mammals, including humans, and (c) preferably achieve at least 6mg/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.

Summary of The Invention

To achieve administration to a subject using a single vial presentation of a commercially available drug product, a solution concentration of at least 6mg/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 drugs containing less than 6mg/ml drug solution (for reconstitution) may require multiple vials to deliver the desired therapeutic dose. In view of current regulatory expectations for these product types, the method of dose delivery with multiple vials is not ideal.

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 particular pharmacokinetic and bioavailability characteristics of this drug.

Intravenous formulations of any drug must be solutions that facilitate safe and effective administration to the patient. It must be particle-free and not form a gel or suspension. Clear aqueous solutions are preferred.

A "clear solution" is defined herein as a visually clear solution, which may have a solution opalescence (solution opalescence) that is substantially free of any visible particles that may be observed upon visual inspection. In general, if any particulate matter is observed, the formulation is not suitable for intravenous administration and should not be used because of the potential for vascular occlusion. Accordingly, in view of the qualitative nature of visual testing, the term "substantially free of any visible particles" is generally applicable when no visible particulate matter is observed.

Particulate matter may be defined as follows:

speckles- -dispersed particles whose shape cannot be determined without magnification

Smoke or vortex- -fine particles that look like smoke or tornado, and are generally derived from the bottom of the sample vial and rotate upward as the vial is turned

Flocculent mass- -loosely agglomerated particles or films

Particles that have a well-defined shape or can be characterized as glass-like, look like metal, etc.

The visual inspection can be carried out according to the Method defined in European Pharmacopoeia Method 2.9.20(European Pharmacopoeia Method 2.9.20) under the title "Particulate conditioning: visual particles" (see FIG. 1). This method measures particulate contamination of injectables and infusions by foreign, mobile, insoluble particles other than air bubbles that may be present in the solution. This test is intended to provide a simple operation for visually assessing the quality of the parenteral solution in terms of visible particles.

The method states that: "remove any adhered label from the container and wash and dry the outside of the container. The container was gently turned or inverted to ensure that no air bubbles were introduced and observed in front of the white panel for about 5 seconds. This operation was repeated before the black panel. The presence of any particles was noted. "

A suitable method according to european pharmacopoeia method 2.9.20 for use in the present invention is described in example 1 (i).

Other validated methods can also be used to determine whether visible particles are present. Such methods include Optical polarization Microscopy ("OPM"). A suitable OPM method for use in the present invention is described in example 1 (ii).

Without wishing to be bound by theory, any milky hue may result from the formation of a chromophoric liquid crystal. The chromogenic liquid crystals are formed by pi-pi stacking of aromatic moieties of molecules, which form a column-like stack of dimers, trimers and low molecular weight oligomers of the molecules. The resulting stacks can be confirmed via OPM as amorphous microstructures associated with chromophoric liquid crystals. The amorphous microstructure exhibits 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 the change in refractive index of the solution due to the formation of these stacks. OPM micrographs of the solution will confirm the absence of crystalline material but the presence of the chromogenic liquid crystal phase. The presence of the liquid crystal phase causes the solution to be opaque or milky white due to the difference in refractive index in the resulting solution. For a discussion of liquid crystal formation, see "Optical Properties of Condensed materials and Applications", Jai Singh (ed.), ISBN: 978-0-470-.

It has now been found, surprisingly, that by using pharmaceutically acceptable beta-or gamma-cyclodextrins, aqueous pharmaceutical formulations can be prepared in the form of clear solutions comprising (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 in concentrations significantly higher than 6mg/ml and (b) one of a range of pharmaceutically acceptable organic or inorganic acids.

Drawings

Fig. 1 reproduces fig. 2.9.20-1 of the publication "european pharmacopoeia method 2.9.20" and describes an apparatus consisting of a viewing station comprising: a properly sized matte black panel (1) held in a vertical position; an appropriately sized anti-glare white panel (2) held in a vertical position next to the black panel; an appropriately sized anti-glare white panel (3) held in a horizontal position at the bottom of the vertical panel; and an adjustable lamp base (4) fitted with a suitable shaded white light source and with a suitable diffuser (inspection illuminators comprising two 13 watt fluorescent tubes each 525mm long are suitable). The illumination intensity at the viewing point is maintained at 2000 to 3750 lux, but higher values are preferably used for colored glass and plastic containers.

Detailed Description

Accordingly, 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, with the proviso that the organic or inorganic acid (including salts thereof) is not a sulfonic acid (hereinafter referred to as "formulation of the invention").

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 beta-cyclodextrin or gamma-cyclodextrin and water, wherein sufficient pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including salts thereof) is not a sulfonic acid.

In one embodiment of the invention there is provided 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, 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, with the proviso that the organic or inorganic acid (including salts thereof) is not a sulfonic acid.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation 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 beta-cyclodextrin or gamma-cyclodextrin and water, wherein sufficient pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including salts thereof) is not a sulfonic acid.

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

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

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

Examples of pharmaceutically acceptable β -cyclodextrins are 2-hydroxypropyl- β -cyclodextrin and sulfobutyl ether- β -cyclodextrin (SBECD). Examples of such pharmaceutically acceptable gamma-cyclodextrins are gamma-cyclodextrin and 2-hydroxypropyl-gamma-cyclodextrin. Preferably, hydroxypropyl- β -cyclodextrin is used in the formulations of the present invention. It has been found that by using pharmaceutically acceptable beta-or gamma-cyclodextrins, clear solutions can be obtained which are not opalescent and/or which contain a higher 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 than would be obtainable in the absence of the cyclodextrin component.

In one embodiment of the invention there is provided 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 6mg/ml And wherein sufficient pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution, provided that the organic or inorganic acid (including salts thereof) is not a sulfonic acid.

In one embodiment of the invention there is provided 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, 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 6mg/ml, and wherein sufficient pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution, provided that the organic or inorganic acid (including salts thereof) is not a sulfonic acid.

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

Lactic acid formulations

In one embodiment of the invention, there is provided 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 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 in a solution concentration of 6mg/ml to 30mg/ml or 6mg/ml to less than 35mg/ml And wherein sufficient lactic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 in a solution concentration of 6mg/ml to 30mg/ml or 6mg/ml to less than 35mg/ml, and wherein sufficient lactic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation 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 in a solution concentration of 6mg/ml to 30mg/ml or 6mg/ml to less than 35mg/ml And wherein sufficient lactic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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 lactate salt 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 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution, and wherein sufficient lactic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution, and wherein sufficient lactic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation 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 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution, and wherein sufficient lactic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

Preferably, for the above embodiments of the 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 beta-cyclodextrin or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment of the invention there is provided 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 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 in a solution concentration of 6mg/ml to 25mg/ml or 6mg/ml to less than 30mg/ml, and wherein sufficient lactic acid and sulfobutyl ether-beta-cyclodextrin (SBECD) are present to provide a clear solution.

In one embodiment of the invention there is provided 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 lactate salt thereof, lactic acid, 2-hydroxypropyl-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 6mg/ml to 30mg/ml or 6mg/ml to less than 35mg/ml, and wherein sufficient lactic acid and 2-hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 lactate salt thereof, lactic acid, 2-hydroxypropyl-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 6mg/ml to 30mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution concentration is present and wherein sufficient lactic acid and 2-hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 lactate salt thereof, lactic acid, 2-hydroxypropyl-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 6mg/ml to 30mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of a solution is present and wherein the lactic acid concentration is 10mM to 100mM, 15mM to 100mM or 30mM to 100mM and the 2-hydroxypropyl-beta-cyclodextrin concentration is 15mg/ml to 120mg/ml, 20mg/ml to 120mg/ml or 35mg/ml to 120mg/ml to provide a clear solution.

In one embodiment of the invention, there is provided 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, lactic acid, 2-hydroxypropyl-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 from 10mg/ml to 30mg/ml or from 10mg/ml to 20mg/ml, and wherein the lactic acid concentration is 20mM to 100mM or 30mM to 100mM and the 2-hydroxypropyl-beta-cyclodextrin concentration is 35mg/ml to 120mg/ml to provide a clear solution.

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

Acetic acid formulations

In one embodiment of the invention, there is provided 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 its acetate, acetic acid, a pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin and water, wherein 1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea is present in a solution concentration of from 3mg/ml to 15mg/ml or from 3mg/ml to less than 20mg/ml And wherein sufficient acetic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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, 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 in a solution concentration of from 3mg/ml to 15mg/ml or from 3mg/ml to less than 20mg/ml, and wherein sufficient acetic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

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

In one embodiment of the invention, there is provided 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 an acetate salt thereof, 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 6mg/ml to 15mg/ml, a solution concentration of 8mg/ml to 15mg/ml or 10mg/ml to 15mg/ml is present and wherein sufficient acetic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 6mg/ml to 15mg/ml, a solution concentration of 8mg/ml to 15mg/ml or 10mg/ml to 15mg/ml is present and wherein sufficient acetic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

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

Preferably, for the above embodiments of the 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 beta-cyclodextrin or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or sulfobutyl ether-beta-cyclodextrin (SBECD).

Maleic acid preparation

In one embodiment of the invention there is provided 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 maleate salt thereof, 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 from 3mg/ml to 30mg/ml or from 3mg/ml to less than 35mg/ml And wherein sufficient maleic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 in a solution concentration of from 3mg/ml to 30mg/ml or from 3mg/ml to less than 35mg/ml, and wherein sufficient maleic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation 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 from 3mg/ml to 30mg/ml or from 3mg/ml to less than 35mg/ml The solution is present in a concentration and wherein sufficient maleic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution concentration is present and wherein sufficient maleic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution concentration is present and wherein sufficient maleic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation comprising the 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution concentration is present and wherein sufficient maleic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

Preferably, for the above embodiment of the 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 beta-cyclodextrin or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment of the invention there is provided 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 its maleate salt, 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 in a solution concentration of from 3mg/ml to 20mg/ml or from 3mg/ml to less than 25mg/ml, and wherein sufficient maleic acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 its maleate salt, 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 in a solution concentration of from 3mg/ml to 15mg/ml or from 3mg/ml to less than 20mg/ml, and wherein sufficient maleic acid and gamma-cyclodextrin are present to provide a clear solution.

Succinic acid preparation

In one embodiment of the invention, there is provided 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 its succinate salt, succinic 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 concentrated in a solution of 3mg/ml to 65mg/ml or 3mg/ml to less than 70mg/ml And wherein sufficient succinic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 in a solution concentration of from 3mg/ml to 65mg/ml or from 3mg/ml to less than 70mg/ml, and wherein sufficient succinic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation comprising the 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 in a solution concentration of 3mg/ml to 65mg/ml or 3mg/ml to less than 70mg/ml And wherein sufficient succinic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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 its succinate salt, 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present, and wherein sufficient succinic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present, and wherein sufficient succinic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation comprising the 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present, and wherein sufficient succinic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

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

In one embodiment of the invention there is provided 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 its succinate salt, 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 in a solution concentration of from 3mg/ml to 25mg/ml or from 3mg/ml to less than 30mg/ml, and wherein sufficient succinic acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 its succinate salt, 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 in a solution concentration of from 3mg/ml to 20mg/ml or from 3mg/ml to less than 25mg/ml, and wherein sufficient succinic acid and sulfobutyl ether-beta-cyclodextrin (SBECD) are present to provide a clear solution.

Citric acid preparation

In one embodiment of the invention, there is provided 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 citrate salt thereof, citric 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 concentrated in a solution of 3mg/ml to 55mg/ml or 3mg/ml to less than 60mg/ml And wherein sufficient citric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 in a solution concentration of from 3mg/ml to 55mg/ml or from 3mg/ml to less than 60mg/ml, and wherein sufficient citric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation 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 beta-cyclodextrin or gamma-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 in a solution concentration of 3mg/ml to 55mg/ml or 3mg/ml to less than 60mg/ml And wherein sufficient citric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 citrate salt thereof, citric acid, a pharmaceutically acceptable beta-or gamma-cyclodextrin and water, wherein 1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea is present at from 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present and wherein sufficient citric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin is present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present and wherein sufficient citric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin is present to provide a clear solution.

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

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

In one embodiment of the invention there is provided 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 citrate salt thereof, 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 in a solution concentration of from 3mg/ml to 25mg/ml or from 3mg/ml to less than 30mg/ml, and wherein sufficient citric acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 citrate salt thereof, 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 in a solution concentration of from 3mg/ml to 20mg/ml or from 3mg/ml to less than 25mg/ml, and wherein sufficient citric acid and sulfobutyl ether-beta-cyclodextrin (SBECD) are present to provide a clear solution.

Malic acid preparation

In one embodiment of the invention there is provided 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 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 concentrated in a solution of from 3mg/ml to 65mg/ml or from 3mg/ml to less than 70mg/ml And wherein sufficient malic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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, 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 in a solution concentration of from 3mg/ml to 65mg/ml or from 3mg/ml to less than 70mg/ml, and wherein sufficient malic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation comprising the 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 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 in a solution concentration of 3mg/ml to 65mg/ml or 3mg/ml to less than 70mg/ml And wherein sufficient malic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 its malate salt, 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 concentration of 4mg/ml to 25mg/ml, a pharmaceutically acceptable salt thereof, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present and wherein sufficient malic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 concentration of 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present and wherein sufficient malic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation comprising the 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present and wherein sufficient malic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

Preferably, for the above embodiments of the 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 beta-cyclodextrin or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment of the invention there is provided 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 malate salt thereof, 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 in a solution concentration of from 3mg/ml to 30mg/ml or from 3mg/ml to less than 35mg/ml, and wherein sufficient malic acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 malate salt thereof, 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 in a solution concentration of from 3mg/ml to 25mg/ml or from 3mg/ml to less than 30mg/ml, and wherein sufficient malic acid and sulfobutyl ether-beta-cyclodextrin (SBECD) are present to provide a clear solution.

Tartaric acid preparation

In one embodiment of the invention there is provided 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 its tartrate salt, tartaric 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 concentrated in a solution of from 3mg/ml to 65mg/ml or from 3mg/ml to less than 70mg/ml And wherein sufficient tartaric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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, 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 in a solution concentration of from 3mg/ml to 65mg/ml or from 3mg/ml to less than 70mg/ml, and wherein sufficient tartaric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation comprising a tartrate 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 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 in a solution concentration of 3mg/ml to 65mg/ml or 3mg/ml to less than 70mg/ml And wherein sufficient tartaric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present and wherein sufficient tartaric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present and wherein sufficient tartaric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation comprising a tartrate 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution is present and wherein sufficient tartaric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

Preferably, for the above embodiments of the 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 beta-cyclodextrin or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment of the invention there is provided 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 its tartrate salt, 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 in a solution concentration of from 3mg/ml to 30mg/ml or from 3mg/ml to less than 35mg/ml, and wherein sufficient tartaric acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 its tartrate salt, tartaric acid, sulfobutyl ether-beta-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 in a solution concentration of from 3mg/ml to 25mg/ml or from 3mg/ml to less than 30mg/ml, and wherein sufficient tartaric acid and sulfobutyl ether-beta-cyclodextrin (SBECD) are present to provide a clear solution.

Hydrochloric acid preparation

In one embodiment of the invention, there is provided 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 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 in a solution concentration of from 3mg/ml to 60mg/ml or from 3mg/ml to less than 65mg/ml And wherein sufficient hydrochloric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 in a solution concentration of from 3mg/ml to 60mg/ml or from 3mg/ml to less than 65mg/ml, and wherein sufficient hydrochloric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation comprising a 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, 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 from 3mg/ml to 60mg/ml or from 3mg/ml to less than 65mg/ml And wherein sufficient hydrochloric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 35mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution concentration is present and wherein sufficient hydrochloric acid and pharmaceutically acceptable β -cyclodextrin or γ -cyclodextrin is present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 35mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution concentration is present and wherein sufficient hydrochloric acid and pharmaceutically acceptable β -cyclodextrin or γ -cyclodextrin is present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation comprising a 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, 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 35mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution concentration is present and wherein sufficient hydrochloric acid and pharmaceutically acceptable β -cyclodextrin or γ -cyclodextrin is present to provide a clear solution.

Preferably, for the above embodiment of the 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 beta-cyclodextrin or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

In one embodiment of the invention there is provided 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 its hydrochloride, hydrochloric acid, hydroxypropyl-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 in a solution concentration of from 3mg/ml to 35mg/ml or from 3mg/ml to less than 40mg/ml, and wherein sufficient hydrochloric acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 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 in a solution concentration of from 3mg/ml to 30mg/ml or from 3mg/ml to less than 35mg/ml, and wherein sufficient hydrochloric acid and sulfobutyl ether-beta-cyclodextrin (SBECD) are present to provide a clear solution.

Orthophosphoric acid preparation

In one embodiment of the invention, there is provided 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 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 in a solution concentration of 4mg/ml to 50mg/ml or 4mg/ml to less than 55mg/ml And wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 in a solution concentration of from 4mg/ml to 50mg/ml or from 4mg/ml to less than 55mg/ml, and wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation 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 in a solution concentration of 4mg/ml to 50mg/ml or 4mg/ml to less than 55mg/ml And wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 35mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution concentration is present and wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided 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, 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 35mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution concentration is present and wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention, there is provided an aqueous pharmaceutical formulation 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 4mg/ml to 25mg/ml, 4mg/ml to 20mg/ml, 4mg/ml to 15mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 4mg/ml to 30mg/ml, 6mg/ml to 30mg/ml, 10mg/ml to 35mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution concentration is present and wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

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

In one embodiment of the invention there is provided 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 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 in a solution concentration of from 4mg/ml to 35mg/ml or from 4mg/ml to less than 40mg/ml, and wherein sufficient orthophosphoric acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

In one embodiment of the invention there is provided 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 phosphate thereof, orthophosphoric acid, sulfobutyl ether-beta-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 in a solution concentration of from 4mg/ml to 30mg/ml or from 4mg/ml to less than 35mg/ml, and wherein sufficient orthophosphoric acid and sulfobutyl ether-beta-cyclodextrin (SBECD) are present to provide a clear solution.

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 formulation of the invention.

The formulations of the invention may be administered directly to the patient intravenously or parenterally (to avoid degradation), with the addition of osmolytes being preferred. Alternatively, for administration to a patient at a later date, such formulations (optionally containing bulking agents and/or osmo-regulators) may first be freeze-dried to prepare a lyophilized solid composition that remains chemically stable (preferably for at least 2 years) upon storage, after which the lyophilized solid composition may be immediately formulated (or reconstituted) to give a clear aqueous solution, preferably with the addition of an osmo-regulator, before administration to the patient by the intravenous (or parenteral) route. The reconstituted or formulated solution may be added to an infusion bag prior to administration to a patient.

The concentration of the pharmaceutically acceptable organic or inorganic acid used in the formulation of the present invention is preferably 10mM to 200mM or 50mM to 200mM, preferably about 50mM, about 100mM or about 150 mM. Preferably, the pharmaceutically acceptable organic or inorganic acid is present at a concentration of about 100 mM.

The amount of pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin used in the formulation of the invention is preferably from 2% w/v to 30% w/v, from 5% w/v to 20% w/v or from 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.

If the formulation of the invention is to be freeze-dried to produce a freeze-dried solid composition, an extender may be added to the formulation prior to the start of the freeze-drying process. The primary function of the bulking agent is to provide a freeze-dried solid with structural integrity that does not collapse, which allows for rapid reconstitution or formulation of an aqueous formulation prior to administration, and which should also facilitate effective lyophilization. Bulking agents are typically used when the total mass of solutes in the formulation is less than 2g/100 ml. Bulking agents may also be added to achieve isotonicity with blood. The bulking agent may be selected from a sugar, a sugar alcohol, an amino acid, or a polymer, or a mixture of any two or more thereof. Preferably, the bulking agent is a sugar or sugar alcohol or a mixture thereof. Preferably, the sugar is sucrose. Preferably, the sugar alcohol is mannitol.

Preferably, if an extender is present, 5 to 10% w/v of the extender is used.

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 osmolyte regulator may be added prior to use.

The 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 agent to ensure that a clear solution is obtained.

Prior to intravenous or parenteral administration of the formulation to a patient via injection, an osmolyte regulator may be present to avoid shrinkage or lysis of the red blood cells and to reduce or avoid pain and discomfort to the patient. This requires that the formulation to be administered to the patient has an effective osmotic pressure about the same as the blood of the patient.

Suitable osmolytes are nonionic osmolytes such as glycerol, sorbitol, mannitol, sucrose, propylene glycol or dextrose or mixtures of any two or more thereof. Preferably, the non-ionic osmolyte regulator is dextrose, sucrose or mannitol or a mixture of any two or more thereof.

Preferably, 1% w/v to 5% w/v of the osmolyte regulator is used.

Aqueous pharmaceutical formulations of the invention suitable for intravenous administration typically have a pH of from 3 to 9. However, lower pH is tolerated in certain environments. Preferably, the pH is 3 to 8 or 4 to 8.

The formulations of the invention are useful for the curative, palliative or prophylactic treatment of cancer in mammals, including humans. The cancer to be treated may 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.

The weekly dose of 1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea administered by intravenous route for the treatment of cancer using the formulation disclosed herein is preferably from 100mg to 400mg per week.

The following examples describe the preparation of the formulations of the present invention.

Example 1

Preparation of an aqueous pharmaceutical formulation comprising 35mg/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-cyclodextrin and hydrochloric acid

Hydrochloric acid (1M in water) (10ml, 100mM) was diluted with perfusion water (80 ml). 2-hydroxypropyl-. beta. -cyclodextrin (93% w/w adjusted titer) (21.57g, 147.2mM) 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-triazin-2-yl) phenyl ] urea (3500mg, 56.9mM) and stirred until a particle-free solution was obtained. The irrigation water was added under stirring to reach the target volume of 100 ml.

(i) Visual analysis

The formulation samples were analysed to determine the presence or absence of crystallites or particles according to the visual method defined in european pharmacopoeia method 2.9.20 (photometer using Verivide (trade mark) light box (light camera) and 3250 lux reading values against matt black and white panels). The samples were tested by this method as the solution was made and then after 24 hours.

(ii) OPM analysis

The formulation samples were placed on clean microscope slides and covered with a coverslip. Next, the formulation samples were analyzed by OPM using both unpolarized and cross-polarized light under a Nikon LV 100POL (trade mark) microscope using a 10 × magnifying lens and a 10 × magnifying eyepiece to determine the presence or absence of crystallites or particles. The image was recorded using the DFK 23UP031 TIS USB 3.0CMOS (trademark) color industrial camera 5MP 1/2, 5' and image acquisition software. The procedure was also repeated in a glass capillary using the formulation sample. Samples were tested by this method as the solution was made and then after 4 hours and 24 hours.

Example 2

Preparation of an aqueous pharmaceutical formulation comprising 30mg/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-beta-cyclodextrin (SBECD) and tartaric acid

Tartaric acid (racemic) (99% w/w titer) (1.5g, 100mM) was diluted with perfusion water (80 ml). Sulfobutyl ether- β -cyclodextrin (90% w/w adjusted titer) (22.18g,195mM) 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-triazin-2-yl) phenyl ] urea (3000mg, 48.7mM) and stirred until a particle-free solution was obtained. The irrigation water was added under stirring to reach the target volume of 100 ml.

A sample of the formulation was analyzed according to the method of example 1.

Example 3

Preparation of an aqueous pharmaceutical formulation comprising 45mg/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

Orthophosphoric acid (99% w/w hypothetical titer) (979mg, 100mM) was diluted with perfusion water (80 ml). Gamma-cyclodextrin (assuming 100% titer) (20g, 154mM) 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-triazin-2-yl) phenyl ] urea (4500mg, 73.1mM) and stirred until a particle-free solution was obtained. The irrigation water was added under stirring to reach the target volume of 100 ml.

A sample of the formulation was analyzed according to the method of example 1.

Example 4

Freeze-dried composition for preparing aqueous solution pharmaceutical preparation of the present invention

An aqueous solution pharmaceutical formulation of the present invention (e.g., prepared according to any one of examples 1-3) was filled into a 10mL vial to a target volume of 3 mL. The vials were partially stoppered (non-sealed) with 20mm Gray Lyo D777-1V 10-F597W FluoroTec Siliconized (trade Mark) stoppers. The vials were loaded into stainless steel trays and inserted into an LSL1000 (trade mark) freeze dryer. The shelf temperature was set to 5 ℃. A freeze-drying cycle is then performed according to conventional procedures.

After the freeze-drying cycle was complete, the lyophilizer was backfilled with sterile filtered nitrogen to a setpoint of 500 torr (about 666 mbar or 66,600 pascals) and the vial was completely closed with a stopper. The freeze dryer was then vented to atmospheric pressure using sterile filtered air and the vials were removed from the freeze dryer.

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

Example 5

Reconstitution of an aqueous pharmaceutical formulation of the invention from a lyophilized solid composition of the invention

The lyophilized solid composition prepared in example 4 in the vial was reconstituted as follows.

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

Example 6

Lyophilized compositions for preparing an aqueous pharmaceutical formulation comprising 10mg/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-cyclodextrin and lactic acid

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

The aqueous solution pharmaceutical formulation of the present invention (described above) was filled into 20mL vials to a target volume of 7 mL. The vials were partially stoppered (non-sealed) with 20mm Gray Lyo D777-1V 10-F597W FluoroTec Siliconized (trade Mark) stoppers. The vials were loaded into stainless steel trays and inserted into an LSL1000 (trade mark) freeze dryer. A freeze-drying cycle is then performed according to conventional procedures.

After the freeze-drying cycle was complete, the lyophilizer was backfilled with sterile filtered nitrogen to a setpoint of 500 torr (about 666 mbar or 66,600 pascals) and the vial was completely closed with a stopper. The freeze dryer was then vented to atmospheric pressure using sterile filtered air and the vials were removed from the freeze dryer.

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

Further examples of the preparation of aqueous pharmaceutical formulations 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, beta-cyclodextrin or gamma-cyclodextrin and a pharmaceutically acceptable organic or inorganic acid

The following tabulated examples (indicated by stippling or forking) were prepared using the ingredient specifications tabulated below using a method similar to that of examples 1 to 3 (target volume 100 ml).

These examples were analyzed by both the visual method defined in the european pharmacopoeia method 2.9.20 and the OPM method as described in example 1. The results are also tabulated below.

In this table, "particle-free" means that the formulation is visually clear and free of visible crystallites or particles, and conforms to the definition of a "clear solution" as desired as previously described.

Keyword

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

Acids used in racemic form

HPBCD ═ 2-hydroxypropyl-beta-cyclodextrin

SBECD-sulfobutyl ether-beta-cyclodextrin

gamma-CD ═ gamma-cyclodextrin

Alpha-cyclodextrin

(1) No particles (and not opalescent). All of these studied examples contained no visible microcrystalline or particulate material and met the definition of "clear solution" required as previously described.

(2) Suspension of particles

Chemical stability of the lyophilized solid preparation of the present invention

A sample of the lyophilized formulation of the present invention ("sample a") was prepared according to example 6.

Separate portions of sample a were each contained in 20mL clear vials, and one portion was stored at 25 ℃/60% relative humidity ("RH") for 6 months, and another portion was stored at 40 ℃/75% RH for 6 months.

After 6 months of 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 test.

UHPLC method

The solutions, samples, standards and UHPLC methods were as follows:

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 of known potency values.

Diluent agent: acetonitrile/Water/trifluoroacetic acid (750:250:1v/v/v)

Mobile phase A: acetonitrile/Water/trifluoroacetic acid (97:3:1v/v/v)

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

(Note: larger or smaller volume solutions can be prepared using appropriate component ratios)

Standard formulation and test standard formulation:

two solutions of a reference standard 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 a concentration of about 0.2mg/mL (+/-10%) are prepared accurately and the concentrations of both are recorded accurately in a diluent. These are standard formulations and test standard formulations.

Sensitive solution:

the standard formulation was diluted precisely with diluent to a concentration of 1- (4- { [4- (dimethylamino) piperidin-1-yl ] carbonyl } phenyl) -3- [4- (4, 6-dimorpholin-4-yl-1, 3, 5-triazin-2-yl) phenyl ] urea of about 0.1 microgram/ml.

Sample preparation:

sample a was reconstituted after storage as follows: to each sample was added 7.0ml of water in a 20ml vial, the vial was shaken to dissolve the solids and to wait for the bubbles to disappear. 1.0ml of this solution was transferred to a 50ml volumetric flask. Diluted to a set volume with diluent.

Chromatographic conditions are as follows:

liquid chromatography System- -with 380. mu.l Jet Weaver^TMAgilent 1290Infinity II^TM

Column: waters BEH C18^TM15cm 2.1mm, 1.7 μm or equivalent

Column temperature: 20 deg.C

Sample size: 2 μ L

Flow rate: 0.25mL/min

Flow-through cell: g4212-60008, path length of 10mm, 1.0. mu.L

Detection: UV at 240nm/4nm slit width

Run time: 77 minutes

Mobile phase A

Mobile phase B

Probe wash solution (needle wash solution): water/acetonitrile (95:5v/v), multiple washes, 20 s.

Seal wash solution (seal wash solution): water/propan-2-ol (90:10v/v)

Linear gradiometer:

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

Illustrative notes

The UHPLC system was conditioned with mobile phase before starting the analysis.

Prior to manipulating the sample, the system is ensured to be suitable for use by injecting blank diluent, sensitive solution and standard formulation using the chromatographic conditions described above.

The following criteria must be met at the initial UHPLC setting or after any significant change in the system. It is recommended to inject at least one conditioning blank prior to testing the system suitability.

Average of all system fitness (reproducibility) samples were used.

The equation for the United States Pharmacopoeia (USP) calculation for efficiency and peak asymmetry.

The standard preparation was tested by sample injection according to the above chromatographic conditions. The response factor (calculated from the area of the standard, the standard weight, the dilution factor and the purity factor) of this test standard preparation must be within ± 2% of the standard preparation.

After confirming the suitability of the system, the blank solution, the standard preparation and the prepared test sample were injected according to the above chromatographic conditions, followed by the standard preparation. It is recommended to inject no more than 6 test samples between standard formulation injections. For each injection (standards and samples) 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 were measured. The retention time and peak area of any peaks present in the sample injection, but not present in the blank injection, were also measured for each sample injection. Gradient artifacts (if present) are not integrated. The blank sample chromatogram is compared to the sample chromatogram to determine which peaks in the sample are associated with blank and gradient artifact peaks. The% w/w of degradation products was calculated and individual degradation product peaks equal to or higher than 0.05% w/w were reported. Unknown degradation products should each be reported in terms of their relative retention times. Known degradation products should be individually reported according to names.

The results are summarized in the table below.

Keyword

NMT ═ does not exceed.

RRT ═ relative retention time

Degradation product 1

Degradation products 2, 3 and 4

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

Sample A results

Conclusion

The results show that sample a remains chemically stable for at least 6 months at 25 ℃/60% RH and for at least 6 months at 40 ℃/75% RH.

Claims (35)

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 sufficient of the pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable β -cyclodextrin or γ -cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including salts thereof) is not a sulfonic acid.

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 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 6mg/ml, and wherein sufficient of said pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution, with the proviso that said organic or inorganic acid (including salts thereof) is not a sulfonic acid.

3. The aqueous pharmaceutical formulation of claim 1 or 2, wherein the pharmaceutically acceptable organic or inorganic acid is selected from the group consisting of lactic acid, acetic acid, maleic acid, succinic acid, citric acid, malic acid, tartaric acid, hydrochloric acid and orthophosphoric acid.

4. The aqueous pharmaceutical formulation of claim 1 or 2 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, 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 6mg/ml to 30mg/ml or 6mg/ml to less than 35mg/ml, and wherein sufficient lactic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

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

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

7. The aqueous pharmaceutical formulation of claim 4 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, a pharmaceutically acceptable beta-cyclodextrin or gamma-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 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution, and wherein sufficient lactic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

8. The aqueous pharmaceutical formulation of claim 4 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 beta-cyclodextrin or gamma-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 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution, and wherein sufficient lactic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

9. The aqueous pharmaceutical formulation of claim 4 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 6mg/ml to 25mg/ml, a, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution, and wherein sufficient lactic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

10. The aqueous pharmaceutical formulation according to any one of claims 4 to 9, wherein the pharmaceutically acceptable β -cyclodextrin or γ -cyclodextrin used is 2-hydroxypropyl- β -cyclodextrin, sulfobutyl ether- β -cyclodextrin (SBECD) or γ -cyclodextrin.

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

12. The aqueous pharmaceutical formulation of claim 4 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 in a solution concentration of 6mg/ml to 25mg/ml or 6mg/ml to less than 30mg/ml, and wherein sufficient lactic acid and sulfobutyl ether-beta-cyclodextrin (SBECD) are present to provide a clear solution.

13. The aqueous pharmaceutical formulation of claim 4 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, 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 in a solution concentration of 6mg/ml to 30mg/ml or 6mg/ml to less than 35mg/ml, and wherein sufficient lactic acid and 2-hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

14. The aqueous pharmaceutical formulation of claim 4 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, 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 6mg/ml to 30mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of solution, and wherein sufficient lactic acid and 2-hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

15. The aqueous pharmaceutical formulation of claim 4 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, 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 6mg/ml to 30mg/ml, 6mg/ml to 25mg/ml, 6mg/ml to 20mg/ml, 6mg/ml to 15mg/ml, 10mg/ml to 30mg/ml, 10mg/ml to 25mg/ml or 10mg/ml to 20mg/ml of a solution is present and wherein the lactic acid concentration is 10mM to 100mM, 15mM to 100mM or 30mM to 100mM and the 2-hydroxypropyl-beta-cyclodextrin concentration is 15mg/ml to 120mg/ml, 20mg/ml to 120mg/ml or 35mg/ml to 120mg/ml to provide a clear solution.

16. The aqueous pharmaceutical formulation of claim 4 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 in a solution concentration of 10mg/ml to 30mg/ml or 10mg/ml to 20mg/ml, and wherein the lactic acid concentration is 20mM to 100mM or 30mM to 100mM and the 2-hydroxypropyl-beta-cyclodextrin concentration is 35mg/ml to 120mg/ml to provide a clear solution.

17. 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 an acetate salt thereof, acetic acid, a pharmaceutically acceptable beta-cyclodextrin or gamma-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 in a solution concentration of from 3mg/ml to 15mg/ml or from 3mg/ml to less than 20mg/ml, and wherein sufficient acetic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

18. 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 maleate salt thereof, maleic 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 in a solution concentration of from 3mg/ml to 30mg/ml or from 3mg/ml to less than 35mg/ml, and wherein sufficient maleic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

19. 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 salt thereof, succinic acid, a pharmaceutically acceptable beta-cyclodextrin or gamma-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 in a solution concentration of from 3mg/ml to 65mg/ml or from 3mg/ml to less than 70mg/ml, and wherein sufficient succinic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

20. 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 citrate salt thereof, citric acid, a pharmaceutically acceptable beta-cyclodextrin or gamma-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 in a solution concentration of from 3mg/ml to 55mg/ml or from 3mg/ml to less than 60mg/ml, and wherein sufficient citric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

21. 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 malate salt thereof, 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 in a solution concentration of from 3mg/ml to 65mg/ml or from 3mg/ml to less than 70mg/ml, and wherein sufficient malic acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

22. 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 tartrate salt thereof, tartaric 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 in a solution concentration of from 3mg/ml to 65mg/ml or from 3mg/ml to less than 70mg/ml, and wherein sufficient tartaric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

23. 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 hydrochloride thereof, hydrochloric acid, a pharmaceutically acceptable beta-cyclodextrin or gamma-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 in a solution concentration of from 3mg/ml to 60mg/ml or from 3mg/ml to less than 65mg/ml, and wherein sufficient hydrochloric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

24. 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 in a solution concentration of 4mg/ml to 50mg/ml or 4mg/ml to less than 55mg/ml, and wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta-cyclodextrin or gamma-cyclodextrin are present to provide a clear solution.

25. The formulation of any one of claims 1 to 14 or 17 to 24, wherein 10mM to 200mM or 50mM to 200mM of the pharmaceutically acceptable organic or inorganic acid is used.

26. The formulation of any one of claims 1 to 14 or 17 to 25, wherein 2% w/v to 30% w/v, 5% w/v to 20% w/v or 15% w/v to 30% w/v of the cyclodextrin is used.

27. A lyophilized formulation obtainable by freeze-drying the formulation of any one of claims 1 to 26.

28. A lyophilized formulation according to claim 27 obtainable by freeze-drying a formulation according to any one of claims 1 to 26, optionally containing a bulking agent.

29. The lyophilized formulation of claim 28, wherein the bulking agent is mannitol.

30. An aqueous pharmaceutical formulation obtainable in the form of a clear solution by reconstitution or formulation (constitution) of a lyophilized formulation according to any one of claims 27 to 29 using water or an aqueous solution comprising an osmotic agent.

31. The aqueous pharmaceutical formulation of claim 30, wherein the osmolyte regulator is dextrose, sucrose, or mannitol, or a mixture of any two or more thereof.

32. The aqueous pharmaceutical formulation of any one of claims 1 to 26 or 30 or 31, adjusted as necessary to have a pH suitable for intravenous or parenteral administration.

33. A formulation according to any one of claims 1 to 32 for use as a medicament.

34. The formulation of any one of claims 1 to 32 for use in the treatment of cancer.

35. A method of treating cancer in a mammal comprising treating the mammal with an effective amount of the formulation of any one of claims 1 to 32.