BR112017010841B1 - FORMULATIONS OF A PI3K/MTOR INHIBITORS FOR INTRAVENOUS ADMINISTRATION - Google Patents

Abstract

FORMULATIONS OF A PI3K/MTOR INHIBITOR FOR INTRAVENOUS ADMINISTRATION. 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 pharmacologically acceptable salt thereof, which is a clear solution. Such a formulation is particularly suitable for intravenous or parenteral administration to a patient.

Description

[0001] 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 pharmacologically acceptable salt thereof. More specifically, the present invention relates to an aqueous pharmaceutical formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin- 4-yl-1,3,5-triazin-2-yl)phenyl]urea, or a pharmacologically acceptable salt thereof, which is a clear solution. Such a formulation is particularly suitable for intravenous administration to a patient.

[0002] 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 preparations are disclosed in WO2009/143313. The compound is a PI3-kinase and mTOR inhibitor that is useful for treating cancer.

[0003] A crystalline form of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3, 5-triazin-2-yl)phenyl]urea and the process for preparing the same are disclosed in WO2010/096619.

[0004] A 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin -2-yl)phenyl]urea has the chemical structure:

[0005] A 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 is chemically and physically stable at 25°C and 60% relative humidity (RH) for up to 3 years in this form. However, this free base is sufficiently water soluble to permit the preparation of an aqueous solution formulation suitable for intravenous or parenteral administration at the required therapeutic dose levels.

[0006] There is a need to develop a pharmaceutically acceptable formulation 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 is (a) chemically stable on storage (e.g., at 25°C and 60% RH) and/or (b), which will to facilitate effective intravenous (or parenteral) administration of the drug to a mammal, including a human.

[0007] Preferably, the formulation is suitable for the intravenous 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 taking into account the specific pharmacokinetic and bioavailability characteristics of the drug.

[0008] It is essential that an intravenous formulation of any drug be a solution to facilitate safe and effective administration to a patient. It should be free of particles and not form a gel or suspension. A clear aqueous solution is preferred.

[0009] A transparent solution is defined as a visually transparent solution essentially free of visible particles that can be observed on visual inspection. Generally, if any particulate matter is observed, the formulation is not suitable for intravenous administration and should not be used as occlusion of blood vessels may occur. Consequently, in view of the qualitative nature of the visual test, the term "essentially free of any visible particles" is generally applied when visible particulate matter is not observed.

[00010] Particulate matter can be defined as follows:

[00011] Discrete grain whose shape cannot be determined without magnification

[00012] Smoke or Swirl - Fine particles that look like smoke or a tornado and usually originate from the bottom of the sample vial and swirl upwards as the vial is rotated

[00013] Flocculant material - loosely aggregated particles or soft flakes

[00014] Particles with a defined shape or characteristic can be described as glass-like, metallic, etc.

[00015] Visual inspection can be conducted according to the method defined in the European Pharmacopoeia 2.9.20 method entitled "Particle contamination: visible particles". This method determines the particulate contamination of injections and infusions by foreign, mobile, undissolved particles, in addition to gas bubbles, which may be present in the solutions. The test is intended to provide a simple procedure for visually assessing the quality of parenteral solutions with respect to visible particles. Other validated methods can also be used.

[00016] In the method of the European Pharmacopoeia 2.9.20 the apparatus (see "Figure 2.9.20.-1" shown in Figure 2) consists of a display station comprising:

[00017] An appropriately sized matte black panel held upright

[00018] An appropriately sized non-gloss white panel held upright next to the black panel

[00019] An adjustable lamp holder equipped with a suitable shaded white light source and a suitable light diffuser (a display illuminator containing two 13 Watt fluorescent tubes, each 525 mm long, is suitable). Illumination intensity at the point of view is maintained between 2000 lux and 3750 lux, although higher values are preferred for colored glass and plastic containers.

[00020] The method states: “Remove any adhering label from the container and wash and dry the exterior. Gently shake or invert the container, ensuring that air bubbles are not introduced, and observe for about 5 seconds in front of the white panel. Repeat the procedure in front of the black panel. Record the presence of any particles."

[00021] It has now surprisingly been found that the technical problem has been solved by a pharmaceutical aqueous solution formulation comprising

[00022] 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 at a solution concentration of less than 6 mg/ml and sufficient lactic acid is present to provide a solution transparent; or

[00023] 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, 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 solution transparent (hereinafter "the formulation of the invention").

[00024] Such a formulation can be directly administered to the patient (in order to avoid the occurrence of degradation), intravenously or parenterally, preferably with the addition of a tonicity modifier. Alternatively, for administration to a patient at a later date, such a formulation, optionally containing a bulking agent and/or tonicity modifier, may first be lyophilized to prepare a lyophilized solid composition that is chemically stable on storage, preferably for at least 2 years and that the lyophilized solid composition can then be constituted, or reconstituted, to provide a clear aqueous solution, preferably with the addition of a tonicity modifier, as needed, immediately prior to administration to a patient intravenously (or parenteral).

[00025] It was found that the use of alternative acids to lactic acid or orthophosphoric acid used in the formulation of the invention, in the preferred concentration of 2.5 - 5.5mg/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, results in cloudy formulations containing particulate matter or gel and does not lead to the essentially clear, particle-free solutions necessary for intravenous (or parenteral) administration to a patient.

[00026] Regarding formulations comprising lactic acid:

[00027] It was found that at solution concentrations of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl - 1,3,5-triazin-2-yl)phenyl]urea of 6 mg/ml or above, the necessary clear solutions at the pH required for intravenous administration to a patient are not obtained, or are not obtained consistently.

[00028] Preferably, the invention features an aqueous solution 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 and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)- 3-[4-(4,6-Dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 6 mg/ml and sufficient lactic acid is present to provide a transparent solution.

[00029] The concentration of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5 -triazin-2-yl)phenyl]urea in the formulation of the invention can be from 1 to 5.5 mg/ml, from 2 to 5.5 mg/ml, or from 3 to 5.5 mg/ml (calculated as the so-called freebase).

[00030] Preferably, the invention provides an aqueous pharmaceutical formulation in which 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 2.5 to 5.5 mg/ml.

[00031] Preferably, the invention provides an aqueous pharmaceutical formulation in which 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 about 5mg/ml.

[00032] Preferably, when 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 is used, above 2.5 mole equivalents of lactic acid are present in the formulation of the invention. More preferably, from 3 to 10, up from 2.5 to 8.0, or from 3.5 to 4.5 mole equivalents of lactic acid are present in the formulation of the invention. Most preferably, about 4.1 mole equivalents of lactic acid are present in the formulation of the invention.

[00033] Preferably, when 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 is used, the invention provides an aqueous pharmaceutical solution formulation in which 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 5.0 to 5.5 mg /ml and at least 2.5 mole equivalents of lactic acid is present.

[00034] Preferably, when 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 is used, the invention provides a pharmaceutical aqueous solution formulation in which 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 about 5 mg/ml and at least 2 .5 mole equivalents of lactic acid is present.

[00035] Preferably, when 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 is used, the invention provides a pharmaceutical aqueous solution 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 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 solution of about 5mg/ml and at least 2.5 mole equivalents of lactic acid is present in sufficient quantity to ensure that a clear solution is formed.

[00036] It should be noted that 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3 ,5-triazin-2-yl)phenyl]urea forms a 1:1 (mole equivalent) lactate salt with lactic acid. The formulation of the invention can be prepared using 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl) free base -1,3,5-triazin-2-yl)phenyl]urea or using a lactic 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. When the lactic acid salt is used, preferably above 1.5 mole equivalents of lactic acid are used to achieve the presence of the lower limit above 2.5 mole equivalents of lactic acid in the formulation of the invention.

[00037] Preferably, the invention features an aqueous solution 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 lactate, lactic acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl) -3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5 mg/ml and at least 1 Enough .5 mole equivalents of lactic acid is present in an amount sufficient to ensure that a clear solution is formed.

[00038] DL-lactic acid, D-lactic acid or L-lactic acid, or any combination thereof, can be used in the formulation process of the invention. Preferably, DL-lactic acid is used.

[00039] Preferably, the pH of the formulation of the invention is not greater than 3.7. More preferably, the pH of the formulation of the invention is from 3.0 to 3.7, from 3.3 to 3.6, or from 3.4 to 3.5.

[00040] In a preferred embodiment, the present invention provides an aqueous solution 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 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 up to 5.5 mg/ml and above 2.5 mole equivalents of sufficient lactic acid is present in an amount sufficient to ensure that a clear solution is formed with a pH of not more than 3.7.

[00041] In a preferred embodiment, the present invention provides an aqueous solution 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 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 about 5 mg/ml and about Enough 4.1 mole equivalents of lactic acid is present in an amount sufficient to ensure that a clear solution is formed with a pH of no more than 3.7.

[00042] A crystalline form of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3, 5-triazin-2-yl)phenyl]urea L-lactate can be used to prepare the formulation of the invention. Preferably, the crystalline form of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3, The 5-triazin-2-yl)phenyl]urea L-lactate used has a PXRD pattern (measured using a Bruker D4 diffractometer and copper K-alpha radiation) with major peaks at about 16.2, 17.3 , 18.4, 18.9, 19.9, 20.9 and 23.1 degrees 2-theta (+/- 0.2 degrees 2-theta). This crystalline form of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin -2-yl)phenyl]urea L-lactate is distinguished from other known forms of this salt by having peaks characterized at around 6.5, 15.9, 20.9, 22.1 and 23.1 degrees 2-theta ( +/- 0.2 degrees 2-theta).

[00043] Regarding formulations comprising ortho-phosphoric acid:

[00044] Preferably, the invention features an aqueous solution 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 and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)- 3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a transparent solution.

[00045] Preferably, the invention provides an aqueous pharmaceutical formulation in which 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 3.0 to 3.5mg/ml.

[00046] Preferably, the invention provides an aqueous pharmaceutical solution formulation where at least 5 mole equivalents of orthophosphoric acid are used.

[00047] Preferably, the invention provides an aqueous pharmaceutical solution formulation where at least 5 to 7 mole equivalents of orthophosphoric acid are used.

[00048] In a preferred embodiment, the present invention provides an aqueous solution 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 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, from 5 The 7 mole equivalents of ortho-phosphoric acid is present in an amount sufficient to ensure that a clear solution is formed.

[00049] Preferably, the pH of the prepared formulation is 2-2.5 before intravenous administration. The pH is then preferably adjusted from 3.0-4.5 for intravenous administration.

[00050] In 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 is used, it is preferably prepared using an orthophosphoric acid.

[00051] If the formulation of the invention is freeze-dried to provide a lyophilized solid composition, a bulking agent is preferably added to the formulation before starting the freeze-drying process. The primary function of the bulking agent is to provide the freeze-dried solid with a non-collapsible structural integrity, which will allow rapid reconstitution or constitution of the aqueous formulation prior to administration and should also facilitate efficient lyophilization. Bulking agents are normally used when the total mass of solutes in the formulation is less than 2g/100ml. Bulking agents can also be added to achieve isotonicity with blood. The bulking agent can be selected from a saccharide, sugar alcohol, amino acid or polymer, or be a mixture of two or more of any of these. 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.

[00052] Reconstitution of the freeze-dried solid composition can be achieved by adding the necessary amount of water that was present before freeze-drying so that a clear solution is obtained. A stress modifier can then be added before use.

[00053] The constitution of the freeze-dried solid composition can be achieved with the use of an appropriate amount of water and/or an aqueous solution of a suitable tonicity modifier in order to ensure that a clear solution is obtained.

[00054] A tonicity modifier must be present prior to intravenous or parenteral administration of the formulation to a patient by injection to prevent crenation or hemolysis of red blood cells and to attenuate or avoid pain and discomfort for the patient. This requires that the formulation to be administered to the patient has an effective osmotic pressure that is approximately the same as that of the patient's blood.

[00055] Suitable tonicity modifiers are non-ionic tonicity modifiers such as glycerol, sorbitol, mannitol, sucrose, propylene glycol or dextrose, or a mixture of 2 or more thereof. Preferably the non-ionic tonicity modifier is dextrose, sucrose or mannitol, or is a mixture of 2 or more thereof.

[00056] Aqueous pharmaceutical formulations that are suitable for intravenous administration generally have a pH of 3 to 9. Formulations of the invention that are to be administered intravenously preferably have a pH of 3 to 4.5.

[00057] The formulation of the invention can be used for the curative, palliative or prophylactic treatment of cancer in a mammal, including a human being. The cancer to be treated can be selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, cancer pancreas, kidney cancer, gastric cancer and brain cancer.

[00058] 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 to be administered intravenously for the treatment of cancer using the formulations disclosed herein is preferably in the range of 100-400mg/ml per week.

[00059] The following examples illustrate the preparation of the formulations of the invention.

EXAMPLES EXAMPLE 1 Preparation of an aqueous pharmaceutical solution 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 and DL-lactic acid

[00060] D,L-lactic acid (334 mg) was dissolved in irrigation water to make a solution with a total volume of 100 ml. 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl )phenyl]urea (200mg) was dissolved in 37 ml of this lactic acid solution, mixing with an Ultra Turrax T25 homogenizer (trademark) for 120 minutes and sonicating the solution for ten minutes in an ultrasonic bath. The mixture was then stirred overnight with a magnetic stirrer to provide a clear solution. This was made up to 40ml in volume with the lactic acid solution using a volumetric flask. The solution was filtered through a 0.2 µm nylon filter into a 50 ml clear container in a laminar air flow (LAF) cabinet. The first 5 ml of filtered solution was used to wet the filter and was discarded as not representative of the filtered solution. The bottle was crimped and sealed with clean lyo-stoppers and hinged caps. The solution was visually inspected and found to be a clear and colorless solution. EXAMPLE 2 Preparation of (a) a 5mg/ml pharmaceutical aqueous solution 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, DL-lactic acid and mannitol; And (b) preparation of a freeze-dried solid composition thereof (a) 36.100g of water for injection was weighed into a vessel. 125.82g of DL-lactic acid (90.6% purity, parenteral nutrition grade) was slowly added and the mixture stirred until the lactic acid dissolved. 195.3g 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 was slowly added and the mixture stirred until the material dissolved. 1900g of powdered mannitol (parenteral) was gradually added and the mixture stirred until the material dissolved. Water for injection was added to bring the solution to a total weight of up to 38,760 g and the solution was stirred for a further 10 minutes. The pH was checked and found to be 3.4 with a solution temperature of 29.3°C. The solution was sterile filtered through a 0.45 µm in-line clarification filter and 0.22 µm filter assembly. This solution was then filled into 50ml vials with a target fill volume of 20.8ml for each vial. The vials were each partially stoppered (not sealed) with a 20mm Lyo Gray Stopper D777-1 V10-F597W Siliconized FluroTec (Trade Mark). (b) These vials were then loaded onto stainless steel trays and inserted into an LSV1000 lyophilizer (trademark). The shelf temperature was set at 5°C. The lyophilizer cycle was performed using the method below.

[00061] The lyophilizer was refilled with sterile filtered nitrogen to a setpoint of ca. 700mbar (70,000 Pascals), and the flasks were completely closed using the stoppers. The lyophilizer was then vented at atmospheric pressure using sterile filtered air and the vials were unloaded from the lyophilizer.

[00062] Each vial contained the freeze-dried (lyophilized) formulation as a white colored solid.

EXAMPLE 3 Reconstitution of a 5mg/ml pharmaceutical aqueous solution 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, DL-lactic acid and mannitol from a freeze-dried solid composition.

[00063] The lyophilized solid composition sample vials prepared in Example 2(b) were reconstituted as follows.

[00064] Approximately 25 ml of water for injection was drawn into a syringe and a 0.2 micron PVDF filter membrane was attached to the syringe. Approximately 5 ml of water was filtered through the membrane and discarded. 20ml of water remaining in the syringe was then filtered into the 50ml vial containing the lyophilized composition prepared as per Example 2(b). The mixture was gently swirled in the flask until a clear, colorless solution was achieved.

[00065] The reconstituted solution was analyzed as follows:

(a) pH

[00066] The pH of the solution in the flask was measured as pH = 3.52 at 23.2 degrees °C.

(b) Visual appearance of the reconstituted solution

[00067] One of the reconstituted vials was visually inspected using a method based on the European Pharmacopoeia 2.9.20 method described above. The method is designed to observe the presence of any visible particles.

[00068] By this method, the solution in the vial was visually inspected in a Verivide DCAC60 (trademark) light cabinet using a light meter reading of 3250 lux against a matte black panel and a white panel.

[00069] The result showed a transparent and colorless solution, free of particulate matter, achieved in reconstitution.

(c) Analysis for sub-visible particles

[00070] The solution in the vial was evaluated for the presence of sub-visible particles using a HIAC apparatus (trade mark) using a sub-visible particle determination method that is based on what was defined in the United States Pharmacopoeia 36 <788> Method 1 ("Light Obscuring Particle Count Test"). In order for a solution to be suitable for parenteral or intravenous administration, the results must conform to the criteria for "Test 1.B" for USP 36 <788> Method 1, as these define the widest possible limits acceptable for particles sub-visible. This test states the following:

[00071] “Test 1.B (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of less than 100 ml) - the preparation complies with the test if the average number of particles present in the tested units does not exceed 6000 per container of 10 μm or more and not to exceed 600 per container of 25 μm or more".

[00072] By this method, first, 10 solutions from the vial samples were pooled. Four samples of not less than 5 ml each were removed from the pooled solution and, for each sample, the number of particles equal to or greater than 10 μm and 25 μm were counted using a HIAC HRLD 400 sensor (trade mark). The result obtained for the first sample was disregarded. For each of the remaining three samples, the average number of particles per container was calculated and compared to the requirements of USP 36 <788> Test 1.B. These samples each met USP 36 acceptance criteria <788> Test 1.B for a solution to be suitable for parenteral or intravenous administration

EXAMPLE 4 Preparation of a crystalline form of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5 -triazin-2-yl)phenyl]urea L-lactate Preparation A:

[00073] A 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin -2-yl)phenyl]urea (52mg) was weighed into a 2ml vial. A solution of 22 mg/ml L-lactic acid in 98:2 v/v ethyl acetate:dimethylformamide (0.5ml) was added to the flask. The aqueous slurry was stirred at about 23°C for 24 hours. The aqueous slurry was then filtered through a 0.2 µm nylon centrifuge filter to isolate the crystalline title compound.

[00074] The product was analyzed by PXRD (see "Investigation 7" below) using a Bruker D4 diffractometer (trademark) and copper K-alpha radiations and produced a pattern that is shown in Figure 1.

Preparation B:

[00075] A 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin -2-yl)phenyl]urea (52mg) was weighed into a 2ml vial. A solution of 22 mg/ml L-lactic acid in 98:2 v/v ethyl acetate:dimethylformamide (0.5ml) was added to the flask. The aqueous slurry was heated to 60°C at a rate of 5°C/minute, held at 60°C for 20min and then cooled at 0.1°C/minute to 5°C where it was held until it was isolated. (24 hours after the start of the heating step). The aqueous slurry was filtered through a 0.2 µm nylon centrifuge filter to isolate the crystalline title compound.

[00076] The product was analyzed by PXRD (see "Investigation 7" below) using a Bruker D4 diffractometer and copper K-alpha radiation and produced a pattern consistent with what is shown in Figure 1.

[00077] The following investigations were conducted in connection with the present invention.

INVESTIGATIONS 1. Investigation regarding a 3mg/ml aqueous formulation 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 with various acids Procedure

[00078] Nine individual acidic buffer solutions were prepared as follows to use ca. 6.8 mole equivalents of each acid (except where noted):

[00079] Stability testing was conducted using samples ca. of 3mg/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 for each acid buffer prepared above. These samples were prepared using a target weight of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1, 15.45mg 3,5-triazin-2-yl)phenyl]urea (due to 97.1% API activity) by weighing the required amount into each vial as follows:

[00080] 5 ml of the respective buffers were introduced for the weighed sample into the flasks and the flasks were each closed by a crimped lid then sealed with a protective film. The vials were placed on a conveyor belt in an oven at 25°C for 5 days.

Results

[00081] At the end of the 5 day period the pH of each sample was measured and a visual observation of each sample was made using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and white background. The sample was also tested by illumination using a narrow beam light source (Tyndall) and then visually inspected from a direction perpendicular to the light beam to identify undissolved solid particles.

Observação visual das amostras após 5 dias a 25°C

[00082] Six vials were found to have fallen off the mat during the course of the experiment meaning that the exact time the vials actually fell is unknown. These samples are marked in the "PH Results" and "Visual Observations" tables below with an asterisk (*). pH results after 5 days at 25°C.

Visual observation of samples after 5 days at 25°C

Conclusion

(WFI = água para irrigação)[00083] The results show that the 3mg/ml samples containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine- 4-yl-1,3,5-triazin-2-yl)phenyl]urea and DL-lactic acid reached a clear solution after 5 days at 25 °C. All other samples except one (orthophosphoric acid - sample N=2) failed to achieve a clear solution. As such, acids other than DL-lactic acid and orthophosphoric acid would not be suitable for preparing pharmaceutical aqueous solution formulations for intravenous administration to a patient at a required API (active pharmaceutical ingredient) concentration. 2. Investigation regarding aqueous formulations of 3mg/ml and 4mg/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 with various acids Procedure (a) Four individual acid buffer solutions were prepared as follows for use in 3mg/ml formulations, the in order to use ca. 6.8 mole equivalents of the respective acid:

(WFI = water for irrigation)

(b) Soluções de tampão ácido individuais foram preparadas como segue para uso em formulações de 4mg/ml, a fim de utilizar ca. 5,1 moles equivalentes do respectivo ácido (exceto onde indicado):

[00084] Stability testing was conducted using samples ca. of 3mg/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 for each acid buffer prepared above. These samples were prepared using a target weight of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1, 15.45mg 3,5-triazin-2-yl)phenyl]urea (due to 97.1% API activity) by weighing the required amount into each vial as follows:

(b) Individual acid buffer solutions were prepared as follows for use in 4mg/ml formulations in order to utilize ca. 5.1 mole equivalents of the respective acid (except where noted):

[00085] The stability test was conducted using samples ca. of 4mg/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 for each acid buffer prepared above. These samples were prepared using a target weight of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1, 20.60mg 3,5-triazin-2-yl)phenyl]urea (due to 97.1% API activity) by weighing the required amount into each vial as follows:

[00086] For the formulations of both (a) and (b) above, 5 ml of the respective buffers was introduced for the weighed sample into the flask and the flasks were each closed by a crimp cap and sealed with a protective film. The vials were placed on a conveyor belt in an oven at 25°C for 5 days.

Results

4mg/ml

Observação visual das amostras após 5 dias a 25°C 3mg/ml

4mg/ml

[00087] At the end of the 5 day period the pH of each sample was measured and a visual observation of each sample was made using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and white background. The sample was also tested by illumination using a narrow beam light source (Tyndall) and then visually inspected from a direction perpendicular to the light beam to identify undissolved solid particles. pH after 5 days at 25°C 3mg/ml

4mg/ml

Visual observation of samples after 5 days at 25°C 3mg/ml

4mg/ml

Conclusion

[00088] The results show that the 3mg/ml and 4mg/ml samples containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6 -dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea and DL-lactic acid, L-lactic acid or DL-lactic acid achieved a clear solution after 5 days at 25°C.

[00089] The results show that the 3mg/ml samples containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4 -yl-1,3,5-triazin-2-yl)phenyl]urea and orthophosphoric acid also reached a clear solution after 5 days at 25°C.

[00090] All other samples did not reach a clear solution and acids other than DL-lactic acid, D-lactic acid, L-lactic acid and orthophosphoric acid would not be suitable for the preparation of pharmaceutical aqueous solution formulations for intravenous administration to a patient at a required API concentration. 3. Investigation regarding the aqueous formulation 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 with DL-lactic acid at various pHs and concentrations. Procedure (a) Buffer solutions for use in preparing 3mg/ml, 5 mg/ml, 5.5mg/ml, 6 mg/ml and 6.5mg/ml 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 were prepared according to the calculations below (WFI = irrigation water) (*90% w/w DL-lactic acid in water).

[00091] 3mg/ml @ 0.9 mole equivalent on a 10ml scale equals 4.39 mg of DL-lactic acid* in 10ml of WFI. (1)

[00092] 3mg/ml @ 2.25 mole equivalent on a 10ml scale is equivalent to 10.98mg of DL-lactic acid* in 10ml of WFI. (two)

[00093] 3mg/ml @ 3.7 mole equivalent on a 10ml scale equals 17.99mg of DL-lactic acid* in 10ml of WFI. (3)

[00094] 5mg/ml @ 0.9 mole equivalent on a 10ml scale equals 7.32mg of DL-lactic acid* in 10ml of WFI. (4)

[00095] 5mg/ml @ 2.25 mole equivalent on a 10ml scale equals 18.29mg of DL-lactic acid* in 10ml of WFI. (5)

[00096] 5mg/ml @ 3.7 mole equivalent on a 10ml scale is equivalent to 30mg of DL-lactic acid* in 10ml of WFI. (6)

[00097] 5mg/ml @ 7.2 mole equivalent on a 10ml scale equals 58.54mg of DL-lactic acid* in 10ml of WFI. (7)

[00098] 5mg/ml @ 10.8 mole equivalent on a 10ml scale equals 87.80mg of DL-lactic acid* in 10ml of WFI. (8)

[00099] 5.5mg/ml @ 2.25 mole equivalent on a 10ml scale equals 20.12mg of DL-lactic acid* in 10ml of WFI. (9)

[000100] 5.5mg/ml @ 3.7 mole equivalent on a 10ml scale equals 33mg of DL-lactic acid* in 10ml of WFI. (10)

[000101] 5.5mg/ml @ 10.8 mole equivalent on a 10ml scale equals 96.58mg of DL-lactic acid* in 10ml of WFI. (11)

[000102] 6mg/ml @ 3.7 mole equivalent on a 10ml scale equals 36mg of DL-lactic acid* in 10ml of WFI. (12)

[000103] 6mg/ml @ 3.7 mole equivalent on a 20ml scale is equivalent to 72mg of DL-lactic acid* in 20ml of WFI. (14)

[000104] 6.5mg/ml @ 3.7 mole equivalent on a 10ml scale equals 39mg of DL-lactic acid* in 10ml of WFI. (13)

[000105] 6.5mg/ml @ 3.7 mole equivalent on a 20ml scale equals 78mg of DL-lactic acid* in 10ml of WFI. (15)

(b) As seguintes quantidades de 1-(4-{[4- (dimetilamino)piperidin-1-ila]carbonil}fenil)-3-[4-(4,6-dimorfolin-4-ila- 1,3,5-triazin-2-ila)fenil]ureia foram pesadas em frascos (n.b. 1-(4-{[4- (dimetilamino)piperidin-1-ila]carbonil}fenil)-3-[4-(4,6-dimorfolin-4-ila- 1,3,5-triazin-2-ila)fenil]ureia tem uma atividade de 97,1% e os pesos alvos abaixo forram corrigidos para essa atividade).

[000106] Buffer solutions are prepared using WFI in 10ml volumetric flasks (*20 ml, where indicated in the Table below), with the following weights of DL-lactic acid (** 90% w/w DL-lactic acid in water ):

(b) The following amounts 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 were weighed into vials (nb 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea has an activity of 97.1% and the target weights below have been corrected for this activity).

[000107] 5ml of the corresponding DL-lactic acid buffer was added to the API in the vial and each vial was then closed with a crimp cap and sealed with a protective film.

[000108] Samples 1 - 11 were placed on a conveyor belt at room temperature and at 50rpm for ca. 21.5 hours.

[000109] Samples 12 and 13 were placed on a conveyor belt at room temperature and at 50rpm for ca. 23 hours.

[000110] Samples 14 and 15 were placed on a conveyor belt at room temperature and at 50rpm for ca. 25 hours.

Results after ca. 21.5 / 23 / 25 hour periods

Avaliação visual

[000111] At the end of the specific rolling period the pH of each sample was measured and a visual observation of each sample was made using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and white background. The sample was also tested by illumination using a narrow beam light source (Tyndall) and then visually inspected from a direction perpendicular to the light beam to identify undissolved solid particles. pH

visual assessment

[000112] The following observations were made:

[000113] Samples 7, 8 & 11 appeared to become solutions within 2 hours of being placed on the conveyor belt

[000114] Sample 6 appeared to become solution within 4 hours of being placed on the conveyor belt

[000115] Samples 3 and 10 appeared to become solutions within 20 hours of being placed on the conveyor belt

Conclusion

[000116] After ca. period of 24 hours it is possible to conclude that to reach a transparent solution the solution concentration of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6 -dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea must be less than 6 mg/ml and more than 2.5 mole equivalents of DL-lactic acid must be used in the formulation. However, the above results for samples 14 and 15 show that clear solutions are achievable at a solution concentration of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl) solution. - 3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea of both 6mg/ml and 6.5mg/ml with 3,6 and 3, 7 mole equivalents, respectively, of DL-lactic acid. These results for Samples 14 and 15, when compared to Samples 12 and 13, reflect the fact that the metastable zone likely exists where both clear and non-transparent solutions can result.

Results after 72 hours

[000117] After ca. above 21.5 hour rolling period, samples 1-11 were stored at room temperature without further rolling to provide a total experimental period of ca. 72 hours. It was observed that some samples became a solution at the end of the total period of 72 hours that were not in solution after the initial phase of ca. 21.5 hour rollover period.

[000118] After ca. above 25 hour rolling period, samples 14 and 15 were stored with rolling at room temperature longer to provide a total experimental period of ca. 73 hours.

(ii) Comparação dos resultados de pH e avaliações visuais após cada período de 24h e 72h

[000119] These samples were evaluated visually using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow beam light source (Tyndall) and then visually inspected from a direction perpendicular to the light beam to identify undissolved solid particles. The pH was also measured. The results were as follows: (i) Visual assessment after 72 hours

(ii) Comparison of pH results and visual assessments after each 24h and 72h period

Conclusion

[000120] After the total experimental period of 72 hours it is possible to conclude that to achieve a transparent solution using the solution concentration of 5 and 5.5mg/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 where at least 2.3 mole equivalents of acid DL-lactic are used in the formulation. A clear solution is also achievable using a solution concentration of 3mg/ml of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine -4-yl-1,3,5-triazin-2-yl)phenyl]urea where above 2.5 mole equivalents of DL-lactic acid are used in the formulation. The above results for samples 14 and 15 show that clear solutions are achievable at a solution concentration of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3- [4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea of both 6mg/ml and 6.5mg/ml with 3.6 and 3.7 moles equi -valents, respectively, of DL-lactic acid. These results for Samples 14 and 15, when compared to Samples 12 and 13, reflect the fact that the metastable zone likely exists where both clear and non-transparent solutions can result.

4. Investigation regarding a 3mg/ml aqueous formulation 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 with 6.8 mole equivalents of orthophosphoric acid Procedure

[000121] An aqueous solution of orthophosphoric acid ca. 33.3 mM was prepared as follows. 0.32569g of orthophosphoric acid was distributed in ca. 80ml of water for irrigation. This was done for a 100ml volume using irrigation water from a volumetric flask and the pH was recorded as 1.92.

[000122] A 3mg/ml 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 was desired and this must be taken into account for a drug potency of 97.1%.

[000123] A 10ml scale was decided upon and therefore the target weight 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 was 30.9mg. Three API samples were prepared using the following weights in each 20 ml vial:

[000124] 10ml of orthophosphoric acid buffer prepared above was dispensed, using an air displacement pipette, into each vial. The vials were each closed with a crimped cap and sealed with protective foil.

[000125] The samples were placed on a conveyor belt at room temperature to ca. 19 hours.

[000126] These samples were evaluated visually using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow beam light source (Tyndall) and then visually inspected from a direction perpendicular to the light beam to identify undissolved solid particles. The pH was also measured. The results were as follows:

Dilutions

[000127] Although transparent particle-free solutions were obtained by the above method, the pH of each sample is too low to be preferred for intravenous administration for which a pH of 3 to 4.5 is preferred.

[000128] The 3 samples were therefore each diluted to 0.5mg/ml, 0.1mg/ml and 0.05mg/ml to identify whether the pH increased to a suitable pH for intravenous administration. Diluted samples were placed on a treadmill overnight to reach equilibrium. The pH was also measured. The pH of the samples was as follows:

[000129] Each of these samples was evaluated visually using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow beam light source (Tyndall) and then visually inspected from a direction perpendicular to the light beam to identify undissolved solid particles. Each sample was observed to be a visually clear solution.

Conclusion

[000130] The results show that it is possible to formulate an aqueous solution formulation of 3mg/ml transparent and free of particles 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 with 6.8 mole equivalents of orthophosphoric acid However, the pH of this formulation or the reconstituted formulation of the anyway, it would not be suitable for intravenous administration and therefore would have to be further diluted below 0.5mg/ml to achieve a solution pH suitable for intravenous administration.

[000131] When these results are compared with the results obtained for the lactic acid formulations above, the pH and concentrations of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3 Achievable -[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea are inferior using orthophosphoric acid. Lactic acid is therefore generally more suitable than orthophosphoric acid for preparing an aqueous solution formulation for the intravenous 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 according to the invention.

5. Investigation regarding aqueous formulations of 3mg/ml, 4mg/ml and 5mg/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 with acetic acid Procedure

[000132] In order to prepare a 33.3 mM acetic acid solution, 0.2071g of glacial acetic acid was distributed in a 250 ml glass beaker and about 80 ml of WFI (water for irrigation) was added.

[000133] 0.0138g of sodium acetate trihydrate was added and dissolved to this solution. The solution was made to 100ml volume in a volumetric flask using WFI and the pH was recorded as 3.35.

[000134] Three concentrations of API (3, 4 and 5mg/ml) were desired, which had to be corrected in order to take into account the potency of an API of 97.1%. API weights were determined according to the following calculations.

[000135] 30mg active is 30.9mg 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1, 3,5-triazin-2-yl)phenyl]urea

[000136] 40mg active is 41.2mg 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1, 3,5-triazin-2-yl)phenyl]urea

[000137] 50mg active is 51.49mg 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1, 3,5-triazin-2-yl)phenyl]urea

[000138] The following weights were dispensed in 20 ml glass bottles:

[000139] 10ml of the acetic acid buffer prepared above was introduced into each of the weighed samples. The vials were each closed with a crimped cap and sealed with protective foil.

[000140] These samples were placed on a treadmill at room temperature and evaluated visually using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow beam light source (Tyndall) and then visually inspected from a direction perpendicular to the light beam to identify undissolved solid particles. Visual analysis was performed in periods of 24 hours, 48 hours, 72 hours and 6 days.

Results

[000141] No sample had achieved a clear solution after any of these periods of 24 hours, 48 hours, 72 hours and 6 days.

[000142] The pH of the samples was evaluated as follows:

(a) pH check after 48h

(ii) re. amostras de 4mg/ml

(iii) re. amostras de 5mg/ml

(b) Verificação do pH após 6 dias (1) re. amostras de 3mg/ml

(ii) re. amostras de 4mg/ml

(iii) re. amostras de 5mg/ml

[000143] Initial buffer pH = 3.35 (1) re. 3mg/ml samples

(ii) re. 4mg/ml samples

(iii) re. 5mg/ml samples

(b) pH check after 6 days (1) re. 3mg/ml samples

(ii) re. 4mg/ml samples

(iii) re. 5mg/ml samples

Conclusion

[000144] The results show that at concentrations of 3, 4 and 5mg/ml containing 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6 -dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea does not produce a clear solution using 33.3 mM acetic acid. The 3mg/ml aqueous formulation used contained ca. 6.8 mole equivalents of acetic acid. The 4mg/ml aqueous formulation used contained ca. 5.1 mole equivalents of acetic acid. The 5mg/ml aqueous formulation used contained ca. 4.1 mole equivalents of acetic acid.

6. Investigation regarding aqueous formulations of 3mg/ml and 3.5mg/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 with orthophosphoric acid

[000145] A 33.3 mM aqueous orthophosphoric acid solution was prepared as follows.

[000146] 0.32767 g of orthophosphoric acid was distributed in ca. 75ml of water for irrigation. This was done for a 100ml volume using irrigation water from a volumetric flask and the pH was recorded as 1.94.

[000147] Formulations of 3 and 3.5mg/ml of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine- 4-yl-1,3,5-triazin-2-yl)phenyl]urea were desired and this must be taken into account for a drug potency of 97.1%.

[000148] The 3mg/ml aqueous formulation used contained ca. 6.8 mole equivalents of orthophosphoric acid. The 3.5mg/ml aqueous formulation used contained ca. 5.9 mole equivalents of ortho-phosphoric acid.

[000149] A 5ml scale was decided upon and therefore the target weight 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 was 15.5mg for the 3mg/ml formulation and 18.0mg for the 3.5mg/ml formulation. Three samples were prepared for each formulation using the following weights in each 20 ml vial:

[000150] 5ml of orthophosphoric acid buffer prepared above was dispensed, using an air displacement pipette, into each vial. The vials were each closed with a crimped cap and sealed with protective foil.

[000151] The samples were placed on a treadmill at room temperature for 15 hours.

[000152] These samples were evaluated visually using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow beam light source (Tyndall) and then visually inspected from a direction perpendicular to the light beam to identify undissolved solid particles. All solutions were observed to be visually clear. The pH was also measured.

[000153] The results were as follows (nb the input pH of 33.3 mM orthophosphoric acid was pH = 1.94)

Conclusion

[000154] The results show that it is possible to formulate an aqueous solution formulation of 3.0 or 3.5mg/ml transparent and free of particles 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 with 5.9 mole equivalents of orthophosphoric acid

[000155] However, pH readings demonstrated that dilution would be necessary to provide an adequate pH to allow direct intravenous or parenteral administration of these formulations.

[000156] When these results are compared with the results obtained for the above lactic acid formulations, the pH and concentrations of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3 Achievable -[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea are inferior using orthophosphoric acid. Lactic acid is therefore preferred for preparing a clear, particulate-free aqueous solution formulation of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3- [4-(4,6-Dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea which is suitable for intravenous and parenteral administration.

7. Characterization of a crystalline form of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1) ,3,5-triazin-2-yl)phenyl]urea L-lactate PXRD Analysis

[000157] X-ray powder diffraction (PXRD) analysis was performed on a Bruker D4 diffractometer (trademark) using copper radiation (wavelength: 1.5406Â). Tube voltage and amperage were set to 35 kV and 40 mA, respectively. The divergence slit used was v6 and the dispersion slit was set at 0.499 mm. A variable receiving the slit was used. Diffractive radiation was detected by a Vantec detector. A continuous theta-two theta scan at 5.4 °/min (0.2 s/0.018° step) from 2.0 to 55° 2θ was used. A standard corundum was analyzed to verify instrument alignment. Data were collected and analyzed using Bruker AXS software. Samples were prepared by placing them on a silicon wafer. The DIFFRAC.EVA V3.1 software was used to visualize and evaluate the PXRD spectrum. PXRD data files (.raw) were not processed before peak polling. Generally, a threshold value of 1.3 and a width value of 0.3 were used to make preliminary peak assignments. Output from automated assignments was visually checked for validity and adjustments made manually if necessary. In addition, peaks were manually assigned within the spectra, if appropriate. A peak at 28.1° 2-theta that related to the mounting medium was manually removed from the list.

[000158] To perform an X-ray diffraction measurement using the Bragg-Brentano geometry on the Bruker instrument used for the measurements reported here, the sample is normally placed on a flat silicon wafer. The powder sample is pressed through a glass slide or equivalent to ensure a random surface and proper sample height. The sample holder is then placed in the instrument. The incident X-ray beam is directed at the sample, initially at a slight angle to the plane of the support, and then moved through an arc that continually increases the angle between the incident beam and the plane of the support. Measurement differences associated with such powder X-ray analyzes result from a variety of factors including: (a) errors in sample preparation (e.g. sample height), (b) instrument errors (e.g. flat samples), (c) calibration errors, (d) operator errors (including those errors present when determining peak locations), and (e) the nature of the material (e.g., orientation errors and preferred transparency) . Calibration errors and sample height errors often result in all peaks shifting in the same direction. Small differences in sample height when using a flat support will lead to large shifts in the PXRD peak positions. A systematic study has shown that, using a Shimadzu DRX-6000 in the typical Bragg-Brentano configuration, a sample height difference of 1 mm leads to peak shifts as high as 1 degree 2-theta (Chen et al.; J Pharmaceutical and Biomedical Analysis, 2001; 26,63). These changes can be identified from the X-ray diffractogram and can be eliminated by compensating for the change (applying a systematic correction factor to all peak position values) or by recalibrating the instrument. As mentioned above, it is possible to correct measurements from several machines by applying a systematic correction factor to bring the peak positions into agreement. In general, this correction factor will bring the measured peak positions of the Bruker in line with the expected peak positions and can be in the range of 0 to 0.2 degree 2-theta.

(*As intensidades relativas podem mudar dependendo do tamanho do cristal e morfologia)[000159] The PXRD pattern of the crystalline form of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea L-lactate of Example 4, Preparation A, is provided in Figure 1 and is characterized by the following peak list which is expressed in terms of degree 2θ (+/- 0 .2 degrees 2-theta) and relative intensity (of < 2.5 %) as measured on a Bruker D4 diffractometer with copper K-alpha (CuKα) radiation:

(*Relative intensities may change depending on crystal size and morphology)

[000160] This crystalline form of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3, 5-triazin-2-yl)phenyl]urea L-lactate is distinguished from other known (semi-crystalline) forms of this salt, having peaks characterized at around 6.5, 15.9, 20.9, 22.1 and 23.1 degrees 2-theta (+/- 0.2 degrees 2-theta).

7. Chemical stability of a freeze-dried solid formulation of the invention

[000161] Samples of a lyophilized solid formulation prepared according to the method of Example 2 in 50ml transparent vials were analyzed for chemical degradation after storage at 25°C/60% relative humidity (RH) and 40°C/75% UR at a variety of different points in time. Multiple samples were evaluated for each condition to allow for representative results at selected time points.

[000162] The 40°C/75% RH samples were tested after 6 months.

[000163] The 25°C/60% RH samples were tested after 6 months, 12 months, 24 months and 36 months.

[000164] The samples were tested for chemical purity using high performance liquid chromatography (HPLC) using the following methodology to measure any degradation during the testing period.

HPLC method

[000165] The solutions, samples and standards for use in the HPLC method are prepared as follows:

[000166] Reference standard: 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3, 5-triazin-2-yl)phenyl]urea with a known potency value.

[000167] Diluent: Acetonitrile/ water R (1:1 v/v).

[000168] Mobile phase A: 10mM aqueous ammonium bicarbonate buffer solution with pH adjusted to 9.8 with aqueous ammonium hydroxide solution

[000169] Mobile phase B: Acetonitrile

[000170] Sample solvent: Add 3 ml of 0.1N aqueous hydrochloric acid solution to a 1000 ml volumetric flask and dilute to make up the volume with the diluent (acetonitrile/water, 1:1 v/v). Mix well.

[000171] Note: larger or smaller volumes of solutions can be prepared with the appropriate ratio of components.

Standard and check standard preparations

[000172] Precisely prepare two solutions of ca. 2 mg/ml (+/10%) 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 Reference standard in the sample solvent, and record accurate concentrations of both. These are the standard and check standard solutions. Produce standard and check standard preparations by accurately diluting these solutions to a concentration of approximately 2 micrograms/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 using the diluent. Sensitivity Solution:

[000173] Precisely dilute the standard preparation to a concentration of approximately 0.06 micrograms/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 using the diluent.

Sample preparation:

[000174] Reconstitute two vials of lyophilized solid formulation 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 (prepared according to the method of Example 2) by adding 20 ml of water to each vial, swirling the vial to dissolve the solid and waiting for bubbles to disappear. Transfer the solution to a 1000 ml volumetric flask. Wash each vial at least twice with diluent and transfer the washing liquid to the volumetric flask. Dilute to volume with thinner. Chromatographic conditions: Liquid chromatography system - eg Waters 2695 (trademark) or Agilent 1100 machine (trademark) Column: Waters Xbridge C18 (trademark), 15 cm x 4.6 mm, 3.5 µm or equivalent Column temperature: 40°C Injection volume: 20 μl Flow rate: 1.0 ml/min. Detection: UV at 303 nm Runtime: 60 minutes Mobile phase A Mobile phase B Linear gradient table:

explanatory notes

[000175] Prime the HPLC machine by pumping Mobile Phase B through the column until a stable baseline is obtained (this usually takes about thirty minutes).

[000176] Re-equilibrate the chromatographic system with Mobile Phase A (usually 10-15 minutes) before running the injection sequence.

[000177] Before running the samples, make sure that the system is suitable for use by injecting the white diluent, sensitivity solution and standard preparation using the above chromatographic conditions.

*A média do uso de todas as injeções de adequação do sistema (repe- tibilidade). **Consulte as equações de cálculo da Farmacopeia dos Estados Unidos (USP) de eficiência e assimetria do pico.[000178] The following criteria must be met upon initial HPLC setup or after any significant change to the system. It is recommended to inject at least one conditioning blank before testing the suitability of the system.

*Average usage of all system suitability injections (repeatability). **See US Pharmacopoeia (USP) calculation equations for peak efficiency and asymmetry.

[000179] Inject the verification standard preparation according to the above chromatographic conditions. The response factor (calculated from the area, standard weight, dilution factor, and standard purity factor) of this check standard preparation must be within ± 5% of the standard preparation.

[000180] After the suitability of the system has been demonstrated, inject the blank solution, standard preparation and prepared test samples, followed by an injection of the standard preparation, according to the above chromatographic conditions. It is recommended that no more than 6 test samples be injected between standard preparation injections. For each injection (standard and sample), measure the retention time and peak area of 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4 ,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea in each chromatogram. For each sample injection, also measure the retention times and peak area of any peaks present in the sample injection that do not appear in the blank injection. Do not integrate gradient artifacts, if present. Compare the injection blank chromatograms to the sample chromatogram to determine which sample peaks are related to the blank and gradient artifact peaks. Calculate % degradants and report individual degradant peaks that are at or above 0.05%. Unknown degradants should be reported individually for their relative retention time. Known degraders must be reported individually by name.

[000181] The results are summarized in the Tables below.

Key

[000182] NMT = Not more than.

[000183] NR = Not reported.

[000184] RRT = Relative retention time

Degradante 2

[000185] All % are in w/w Degrading 1

Degrading 2

Degradants 3, 4, 5 and 6

• Os degradantes 3, 5 e 6 foram identificados como impu- rezas relacionadas com o processo que não altera a estabilidade, e assim não foram relatados no ponto de tempo de 36 meses.

[000186] These were each characterized by their RRT only.

• Degradants 3, 5, and 6 were identified as process-related impurities that do not alter stability, and thus were not reported at the 36 month time point.

Conclusion

[000187] The results show that samples of a lyophilized solid formulation prepared according to the method of Example 2 in a 50ml transparent vial are chemically stable for at least 36 months at 25 °C/60% RH and for at least 6 months at 40°C/75% RH.

Claims (29)

1. Lyophilized formulation obtained by lyophilizing an aqueous pharmaceutical solution formulation characterized by the fact that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4 ,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or 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 at a concentration of solution less than 6 mg/ml and enough lactic acid is present to provide a clear solution; or 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 salt 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. 2. Lyophilized formulation according to claim 1, the pharmaceutical aqueous solution formulation characterized in that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4- (4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or 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 at a solution concentration less than 6 mg/ml and sufficient lactic acid is present to provide a clear solution. 3. Lyophilized formulation according to claim 1, the pharmaceutical aqueous solution formulation characterized in that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4- (4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 6 mg/ ml and enough lactic acid is present to provide a clear solution. 4. Lyophilized formulation according to claim 2, characterized in that 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine -4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in the pharmaceutical aqueous solution formulation at a solution concentration of 2.5 to 5.5 mg/ml. 5. Lyophilized formulation according to claim 4, characterized in that 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine -4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in the pharmaceutical aqueous solution formulation at a solution concentration of 5.0 to 5.5 mg/ml and at least 2.5 mole equivalents of lactic acid is present. 6. Lyophilized formulation according to claim 4, characterized in that 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine -4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in the pharmaceutical aqueous solution formulation at a solution concentration of 5mg/ml. 7. Lyophilized formulation according to claim 6, characterized in that 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine -4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in the aqueous solution formulation at a solution concentration of about 5 mg/ml and at least 2.5 mole equivalents of lactic acid is present. gift. 8. Lyophilized formulation according to claim 3, the pharmaceutical aqueous solution formulation characterized in that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4 -(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, lactic acid 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 about 5 mg/ml and at least 2.5 mole equivalents of sufficient lactic acid is present in an amount sufficient to ensure that a clear solution is formed. 9. Lyophilized formulation according to claim 2, the pharmaceutical aqueous solution formulation characterized in that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4 -(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, lactic acid 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 about 5 mg/ml and at least 1.5 mole equivalents of sufficient lactic acid is present in an amount sufficient to ensure that a clear solution is formed. 10. Lyophilized formulation according to claim 8, the pharmaceutical aqueous solution formulation characterized in that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4 -(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, lactic acid 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 about 5 mg /ml and about 4.1 mole equivalents of sufficient lactic acid is present in an amount sufficient to ensure that a clear solution is formed with a pH of no more than 3.7. 11. Lyophilized formulation according to claim 2, the pharmaceutical aqueous solution formulation characterized in that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4 -(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, lactic acid 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 2.5 at 5.5mg/ml and above 2.5 to 8.0 mole equivalents of lactic acid is present in an amount sufficient to ensure that a clear solution is formed. 12. Lyophilized formulation according to any one of claims 1 to 11, characterized in that DL-lactic acid, L-lactic acid or D-lactic acid are used in the formulation of the pharmaceutical aqueous solution. 13. Lyophilized formulation according to claim 12, characterized in that DL-lactic acid is used in the formulation of pharmaceutical aqueous solution. 14. Lyophilized formulation according to claim 1, the pharmaceutical aqueous solution formulation characterized in that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4- (4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, or a phosphate salt 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 less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a clear solution. 15. Lyophilized formulation according to claim 14, the pharmaceutical aqueous solution formulation characterized in that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4- (4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1- yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ ml and enough orthophosphoric acid is present to provide a clear solution. 16. Lyophilized formulation according to claim 15, characterized in that 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholine -4-yl-1,3,5-triazin-2-yl)phenyl]urea is present in the pharmaceutical aqueous solution formulation at a solution concentration of 3.0 to 3.5mg/ml. 17. Lyophilized formulation according to claim 15, characterized in that at least 5 mole equivalents of orthophosphoric acid are used in the pharmaceutical aqueous solution formulation. 18. Lyophilized formulation according to claim 17, characterized in that 5 to 7 mole equivalents of orthophosphoric acid are used in the formulation of pharmaceutical aqueous solution. 19. Lyophilized formulation as claimed in any of claims 1 to 8 and 13 to 18 characterized in that it additionally contains a bulking agent. 20. Lyophilized formulation according to claim 19, characterized in that the bulking agent is mannitol. 21. Pharmaceutical aqueous solution formulation obtained as a transparent solution by reconstitution or constitution of a lyophilized formulation as defined in any one of claims 1 to 8 and 13 to 18 characterized in that it uses water or an aqueous solution containing a modifier of tonicity. 22. Pharmaceutical aqueous solution formulation according to claim 21, characterized in that the tonicity modifier is dextrose, sucrose or mannitol, or is a mixture of 2 or more of them. 23. Pharmaceutical aqueous solution formulation according to claim 21, characterized in that it is adjusted as necessary to have a suitable pH for intravenous or parenteral administration. 24. Pharmaceutical aqueous solution formulation according to claim 23, characterized in that the pH is from 3 to 4.5. 25. Pharmaceutical aqueous solution formulation characterized by the fact that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl) -1,3,5-triazin-2-yl)phenyl]urea, or a phosphate salt thereof, orthophosphoric acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl] carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and enough orthophosphoric acid is present to provide a clear solution. 26. Pharmaceutical aqueous solution formulation according to claim 25, characterized in that it comprises 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4, 6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl }phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and the Enough orthophosphoric acid is present to provide a clear solution. 27. Pharmaceutical aqueous solution formulation according to claim 26, characterized in that 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 3.0 to 3.5mg/ml. 28. Pharmaceutical aqueous solution formulation according to claim 26 or 27, characterized in that at least 5 mole equivalents of orthophosphoric acid are used. 29. Pharmaceutical aqueous solution formulation according to claim 28, characterized in that 5 to 7 mole equivalents of orthophosphoric acid are used.

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