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

Abstract

The present invention relates to a 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, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta- or gamma-cyclodextrin and water, that is a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid. Such a formulation is particularly suitable for intravenous or parenteral administration to a patient.

Description

(19) *EP004649940A2* (11) EP 4 649 940 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: 19.11.2025 Bulletin 2025 / 47 (21) Application number: 25207215.2 (22) Date of filing: 04.06.2019 (51) International Patent Classification (IPC): A61K 9 / 00 (2006.01) (52) Cooperative Patent Classification (CPC): A61K 9 / 0019; A61K 9 / 08; A61K 9 / 19; A61K 31 / 5377; A61K 47 / 12; A61K 47 / 40; A61P 35 / 00 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 07.06.2018 US 201862681722 P 02.11.2018 US 201862754651 P 24.01.2019 US 201962796133 P 02.05.2019 US 201962841882 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 23176968.8 / 4 249 069 19742898.0 / 3 810 089 (71) Applicant: Pfizer Inc. New York, NY 10001‑2192 (US) (72) Inventors: • HUSSEY, James Joseph Sandwich, CT13 9NJ (GB) • BRIGHT, Andrew Gilbert Sandwich, CT13 9NJ (GB) (74) Representative: J A Kemp LLP 80 Turnmill Street London EC1M 5QU (GB) Remarks: This application was filed on 07‑10‑2025 as a divisional application to the application mentioned under INID code 62. (54) 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 (57) The present invention relates to a pharmaceu- tical aqueous formulation comprising 1‑(4‑{[4‑(dimethy- lamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimor- pholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a pharma- ceutically acceptable organic or inorganic acid salt there- of, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta‑ or gamma- cyclodextrin and water, that is a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid. Such a formulation is particularly suitable for intravenous or parenteral admin- istration to a patient. EP 4 64 9 94 0 A 2 Processed by Luminess, 75001 PARIS (FR) Description FORMULATION

[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 pharmaceutically acceptable organic or inorganic acid salt thereof. More specifically, the present invention relates to a 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, that is a clear solution. Such a formulation is particularly suitable for intravenous or parenteral administration to a patient. Background

[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 preparations thereof, are disclosed inWO2009 / 143313. The compound is an inhibitor of PI3 kinase andmTOR that is useful for the treatment of 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 process for the preparation thereof, are disclosed in WO2010 / 096619.

[0004] WO2016 / 097949 describes a pharmaceutical aqueous solution formulation suitable for intravenous adminis- tration 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 at 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 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-tria- zin‑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. Lyophilisation of such formulations are also described. Of the many 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 acidandorthophosphoricacidare found tobecapableofachievingaclear solutionwitha 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 above.

[0005] 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 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

[0006] 1‑(4‑{[4‑(Dimethylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl] ureamay 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 insufficiently water soluble to allow the preparation of an aqueous solution formulation suitable for intravenous or parenteral administration at the therapeutic dosage levels required.

[0007] There is a need to develop a pharmaceutically acceptable aqueous solution formulation of 1‑(4‑{[4‑(dimethy- lamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea that preferably is (a) chemically stable on storage (e.g. at 25°C and 60% RH), (b) that will facilitate effective intravenous (or parenteral) administrationof thedrug toamammal, includingahumanbeing,and (c) , preferably, toachieveasolutionconcentrationof 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 at least 6mg / ml. 2 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 Summary

[0008] 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 that is at least 6mg / ml is desirable to allow dose administration to subjects using a single vial presentation of the commercial drug product. A lyophilised drug product (for reconstitution) containing less than 6 mg / ml drug product solution will require multiple vials to deliver the required therapeutic dose. Amultiple vial approach to dose delivery is not desirable given current regulatory expectations for these product types.

[0009] 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 pharma- cokinetic and bioavailability characteristics of this drug.

[0010] It is essential that an intravenous formulationof anydrug is a solution to facilitate safeandeffectiveadministration to a patient. It must be particle-free, and not form a gel or suspension. A clear, aqueous solution is preferred.

[0011] A "clear solution" is defined herein as a visually clear solution, which may bear a solution opalescence, that is essentially free from any visible particulates that can be observed on a visual inspection. Generally, if any particulate matter is observed, the formulation is not suitable for intravenous administration and should not be utilised as occlusion of blood vesselsmay occur. Accordingly, in view of the qualitative nature of the visual test, the term "essentially free fromany visible particulates" is usually applied when no visible particulate matter is observed.

[0012] Particulate matter may be defined as follows: • speck - discrete particle whose shape cannot be determined without magnification • smokeor swirl - fineparticles that look like smokeor a tornadoandusually originate from thesample vial floor and twist upward as the vial is swirled • flocculent material - loosely aggregated particles or soft flakes • particulates with a definite shape or characteristic can be described as glass-like, metallic-looking, etc.

[0013] The visual inspection can be conducted in accordance with the method defined in European Pharmacopoeia Method 2.9.20 entitled "Particulate contamination: visible particles" (see Figure 1). This method determines particulate contamination of injections and infusions by extraneous, mobile, undissolved particles, other than gas bubbles, that may be present in the solutions. The test is intended to provide a simple procedure for the visual assessment of the quality of parenteral solutions as regards visible particles.

[0014] TheMethod states: "Remove any adherent labels from the container and wash and dry the outside. Gently swirl 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."

[0015] A suitable method in accordance with European Pharmacopoeia Method 2.9.20 that has been used for the present invention is described in Example 1(i).

[0016] Other validatedmethodsmay be also be used for the dermination of if any visible particulates are present. Such methods include Optical Polarised Microscopy ("OPM"). A suitable OPM method that has been used for the present invention is described in Example 1(ii).

[0017] Without being bound by theory, any opalescent hue may be caused by chromonic liquid crystal formation. Chromonic liquid crystals are formed by the formation of pi-pi stacked aromatic sections of amolecule forming column like stacksofdimers, trimersand lowmolecularweightoligomersof themolecules.Thestacks that formcanbeshownviaOPM to be non-crystalline microstructures associated to a chromonic liquid crystal. The non-crystalline microstructures exhibit interactions that are not permanent and there is movement to maintain the system in a free energy equilibrium. The opalescence of the solution comes from the alteration of the refractive index of the solution due to the formation of these stacks. OPM micrographs of the solutions will show that there is no crystalline material present and instead there is a chromonic liquid crystal phase. Thepresenceof a liquid crystal phase results in a solutionwith opacity and / or opalescence due to a difference in refractive index within the solution formed. For a discussion on liquid crystal formation see "Optical Properties of Condensed Matter and Applications", Jai Singh (Editor), ISBN: 978‑0‑470‑02193‑4, Wiley, October 2006.

[0018] It has now been unexpectedly found that by use of a pharmaceutically acceptable beta‑ or gamma-cyclodextrin, pharmaceutical aqueous formulations can be prepared as a clear solution comprising (a) 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 that is significantly above 6mg / ml and (b) one of a range of pharmaceutically acceptable organic or inorganic acids. Description of the Drawings

[0019] Figure 1 reproduces Figure 2.9.20.‑1 of the publication "European Pharmacopoeia Method 2.9.20" and describes an apparatus consisting of a viewing station comprising: a matt black panel (1) of appropriate size held in a vertical position; a non-glare white panel (2) of appropriate size held in a vertical position next to the black panel; a non- 3 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 glare white panel (3) of appropriate size held in a horizontal position at the base of the verticle panels; and an adjustable lampholder (4) fitted with a suitable, shaded, white-light source and with a suitable light diffuser (a viewing illuminator containing two 13Watt fluorescent tubes, each 525 mm in length, is suitable). The intensity of illumination at the viewing point is maintained between 2000 lux and 3750 lux, although higher values are preferable for coloured glass and plastic containers. Detailed Description

[0020] Accordingly, the present invention relates to a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a pharmaceu- tically acceptable organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, that is a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid (hereafter "the formulation of the invention").

[0021] More specifically, the present invention relates to a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a pharmaceu- tically acceptable organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein sufficient of the pharmaceutically accep- table organic or inorganic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid.

[0022] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, a pharmaceuti- cally acceptable organic or inorganic acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein sufficient of the pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid.

[0023] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising a pharma- ceutically acceptable organic or inorganic acid salt of 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyllphenyl)‑3‑[4‑(4,6- dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, a pharmaceutically acceptable organic or inorganic acid, a pharmaceu- tically acceptablebeta‑orgamma-cyclodextrin andwater,wherein sufficient of thepharmaceutically acceptableorganicor inorganic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid.

[0024] In such embodiments, where applicable, the acid forming the pharmaceutically acceptable organic or inorganic acid salt, and the pharmaceutically acceptable organic or inorganic acid, preferably are the same.

[0025] Preferably, the pharmaceutically acceptable organic acid used (including for a salt thereof) is lactic acid, tartaric acid,malic acid, citric acid, succinic acid, acetic acid ormaleic acid. Theacidmaybeused in its racemic form, or as a single stereoisomeric form (or mixtures thereof), where applicable.

[0026] Preferably, the pharmaceutically acceptable inorganic acid used (including for a salt thereof) is hydrochloric acid or orthophosphoric acid.

[0027] Examples of a pharmaceutically acceptable beta-cyclodextrin are 2-hydroxypropyl-beta-cyclodextrin and sulphobutylether-β-cyclodextrin (SBECD). Examples of such a pharmaceutically acceptable gamma-cyclodextrin are gamma-cyclodextrin and 2-hydroxypropyl-gamma-cyclodextrin. Preferably, hydroxypropyl-beta-cyclodextrin is used in the formulations of the invention. By use of a pharmaceutically acceptable beta- or gamma-cyclodextrin it has been found that clear solutions may be achieved with no opalescence and / or containing higher concentrations of 1‑(4‑{[4‑(dimethy- lamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea than are obtainable in the absence of the cyclodextrin component.

[0028] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a pharmaceu- tically acceptable organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic 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 ispresentat asolutionconcentrationofat least 6mg / ml and wherein sufficient of the pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid.

[0029] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, a pharmaceuti- cally acceptable organic or inorganic acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyllphenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl] urea is present at a solution concentration of at least 6mg / ml and wherein sufficient of the pharmaceutically acceptable 4 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 organic or inorganic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid.

[0030] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising a pharma- ceutically 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 pharmaceu- tically 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 a solution concentration of at least 6mg / ml andwhereinsufficientof thepharmaceuticallyacceptableorganicor inorganicacidandpharmaceuticallyacceptablebeta- or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid. Lactic acid formulations

[0031] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from 6 to 30mg / ml or from 6 to less than 35mg / ml and wherein sufficient lactic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0032] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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‑ 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 a solution concentration of from 6 to 30mg / ml or from 6 to less than 35mg / ml and wherein sufficient lactic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0033] In an embodiment of the invention is provided a pharmaceutical aqueous 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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 6 to 30mg / ml or from 6 to less than 35mg / ml and wherein sufficient lactic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0034] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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- or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient lactic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

[0035] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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‑ 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 a solution concentration of from 6 to25, 6 to20, 6 to15, 10 to30, 10 to25, or10 to20mg / mlandwherein sufficient lactic acidandpharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0036] In an embodiment of the invention is provided a pharmaceutical aqueous 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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient lactic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0037] Preferably, for the above embodiments of the invention containing lactic acid, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydro- xypropyl-beta-cyclodextrin or gamma-cyclodextrin.

[0038] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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, sulphobutylether-β-cyclodextrin (SBECD) and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1- yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentrationof from 6 to 25mg / ml or from 6 to less than 30mg / ml and wherein sufficient lactic acid and sulphobutylether-β-cyclodextrin 5 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 (SBECD) are present to provide a clear solution.

[0039] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbo- nyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 6 to 30mg / ml or from 6 to less than 35mg / ml and wherein sufficient lactic acid and 2-hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

[0040] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbo- nyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from6 to 30, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient lactic acid and 2-hydroxypropyl-beta- cyclodextrin are present to provide a clear solution.

[0041] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbo- nyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from6 to 30, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml andwherein the lactic acid concentration is from10 to 100, 15 to 100 or 30 to 100mM and the 2-hydroxypropyl-beta-cyclodextrin concentration is from 15 to 120, 20 to 120 or 35 to 120mg / ml to provide a clear solution.

[0042] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, lactic acid, 2-hy- droxypropyl-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-di- morpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 10 to 30 or 10 to 20mg / ml and wherein the lactic acid concentration is from 20 to 100 or 30 to 100mM and the 2-hydroxypropyl-beta-cyclodextrin concentration is from 35 to 120mg / ml to provide a clear solution.

[0043] 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

[0044] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a acetate salt thereof, acetic acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from3 to 15mg / ml or from3 to less than 20mg / ml andwherein sufficient acetic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0045] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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‑ 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 a solution concentration of from 3 to 15mg / ml or from 3 to less than 20mg / ml and wherein sufficient acetic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0046] In anembodiment of the invention is provided apharmaceutical aqueous formulation comprising aacetate 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‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 3 to 15mg / ml or from 3 to less than 20mg / ml and wherein sufficient acetic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0047] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a acetate salt thereof, acetic acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from6 to 15, 8 to 15, or 10 to 15mg / ml andwherein sufficient acetic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0048] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl] 6 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 6 to 15, 8 to 15, or 10 to 15mg / ml and wherein sufficient acetic acid and pharmaceutically acceptable beta‑ or gamma- cyclodextrin are present to provide a clear solution.

[0049] In anembodiment of the invention is provided apharmaceutical aqueous formulation comprising aacetate 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‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 6 to 15, 8 to 15, or 10 to 15mg / ml and wherein sufficient acetic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0050] Preferably, for the above embodiments of the invention containing acetic acid, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydro- xypropyl-beta-cyclodextrin or sulphobutylether-β-cyclodextrin (SBECD). Maleic acid formulations

[0051] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 beta- or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from3 to 30mg / ml or from3 to less than 35mg / ml andwherein sufficientmaleic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

[0052] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 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 a solution concentration of from 3 to 30mg / ml or from 3 to less than 35mg / ml and wherein sufficient maleic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0053] Inanembodimentof the invention isprovidedapharmaceutical aqueous formulationcomprisingamaleatesalt 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 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 a solution concen- tration of from 3 to 30mg / ml or from 3 to less than 35mg / ml and wherein sufficient maleic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0054] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient maleic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0055] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 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 a solution concentration of from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient maleic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

[0056] Inanembodimentof the invention isprovidedapharmaceutical aqueous formulationcomprisingamaleatesalt 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 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 a solution concen- tration of from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient maleic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0057] Preferably, for the above embodiments of the invention containingmaleic acid, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydro- xypropyl-beta-cyclodextrin or gamma-cyclodextrin.

[0058] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- 7 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 methylamino)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, hydroxypropyl-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbo- nyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 3 to 20mg / ml or from 3 to less than 25mg / ml and wherein sufficient maleic acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

[0059] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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, gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phe- nyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 3 to 15mg / ml or from 3 to less than 20mg / ml and wherein sufficient maleic acid and gamma-cyclodextrin are present to provide a clear solution. Succinic acid formulations

[0060] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a so- lution concentration of from 3 to 65mg / ml or from 3 to less than 70mg / ml and wherein sufficient succinic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0061] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 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 a solution concentration of from 3 to 65mg / ml or from 3 to less than 70mg / ml and wherein sufficient succinic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0062] In an embodiment of the invention is provided apharmaceutical aqueous formulation comprising a succinate salt of 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, succinic acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylami- no)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 con- centration of from 3 to 65mg / ml or from 3 to less than 70mg / ml and wherein sufficient succinic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0063] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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- or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a so- lution concentration of from4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml andwherein sufficient succinic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

[0064] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 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 a solution concentration of from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient succinic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0065] In an embodiment of the invention is provided apharmaceutical aqueous formulation comprising a succinate salt of 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, succinic acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylami- no)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 con- centration of from4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml andwherein sufficient succinic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0066] Preferably, for the above embodiments of the invention containing succinic acid, the pharmaceutically accep- table beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2- hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

[0067] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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, hydroxypropyl-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl] 8 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 3 to 25mg / ml or from 3 to less than 30mg / ml and wherein sufficient succinic acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

[0068] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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, sulphobutylether-β-cyclodextrin (SBECD) and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 3 to 20mg / ml or from 3 to less than 25mg / ml and wherein sufficient succinic acid and sulphobutylether-β- cyclodextrin (SBECD) are present to provide a clear solution. Citric acid formulations

[0069] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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‑(dimethy- lamino)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 from 3 to 55mg / ml or from 3 to less than 60mg / ml and wherein sufficient citric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0070] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, citric acid, aphar- maceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbo- nyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 3 to 55mg / ml or from 3 to less than 60mg / ml and wherein sufficient citric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0071] In an embodiment of the invention is provided a pharmaceutical aqueous 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- or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from3 to55mg / mlor from3 to less than60mg / mlandwhereinsufficient citric acidandpharmaceuticallyacceptablebeta- or gamma-cyclodextrin are present to provide a clear solution.

[0072] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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‑(dimethy- lamino)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 from4 to25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient citric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0073] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, citric acid, aphar- maceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbo- nyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20mg / ml andwherein sufficient citric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0074] In an embodiment of the invention is provided a pharmaceutical aqueous 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‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient citric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0075] Preferably, for the above embodiments of the invention containing citric acid, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydro- xypropyl-beta-cyclodextrin or gamma-cyclodextrin.

[0076] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbo- nyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 3 to 25mg / ml or from3 to less than 30mg / ml andwherein sufficient citric acid and hydroxypropyl-beta-cyclodextrin are present 9 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 to provide a clear solution.

[0077] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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, sulphobutylether-β-cyclodextrin (SBECD) and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1- yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentrationof from 3 to 20mg / ml or from 3 to less than 25mg / ml and wherein sufficient citric acid and sulphobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution. Malic acid formulations

[0078] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from 3 to 65mg / ml or from 3 to less than 70mg / ml and wherein sufficient malic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0079] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 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 a solution concentration of from 3 to 65mg / ml or from 3 to less than 70mg / ml and wherein sufficient malic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

[0080] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising amalate 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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 3 to 65mg / ml or from 3 to less than 70mg / ml and wherein sufficient malic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0081] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from4 to25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficientmalic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0082] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 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 a solution concentration of from 4 to25, 4 to 20, 4 to15, 6 to 25, 6 to 20, 6 to15, 4 to 30, 6 to 30, 10 to 30, 10 to25, or 10 to20mg / ml andwherein sufficientmalic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0083] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising amalate 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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficientmalic acid andpharmaceutically acceptable beta‑or gamma-cyclodextrin are present to provide a clear solution.

[0084] Preferably, for the above embodiments of the invention containing malic acid, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydro- xypropyl-beta-cyclodextrin or gamma-cyclodextrin.

[0085] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl} phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 3 to 30mg / ml or from 3 to less than 35mg / ml and wherein sufficient malic acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

[0086] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- 10 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 methylamino)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, sulphobutylether-β-cyclodextrin (SBECD) and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl] carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 3 to 25mg / ml or from3 to less than30mg / ml andwherein sufficientmalic acid and sulphobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution. Tartaric acid formulations

[0087] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from3 to65mg / ml or from3 to less than70mg / ml andwherein sufficient tartaric acid andpharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0088] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 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 a solution concentration of from 3 to 65mg / ml or from 3 to less than 70mg / ml and wherein sufficient tartaric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0089] In an embodiment of the invention is provided apharmaceutical aqueous 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, tarta- ric 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 a solution concen- tration of from 3 to 65mg / ml or from 3 to less than 70mg / ml and wherein sufficient tartaric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0090] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from4 to25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient tartaric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

[0091] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 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 a solution concentration of from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient tartaric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0092] In an embodiment of the invention is provided apharmaceutical aqueous 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, tarta- ric 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 a solution concen- trationof from4 to25, 4 to20, 4 to15, 6 to25, 6 to20, 6 to15, 4 to30, 6 to30, 10 to30, 10 to25, or 10 to20mg / mlandwherein sufficient tartaric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0093] Preferably, for the above embodiments of the invention containing tartaric acid, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydro- xypropyl-beta-cyclodextrin or gamma-cyclodextrin.

[0094] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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, hydroxypropyl-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbo- nyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 3 to 30mg / ml or from 3 to less than 35mg / ml and wherein sufficient tartaric acid and hydroxypropyl-beta-cyclodextrin are present to provide a clear solution.

[0095] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a tartrate salt 11 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 thereof, tartaric acid, sulphobutylether-β-cyclodextrin (SBECD) and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1- yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentrationof from 3 to 25mg / ml or from 3 to less than 30mg / ml and wherein sufficient tartaric acid and sulphobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution. Hydrochloric acid formulations

[0096] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a hydrochlor- ide salt thereof, hydrochloric 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 pre- sent at a solutionconcentrationof from3 to60mg / mlor from3 to less than65mg / mlandwherein sufficienthydrochloric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0097] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 3 to 60mg / ml or from 3 to less than 65mg / ml and wherein sufficient hydrochloric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0098] In anembodiment of the invention is providedapharmaceutical aqueous formulation comprisingahydrochloride 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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethyla- mino)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 from 3 to 60mg / ml or from 3 to less than 65mg / ml and wherein sufficient hydrochloric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

[0099] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a hydrochlor- ide salt thereof, hydrochloric 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 pre- sent at asolution concentrationof from4 to25, 4 to20, 4 to15, 6 to25, 6 to20, 6 to15, 4 to30,6 to30,10 to30, 10 to35, 10 to 25, or 10 to 20mg / ml and wherein sufficient hydrochloric acid and pharmaceutically acceptable beta‑ or gamma- cyclodextrin are present to provide a clear solution.

[0100] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 35, 10 to 25, or 10 to 20mg / ml and wherein sufficient hydrochloric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0101] In anembodiment of the invention is providedapharmaceutical aqueous formulation comprisingahydrochloride 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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethyla- mino)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 from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 35, 10 to 25, or 10 to 20mg / ml and wherein sufficient hydrochloric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0102] Preferably, for the above embodiments of the invention containing hydrochloric acid, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

[0103] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a hydrochlor- ide salt thereof, hydrochloric acid, hydroxypropyl-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 3 to 35mg / ml or from 3 to less than 40mg / ml and wherein sufficient hydrochloric acid and hydroxypropyl-beta- cyclodextrin are present to provide a clear solution.

[0104] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a hydrochlor- 12 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 ide salt thereof, hydrochloric acid, sulphobutylether-β-cyclodextrin (SBECD) andwater, 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 concen- trationof from3 to30mg / mlor from3 to less than35mg / mlandwherein sufficienthydrochloric acidandsulphobutylether-β- cyclodextrin (SBECD) are present to provide a clear solution. Orthophosphoric acid formulations

[0105] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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, 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 pre- sent at a solution concentration of from4 to50mg / ml or from4 to less than55mg / ml andwherein sufficient orthophosphoric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0106] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 4 to 50mg / ml or from 4 to less than 55mg / ml and wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0107] In an embodiment of the invention is provided a pharmaceutical aqueous 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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from 4 to 50mg / ml or from 4 to less than 55mg / ml and wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0108] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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, 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 pre- sent at asolution concentrationof from4 to25, 4 to20, 4 to15, 6 to25, 6 to20, 6 to15, 4 to30,6 to30,10 to30, 10 to35, 10 to 25, or 10 to 20mg / ml and wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta‑ or gamma- cyclodextrin are present to provide a clear solution.

[0109] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 35, 10 to 25, or 10 to 20mg / ml and wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution.

[0110] In an embodiment of the invention is provided a pharmaceutical aqueous 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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethy- lamino)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 from 4 to 25, 4 to 20, 4 to 15, 6 to 25, 6 to 20, 6 to 15, 4 to 30, 6 to 30, 10 to 30, 10 to 35, 10 to 25, or 10 to 20mg / ml and wherein sufficient orthophosphoric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution.

[0111] Preferably, for the above embodiments of the invention containing orthophosphoric acid, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-β-cyclodextrin (SBECD) or gamma-cyclodextrin. More preferably, the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin.

[0112] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)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, hydroxypropyl-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piper- idin‑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 from 4 to 35mg / ml or from 4 to less than 40mg / ml and wherein sufficient orthophosphoric acid and hydroxypropyl-beta- cyclodextrin are present to provide a clear solution.

[0113] In an embodiment of the invention is provided a pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a phosphate 13 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 salt thereof, orthophosphoric acid, sulphobutylether-β-cyclodextrin (SBECD) and water, wherein 1‑(4‑{[4‑(dimethylami- no)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 con- centration of from 4 to 30mg / ml or from 4 to less than 35mg / ml and wherein sufficient orthophosphoric acid and sulphobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution.

[0114] The "solution concentration" values referred to herein relate to the concentration of the free base of 1‑(4‑{[4‑(di- methylamino)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.

[0115] The formulations of the invention can be directly administered to the patient (in order to avoid degradation occurring), 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 be first freeze-dried topreparea lyophilisedsolid composition that is chemically stableonstorage (preferablyat least 2years), and which lyophilised solid composition then can be constituted, or reconstituted, to provide a clear aqueous solution, preferably with the addition of a tonicity modifier, as necessary, immediately prior to administration to a patient by the intravenous (or parenteral) route. The reconstituted or constituted solution may be added to an infusion bag prior to administration to a patient.

[0116] The preferred concentration of pharmaceutically acceptable organic or inorganic acid for use in a formulation of the invention is from 10 to 200mM or from 50 to 200mM, and preferably is about 50mM, about 100mM or about 150mM. Preferably, the concentration of pharmaceutically acceptable organic or inorganic acid is about 100mM.

[0117] Thepreferredamount of pharmaceutically acceptable beta‑or gamma-cyclodextrin for use in a formulationof the invention is from2 to 30%w / v, from5 to 20%w / v, or from 15 to 30%w / v, and preferably is about 20%w / v or about 25%w / v. Preferably, the amount of pharmaceutically acceptable beta‑ or gamma-cyclodextrin for use in a formulation of the invention is about 20% w / v.

[0118] If the formulation of the invention is to be freeze-dried to provide a lyophilised solid composition, a bulking agent may be added to the formulation prior to the freeze-drying process commencing. The primary function of the bulking agent is to provide the freeze-dried solid with a non-collapsible, structural integrity that will allow rapid reconstitution on constitution of the aqueous formulation prior to administration, and it should also facilitate efficient lyophilisation. Bulking agents are typically usedwhen the total mass of solutes in the formulation is less than 2g / 100ml. Bulking agentsmay also be added to achieve isotonicity with blood. The bulking agent may be selected from a saccharide, sugar alcohol, amino acid or polymer, or be amixture of two ormore of any 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.

[0119] Preferably, from 5 to 10% w / v of a bulking agent is used, if present .

[0120] Reconstitution of the lyophilised solid compositionmay be achieved by addition of the requisite quantity of water that was present prior to lyophilisation in order that a clear solution is obtained. A tonicitymodifiermay then be added prior to use.

[0121] Constitution of the lyophilised solid composition may be achieved using an appropriate quantity of water and / or an aqueous solution of a suitable tonicity modifier in order to ensure that a clear solution is obtained.

[0122] A tonicitymodifiermay be present prior to intravenous or parenteral administration of the formulation to a patient by injection to avoid crenation or hemolysis of red blood cells, and to mitigate or avoid pain and discomfort to 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 blood of the patient.

[0123] Suitable tonicitymodifiersarenon-ionic tonicitymodifiers suchasglycerol, sorbitol,mannitol, sucrose, propylene glycol or dextrose, or a mixture of any 2 or more thereof. Preferably the non-ionic tonicity modifier is dextrose, sucrose or mannitol, or is a mixture of any 2 or more thereof.

[0124] Preferably, from 1 to 5% w / v of a tonicity modifier is used.

[0125] Aqueous pharmaceutical formulations of the invention that are suitable for intravenous administration generally haveapHof from3 to9.However, lowerpHvaluesare tolerated incertain settings.Preferably, thepH is from3 to8or from4 to 8.

[0126] The formulation of the invention may be used for the curative, palliative or prophylactic treatment of cancer in a mammal, including a human being. The cancer to be treatedmay be selected from the group consisting of leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer and brain cancer.

[0127] 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 by the intravenous route for the treatment of cancer using the formulations disclosed herein is preferably in the range of from 100 to 400mg per week.

[0128] The following Examples describe the preparation of the formulations of the invention. EXAMPLE 1 14 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 Preparation of a pharmaceutical aqueous solution formulation comprising 35mg / ml of 1‑(4‑{[4‑(dimethylami- no)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4.6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, 20% w / v 2-hydro- xypropyl-beta-cyclodextrin and hydrochloric acid

[0129] Hydrochloric acid (1M aqueous solution) (10ml, 100mM) was diluted with water for irrigation (80ml). 2-Hydro- xypropyl-beta-cyclodextrin (93%w / wadjusted potency) (21.57g, 147.2mM)was added and the solutionwas stirred until a particle-free solution was achieved. 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) was added to the solution and stirred until a particle-free solution was achieved. Water for irrigation was added with stirring to achieve a target volume of 100ml. (i) Visual analysis A sample of the formulationwas analysed in accordancewith the visualmethod defined in EuropeanPharmacopoeia Method 2.9.20 (using a Verivide (trade mark) light cabinet and a light meter reading of 3250 lux against a matt black panel and a white panel) to determine if crystallites or particles were present. The sample was tested by this method both when the solution was first made up and then 24 hours thereafter. (ii) OPM analysis A sample of the formulation was placed on a clean glass microscopy slide and covered with a glass cover slip. It was then analysed by OPM using both non-polarised and cross-polarised light under a Nikon LV 100POL (trade mark) microscope with a 10x magnification lens and a 10x magnification eyepiece to determine if crystallites or particles were present. The image was recorded using a DFK 23UP031 TIS USB 3.0 CMOS (trade mark) Colour Industrial Camera 5MP1 / 2,5" and image capture software. The procedurewas also repeated using a sample of the formulation in a glass capillary tube. The samplewas tested by thismethodwhen the solutionwas firstmade up, and then at 4 and 24 hours thereafter. EXAMPLE 2 Preparation of a pharmaceutical aqueous solution formulation comprising 30mg / ml of 1‑(4‑{[4‑(dimethylami- no)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4.6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, 20% w / v sulpho- butylether-beta-cyclodextrin (SBECD) and tartaric acid

[0130] Tartaric acid (racemic) (99% w / w potency) (1.5g, 100mM) was diluted with water for irrigation (80ml). Sulpho- butylether-beta-cyclodextrin (90%w / w adjusted potency) (22.18g, 195mM)was added and the solution was stirred until a particle-free solution was achieved.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) was added to the solution and stirred until a particle-free solution was achieved. Water for irrigation was added with stirring to achieve target volume of 100ml.

[0131] Samples of the formulation were analysed in accordance with the methods of Example 1. EXAMPLE 3 Preparation of a pharmaceutical aqueous solution formulation comprising 45mg / ml of 1‑(4‑{[4‑(dimethylami- no)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyllurea, 20% w / v gamma- cyclodextrin and orthophosphoric acid

[0132] Orthophosphoric acid (99%w / wassumedpotency) (979mg, 100mM)was dilutedwithwater for irrigation (80ml). Gamma-cyclodextrin (assumed 100%potency) (20g, 154mM)was added and the solution was stirred until a particle-free solution was achieved. 1‑(4‑{[4‑(Dimethylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-tria- zin‑2-yl)phenyl]urea (4500mg, 73.1mM) was added to the solution and stirred until a particle-free solution was achieved. Water for irrigation was added with stirring to achieve target volume of 100ml.

[0133] Samples of the formulation were analysed in accordance with the methods of Example 1. EXAMPLE 4 Preparation of a lyophilised composition of a pharmaceutical aqueous solution formulation of the invention

[0134] A pharmaceutical aqueous solution formulation of the invention (e.g. prepared in accordance with any one of Examples 1‑3) is filled into 10mLvials to a target volumeof 3ml. The vials are partially stoppered (not sealed)with a 20mm GrayLyoD777‑1V10-F597WFluroTecSiliconised (trademark) stopper. Thevials are loaded into stainless steel traysand inserted intoaLSL1000 (trademark) freezedryer.Theshelf temperaturewassetat 5°C.The freezedryingcycle is then run 15 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 in accordance with conventional procedures.

[0135] Oncompletion of the freezedrying cycle the freezedryer is back-filledwith sterile filtered nitrogen to a set point of 500Torr (ca. 666mbar or 66,600Pascals), and the vials are fully closed using the stoppers. The freezedryer is then vented to atmospheric pressure using sterile filtered air and the vials are unloaded from the freeze dryer.

[0136] Each vial contains the freeze dried (lyophilised) formulation as a solid. EXAMPLE 5 Reconstitution of a pharmaceutical aqueous solution formulation of the invention from a lyophilised solid composition of the invention

[0137] Avial of lyophilised solid composition prepared in Example 4 is reconstituted as follows.Water for irrigation (3ml) is injectedusingasyringe into the vial containing the lyophilisedcompositionprepared inExample4. Themixture is swirled until a particle-free solution was obtained. EXAMPLE 6 Preparation of a lyophilised composition of a pharmaceutical aqueous solution 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)phe- nyl]urea, 5% w / v 2-hydroxypropyl-beta-cyclodextrin and lactic acid

[0138] DL-lactic acid (4.505g, 30mM)was dilutedwithwater for irrigation (1275mL). 2-Hydroxypropyl-beta-cyclodextrin (92.85% w / w adjusted potency) (80.775g, 35.7mM) was added and the solution was stirred until a particle-free solution was achieved. 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) was added to the solution and stirred until a particle-free solution was achieved. Water for irrigation was added with stirring to achieve a target volume of 1500mL.

[0139] The pharmaceutical aqueous solution formulation of the invention (above) is filled into 20 mL vials to a target volume of 7 ml. The vials are partially stoppered (not sealed) with a 20mm Gray Lyo D777‑1 V10-F597W FluroTec Siliconised (trade mark) stopper. The vials are loaded into stainless steel trays and inserted into a LSL1000 (trade mark) freeze dryer. The freeze drying cycle is then run in accordance with conventional procedures.

[0140] Oncompletion of the freezedrying cycle the freezedryer is back-filledwith sterile filtered nitrogen to a set point of 500Torr (ca. 666mbar or 66,600Pascals), and the vials are fully closed using the stoppers. The freezedryer is then vented to atmospheric pressure using sterile filtered air and the vials are unloaded from the freeze dryer.

[0141] Each vial contains the freeze dried (lyophilised) formulation as a solid. FURTHER EXAMPLES of the preparation of pharmaceutical aqueous solution 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, a beta- or gamma-cyclodextrin and a pharmaceutically acceptable organic or inorganic acid

[0142] The following, tabulated Examples (indicated by a tick or a cross) (target volume = 100ml) were prepared using similar methods to those of Examples 1‑3 using the ingredient specification tabulated below.

[0143] These Examples were analysed by the visual method defined in European Pharmacopoeia Method 2.9.20 and the OPM method both as described in Example 1. The results are also tabulated below.

[0144] In this Table "particle-free" means that the the formulation was visually clear and free of visible crystallites or particulates and meet the required "clear solution" definition as described earlier. 16 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 A PI m g / m l / A PI m M 10 / 16 .7 15 / 24 .4 20 / 32 .5 25 / 40 .6 30 / 48 .7 35 / 56 .8 40 / 65 .0 45 / 73 .1 50 / 81 .2 55 / 89 .3 60 / 97 .5 65 / 10 5. 6 70 / 11 3. 7 H C L 10 0 m M SB EC D (2 0% w / v ) ✔ ✔ ✔ ✔ (1 ) ✔ (1 ) x (2 ) H C L 10 0 m M H PB C D (2 0% w / v ) ✔ ✔ (1 ) ✔ (1 ) x (2 ) x (2 ) H C L 10 0 m M G am m a- C D (2 0% w / v ) ✔ ✔ ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) x (2 ) O rth op ho sp ho ric ac id 10 0 m M SB EC D (2 0% w / v ) ✔ ✔ ✔ (1 ) ✔ (1 ) ✔ (1 ) x (2 ) O rth op ho sp ho ric ac id 10 0 m M H PB C D (2 0% w / v ) ✔ (1 ) ✔ (1 ) ✔ (1 ) x (2 ) x (2 ) O rth op ho sp ho ric ac id 10 0 m M G am m a- C D (2 0% w / v ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) X (2 ) La ct ic ac id * 10 0 m M H PB C D (2 0% w / v ) ✔ ✔ ✔ ✔ (1 ) ✔ (1 ) x (2 ) La ct ic ac id * 10 0 m M Al ph a C D (2 0% w / v ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) La ct ic ac id * 10 0 m M G am m a- C D (2 0% w / v ) ✔ ✔ ✔ ✔ (1 ) ✔ (1 ) x (2 ) La ct ic ac id * 10 0 m M SB EC D (2 0% w / v ) ✔ ✔ ✔ (1 ) ✔ (1 ) x (2 ) 17 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 A PI m g / m l / A PI m M 10 / 16 .7 15 / 24 .4 20 / 32 .5 25 / 40 .6 30 / 48 .7 35 / 56 .8 40 / 65 .0 45 / 73 .1 50 / 81 .2 55 / 89 .3 60 / 97 .5 65 / 10 5. 6 70 / 11 3. 7 Ta rta ric ac id * 10 0 m M SB EC D (2 0% w / v ) ✔ ✔ ✔ (1 ) (1 ) x (2 ) Ta rta ric ac id * 10 0 m M H PB C D (2 0% w / v ) ✔ (1 ) (1 ) x (2 ) x (2 ) Ta rta ric ac id * 10 0 m M G am m a- C D (2 0% w / v ) ✔ ✔ (1 ) (1 ) (1 ) (1 ) (1 ) (1 ) (1 ) (1 ) x (2 ) M al ic ac id * 10 0 m M SB EC D (2 0% w / v ) ✔ ✔ ✔ (1 ) (1 ) x (2 ) M al ic ac id * 10 0 m M H PB C D (2 0% w / v ) ✔ (1 ) (1 ) x (2 ) x (2 ) M al ic ac id * 10 0 m M G am m a- C D (2 0% w / v ) ✔ ✔ ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) x (2 ) C itr ic ac id 10 0 m M SB EC D (2 0% w / v ) ✔ (1 ) ✔ (1 ) x (2 ) C itr ic ac id 10 0 m M H PB C D (2 0% w / v ) ✔ ✔ (1 ) ✔ (1 ) x (2 ) x (2 ) C itr ic ac id 10 0 m M G am m a- C D (2 0% w / v ) ✔ ✔ ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) x (2 ) Su cc in ic ac id 10 0 m M SB EC D (2 0% w / v ) ✔ (1 ) ✔ (1 ) x (2 ) Su cc in ic ac id 10 0 m M H PB C D (2 0% w / v ) ✔ ✔ (1 ) ✔ (1 ) x (2 ) x (2 ) Su cc in ic ac id 10 0 m M G am m a- C D (2 0% w / v ) ✔ ✔ ✔ (1 ) (1 ) (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) ✔ (1 ) x (2 ) 18 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 A PI m g / m l / A PI m M 10 / 16 .7 15 / 24 .4 20 / 32 .5 25 / 40 .6 30 / 48 .7 35 / 56 .8 40 / 65 .0 45 / 73 .1 50 / 81 .2 55 / 89 .3 60 / 97 .5 65 / 10 5. 6 70 / 11 3. 7 P- to lu en es ul fo ni c ac id 10 0 m M H PB C D (2 0% w / v ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) P- to lu en es ul fo ni c ac id 10 0 m M SB EC D (2 0% w / v ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) x (2 ) Ac et ic ac id 10 0 m M H PB C D (2 0% w / v ) ✔ (1 ) x (2 ) Ac et ic ac id 10 0 m M SB EC D (2 0% w / v ) ✔ (1 ) x (2 ) Ac et ic ac id 10 0 m M G am m a- C D (2 0% w / v ) ✔ (1 ) x (2 ) M al ei c ac id 10 0 m M H PB C D (2 0% w / v ) ✔ (1 ) x (2 ) x (2 ) M al ei c ac id 10 0 m M SB EC D (2 0% w / v ) ✔ (1 ) ✔ (1 ) x (2 ) M al ei c ac id 10 0 m M G am m a- C D (2 0% w / v ) ✔ (1 ) x (2 ) K ey A PI = 1‑ (4 ‑{[ 4‑ (d im et hy la m in o) pi pe rid in ‑1 -y l]c ar bo ny l}p he ny l)‑ 3‑ [4 ‑(4 ,6 -d im or ph ol in ‑4 -y l‑1 ,3 ,5 -tr ia zi n‑ 2- yl )p he ny l]u re a *= ac id us ed in ra ce m ic fo rm H PB C D = 2- hy dr ox yp ro py l-b et a- cy cl od ex tri n SB EC D = su lp ho bu ty le th er -β -c yc lo de xt rin G am m aC D = ga m m a- cy cl od ex tri n A lp ha C D = al ph a- cy cl od ex tri n (1 )= pa rti cl e- fre e (a nd no n- op al es ce nt ). Al lt he se Ex am pl es st ud ie d ar e fre e of vi si bl e cr ys ta llit e or pa rti cu la te m at te ra nd m ee tt he re qu ire d "c le ar so lu tio n" de fin iti on as de sc rib ed ea rli er . (2 )= pa rti cu la te su sp en si on 19 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 Chemical stability of a lyophilised solid formulation of the invention

[0145] A sample of a lyophilised formulation of the invention was prepared in accordancewith Example 6 ("Sample A").

[0146] Separate portions of Sample Awere each housed in 20mL clear vials and onewas stored at 25°C / 60%Relative Humidity ("RH") for 6 months, and the other was stored at 40°C / 75% RH for 6 months.

[0147] After 6 months storage as above, the separate Samples were each tested for chemical purity using Ultra High Performance Liquid Chromatography (UHPLC) using the following methodology in order to measure any chemical degradation during the period of testing. UHPLC method

[0148] The solutions, samples, standards and UHPLC method are as below: ReferenceStandard:1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-tria- zin‑2-yl)phenyl]urea with a known potency value. Diluent: Acetonitrile / Water / Trifluoroacetic acid (750:250:1 v / v / v) Mobile Phase A: Acetonitrile / Water / Trifluoroacetic acid (97:3:1 v / v / v) Mobile Phase B: Acetonitrile / Trifluoroacetic acid (1000:1 v / v). (Note: larger or smaller volumes of solutions may be prepared using the appropriate ratio of components) Standard and Check standard preparations:

[0149] • Accurately prepare two solutions of ca. 0.2 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 Diluent, and record the concentrations accurately of both. These are the Standard and Check standard preparations. Sensitivity solution:

[0150] • Accurately dilute the Standard preparation to a concentration of approximately 0.1 microgram / ml of 1‑(4‑{[4‑(di- methylamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea using the Di- luent. Sample preparation:

[0151] • Reconstitute Sample A after storage by adding 7.0 ml of water to each in the 20ml vial, shake the vial to dissolve the solid and wait for the bubbles to disappear. Transfer 1.0ml of the solution into a 50ml volumetric flask. Dilute to the set volume with Diluent. Chromatographic conditions:

[0152] • Liquid chromatographic system ‑Agilent 1290 Infinity II™ with 380µl Jet Weaver™ • Column: Waters BEH C18™15 cm x 2.1 mm, 1.7 µm or equivalent • Column Temperature: 20°C • Injection Volume: 2 µL • Flow Rate: 0.25 mL / min. • Flow Cell: G4212‑60008, 10mm path length, 1.0µL 20 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 • Detection: UV at 240 nm / 4nm slit width • Run Time: 77 minutes • Mobile Phase A • Mobile Phase B • Needle wash solution: Water / Acetonitrile (95:5 v / v), multi wash 20s. • Seal wash solution: Water / Propan‑2-ol (90:10 v / v) Linear Gradient Table:

[0153] 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 Explanatory notes

[0154] Condition the UHPLC system, prior to starting the analysis, with the mobile phases.

[0155] Prior to running samples, ensure that the system is suitable for use by injecting blank diluent, sensitivity solution and standard preparation using the chromatographic conditions above.

[0156] The following criteria must be satisfied on initial UHPLC set-up or after any significant change to the system. It is recommended to inject at least one conditioning blank prior to testing system suitability. Test No. of Injections Solution Criteria Blank 1 Diluent Free from interfering peaks Signal to Noise 1 Sensitivity Solution European Pharmacopoeia (EP) / United States Pharmacopoeia (USP) Signal to Noise ≥ 10 Repeatability 5 Standard preparation Relative Standard Deviation ≤ 2.0% Retention time 1* 38‑44 minutes Efficiency (Plate)** Plate number for 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 ≥ 10,000 Peak Asym- metry (T)** 0.9 ≤ T ≤ 2.0 for 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phe- nyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea peak Resolution 1 Resolution between 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 and Degradant 2 [((4‑(4,6-dimorpholino‑1,3,5-triazin‑2-yl)phenyl)‑12- azaneyl)((4‑(4‑(methyl‑12-azaneyl)piperidine‑1-carbonyl)phenyl)‑I2- azaneyl)methanone ≥ 1.0] * Use average of all system suitability (repeatability) injections. ** Refer to United States Pharmacopoeia (USP) calculation equations for Efficiency and Peak Asymmetry. 21 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55

[0157] Inject the check standard preparation according to the chromatographic conditions above. The response factor (calculated from the area, standard weight, dilution factor and purity factor of the standard) of this check standard preparation must be within ± 2% of the standard preparation.

[0158] After the system suitability has been demonstrated, inject the blank solution, standard preparation and prepared test samples, followedbyan injectionof the standardpreparation, according to the chromatographic conditionsabove. 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 area of the 1‑(4‑{[4‑(dimethylamino) piperidin‑1-yl]carbonyl} phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea peak in each chromatogram. For each sample injection, alsomeasure the retention timesandpeakareaof anypeakspresent in the sample injection that donot appear in theblank injection. Do not integrate gradient artifacts, if present. Compare the blank injection chromatogram to the sample chromatogram to determine which peaks in the sample are related to the blank and gradient artifact peaks. Calculate the%w / w degradants and report the individual degradant peaks which are at or above 0.05%w / w. Unknown degradants shouldbe reported individually by their relative retention time.Knowndegradants shouldbe reported individually byname.

[0159] The results are summarised in the Table below. Key

[0160] • NMT = Not More Than. • RRT = Relative Retention Time Degradant 1

[0161] Degradants 2, 3 and 4

[0162] These were each characterised by their RRTonly. Sample A results

[0163] 25°C / 60% RH 40°C / 75% RH Degradant Acceptance Criteria Initial 6 months 6 months Degradant 1 (RRT~0.72) NMT 0.5% 0.10% 0.12% 0.14% Degradant 2 (RRT~0.98) NMT 1.1% NMT0.05% NMT 0.05% 0.10% Degradant 3 (RRT~1.07) NMT 0.5% NMT0.05% NMT 0.05% 0.13% Degradant 4 (RRT~1.17) NMT 0.5% 0.06% NMT 0.05% NMT0.05% Total Degradants NMT 3.0% 0.16% 0.12% 0.37% 22 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 Conclusion

[0164] The results show that Sample A is chemically stable for at least 6 months at 25°C / 60% RH and for at least 6 months at 40°C / 75% RH. ASPECTS OF THE INVENTION

[0165] 1. A pharmaceutical aqueous formulation comprising 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phe- nyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a pharmaceutically acceptable organic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein sufficient of the pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptablebeta‑or gamma-cyclodextrin arepresent toprovideaclear solution,with theproviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid. 2. A pharmaceutical aqueous formulation as claimed in aspect 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, orapharmaceutically acceptableorganic or inorganic acid salt thereof, a pharmaceutically acceptable organic or inorganic 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 a solution concentration of at least 6mg / ml and wherein sufficient of the pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid. 3.Apharmaceutical aqueous formulationasclaimed inaspect1or2wherein thepharmaceutically acceptableorganic or inorganic acid is selected from lactic acid, acetic acid,maleic acid, succinic acid, citric acid,malic acid, tartaric acid, hydrochloric acid and orthophosphoric acid. 4. A pharmaceutical aqueous formulation as claimed in aspect 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 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 a solution concentration of from 6 to 30mg / ml or from 6 to less than 35mg / ml and wherein sufficient lactic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution. 5. A pharmaceutical aqueous formulation as claimed in aspect 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 accepta- ble beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phe- nyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 6 to 30mg / ml or from 6 to less than 35mg / ml and wherein sufficient lactic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 6. A pharmaceutical aqueous formulation as claimed in aspect 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 pharmaceuti- cally 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 a solution concentration of from 6 to 30mg / ml or from 6 to less than 35mg / ml and wherein sufficient lactic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 7. A pharmaceutical aqueous formulation as claimed in aspect 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‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperi- din‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concen- tration of from 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml and wherein sufficient lactic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution. 8. A pharmaceutical aqueous formulation as claimed in aspect 4 comprising 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl] 23 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, lactic acid, a pharmaceutically accepta- ble beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phe- nyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml andwherein sufficient lactic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 9. A pharmaceutical aqueous formulation as claimed in aspect 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 pharmaceuti- cally 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 a solution concentration of from6 to25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml andwherein sufficient lactic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 10. A pharmaceutical aqueous formulation as claimed in aspect any one of aspects 4 to 9 wherein the pharmaceu- tically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-β- cyclodextrin (SBECD) or gamma-cyclodextrin. 11. A pharmaceutical aqueous formulation as claimed in aspect 10wherein the pharmaceutically acceptable beta‑ or gamma-cyclodextrin used is 2-hydroxypropyl-beta-cyclodextrin or gamma-cyclodextrin. 12. A pharmaceutical aqueous formulation as claimed in aspect 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, sul- phobutylether-β-cyclodextrin (SBECD) and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phe- nyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 6 to 25mg / ml or from 6 to less than 30mg / ml and wherein sufficient lactic acid and sulphobutylether-β-cyclodextrin (SBECD) are present to provide a clear solution. 13. A pharmaceutical aqueous formulation as claimed in aspect 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-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phe- nyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 6 to 30mg / ml or from 6 to less than 35mg / ml and wherein sufficient lactic acid and 2-hydroxypropyl-beta-cyclodextrin are present to provide a clear solution. 14. A pharmaceutical aqueous formulation as claimed in aspect 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-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phe- nyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 6 to 30, 6 to 25, 6 to 20, 6 to15, 10 to30, 10 to25, or 10 to20mg / ml andwherein sufficient lactic acidand2-hydroxypropyl-beta- cyclodextrin are present to provide a clear solution. 15. A pharmaceutical aqueous formulation as claimed in aspect 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-beta-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperidin‑1-yl]carbonyl}phe- nyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concentration of from 6 to 30, 6 to 25, 6 to 20, 6 to 15, 10 to 30, 10 to 25, or 10 to 20mg / ml andwherein the lactic acid concentration is from10 to 100, 15 to100or 30 to100mMand the2-hydroxypropyl-beta-cyclodextrin concentration is from15 to120, 20 to120or 35 to 120mg / ml to provide a clear solution. 16. A pharmaceutical aqueous formulation as claimed in aspect 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-beta-cyclo- dextrin andwater, 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 from 10 to 30 or 10 to 20mg / ml and wherein the lactic acid concentration is from20 to 100 or 30 to 100mMand the 2-hydroxypropyl-beta-cyclodextrin concentration is from 35 to 120mg / ml to provide a clear solution 17.A pharmaceutical aqueous formulation as claimed in aspect 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 acetate salt thereof, acetic acid, a 24 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 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 a solution concentration of from 3 to 15mg / ml or from 3 to less than 20mg / ml andwherein sufficient acetic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 18.A pharmaceutical aqueous formulation as claimed in aspect 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 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 a solution concentration of from 3 to 30mg / ml or from3 to less than 35mg / ml andwherein sufficientmaleic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 19.A pharmaceutical aqueous formulation as claimed in aspect 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‑or gamma-cyclodextrin andwater, 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 from3 to65mg / mlor from3 to less than70mg / mlandwhereinsufficient succinicacidandpharmaceuticallyacceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 20.A pharmaceutical aqueous formulation as claimed in aspect 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‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperi- din‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concen- tration of from 3 to 55mg / ml or from 3 to less than 60mg / ml and wherein sufficient citric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 21.A pharmaceutical aqueous formulation as claimed in aspect 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 beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethylamino)piperi- din‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solution concen- tration of from 3 to 65mg / ml or from 3 to less than 70mg / ml and wherein sufficient malic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 22.A pharmaceutical aqueous formulation as claimed in aspect 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 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 a solution concentration of from3 to 65mg / ml or from3 to less than 70mg / ml andwherein sufficient tartaric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 23. A pharmaceutical aqueous formulation as claimed in aspect 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 salt thereof, hydro- chloric acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethyla- mino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solu- tion concentration of from 3 to 60mg / ml or from 3 to less than 65mg / ml and wherein sufficient hydrochloric acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 24. A pharmaceutical aqueous formulation as claimed in aspect 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 salt thereof, orthopho- sphoric acid, a pharmaceutically acceptable beta‑ or gamma-cyclodextrin and water, wherein 1‑(4‑{[4‑(dimethyla- mino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimorpholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea is present at a solu- tionconcentrationof from4 to50mg / mlor from4 to less than55mg / mlandwherein sufficient orthophosphoric acidand pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution. 25.A formulationas claimed inanyoneof aspects 1 to 14or 17 to24wherein from10 to200mMor from50 to200mMof the pharmaceutically acceptable organic or inorganic acid is used. 26. A formulation as claimed in any one of aspects 1 to 14 or 17 to 25 wherein from 2 to 30%w / v, from 5 to 20%w / v or 25 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 from 15 to 30% w / v of the cyclodextrin is used. 27. A lyophilised formulation obtainable by freeze drying a formulation as claimed in any one of aspects 1 to 26. 28.A lyophilised formulationas claimed inaspect 27obtainableby freezedryinga formulationasclaimed inanyoneof aspects 1 to 26 optionally containing a bulking agent. 29. A lyophilised formulation as claimed in aspect 28 wherein the bulking agent is mannitol. 30. A pharmaceutical aqueous solution formulation obtainable as a clear solution by reconstitution or constitution of a lyophilized formulation as claimed in any one of aspects 27 to 29 using water or an aqueous solution comprising a tonicity modifier. 31. A pharmaceutical aqueous solution formulation as claimed in aspect 30 wherein the tonicity modifier is dextrose, sucrose or mannitol, or is a mixture of any 2 or more thereof. 32. A pharmaceutical aqueous solution formulation as claimed in any one of aspects 1 to 26, or 30 or 31, that is adjusted, as necessary, to have a pH suitable for intravenous or parenteral administration. 33. A formulation as claimed in any one of aspects 1 to 32 for use as a medicament. 34.A formulation as claimed in any one of aspects 1 to 32 for use in the treatment of cancer. 35. A method of treatment of cancer in a mammal comprising treatment of the mammal with an effective amount of a formulation as claimed in any one of aspects 1 to 32. Claims 1. A pharmaceutical aqueous formulation comprising: (i) Gedatolisib, or a pharmaceutically acceptable organic or inorganic acid salt thereof, with the proviso that the organic or inorganic acid salt is not a sulphonic acid; (ii) a pharmaceutically acceptable organic or inorganic acid, with the proviso that the organic or inorganic acid is not a sulphonic acid; (iii) a pharmaceutically acceptable beta‑ or gamma-cyclodextrin; and (iv) water, wherein sufficient of the pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution with no opalescence caused by chromonic liquid crystal formation. 2. The pharmaceutical aqueous formulation of claim 1, wherein: (a) the beta‑ or gamma-cyclodextrin is 2-hydroxypropyl-beta-cyclodextrin; or (b) the beta‑or gamma-cyclodextrin is used in the formulation at an amount from2 to 30%w / v, preferablywherein the beta‑ or gamma-cyclodextrin is used in the formulation at 5% w / v. 3. Thepharmaceutical aqueous formulationof claim1,wherein theorganicor inorganicacid, or salt thereof, is lactic acid, or salt thereof. 4. The pharmaceutical aqueous formulation of claim 3, wherein the lactic acid concentration is from 10 to 200 mM, preferably wherein the lactic acid concentration is about 50 mM. 5. The pharmaceutical aqueous formulation of claim 3, wherein the beta-or gamma-cyclodextrin is 2-hydroxypropyl- beta-cyclodextrin. 6. The pharmaceutical aqueous formulation of claim 5, wherein 2-hydroxypropyl-beta-cyclodextrin is present at a 26 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 concentration of 15 to 120 mg / ml. 7. Thepharmaceutical aqueous formulation of claim5,wherein gedatolisib, or a pharmaceutically acceptable organic or inorganic acid salt thereof, is present at a concentration of 6 to 30 mg / ml. 8. Thepharmaceutical aqueous formulationof claim1,wherein chromonic liquid crystal formation isassessedbyOptical Polarized Microscopy (OPM). 9. A lyophilized formulation obtainable by freeze drying a formulation according to any one of the preceding claims. 10. The lyophilized formulationof claim9,which further comprises abulkingagent, optionallywherein thebulking agent is selected from thegroup consisting of saccharides, sugar alcohols, aminoacidsandpolymers, andpreferablywherein the bulking agent is sucrose or mannitol. 11. A pharmaceutical aqueous solution formulation obtainable as a clear solution by reconstitution of the lyophilized formulation of claim 10 using water or an aqueous solution comprising a tonicity modifier. 12. The pharmaceutical aqueous solution formulation of claim 11, wherein the tonicitymodifier is selected from the group consisting of glycerol, sorbitol, mannitol, sucrose, propylene glycol and dextrose. 13. A lyophilized formulation comprising: (i) Gedatolisib, or a pharmaceutically acceptable organic or inorganic acid salt thereof, with the proviso that the organic or inorganic acid salt is not a sulphonic acid; (ii) a pharmaceutically acceptable organic or inorganic acid, with the proviso that the organic or inorganic acid is not a sulphonic acid; and (iii) a pharmaceutically acceptable beta‑ or gamma-cyclodextrin; wherein sufficient of the pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta‑ or gamma-cyclodextrin are present to provide a clear solution with no opalescence caused by chromonic liquid crystal formation upon reconstitution of the lyophilized formulation with water or an aqueous solution comprising a tonicity modifier. 14. The lyophilized formulation of claim 13, which further comprises a bulking agent, optionally wherein the bulking agent is selected from the group consisting of saccharides, sugar alcohols, amino acids and polymers, and preferably wherein the bulking agent is sucrose or mannitol. 15. The lyophilized formulation of claim 13, wherein the tonicity modifier is selected from the group consisting of glycerol, sorbitol, mannitol, sucrose, propylene glycol and dextrose. 27 EP 4 649 940 A2 5 10 15 20 25 30 35 40 45 50 55 28 EP 4 649 940 A2 29 EP 4 649 940 A2 REFERENCES CITED IN THE DESCRIPTION This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard. Patent documents cited in the description • WO 2009143313 A

[0002] • WO 2010096619 A

[0003] • WO 2016097949 A

[0004] Non-patent literature cited in the description • Optical Properties of CondensedMatter and Applica- tions. Wiley, October 2006

[0017] (19) *EP004649940A3* (11) EP 4 649 940 A3 (12) EUROPEAN PATENT APPLICATION (88) Date of publication A3: 21.01.2026 Bulletin 2026 / 04 (43) Date of publication A2: 19.11.2025 Bulletin 2025 / 47 (21) Application number: 25207215.2 (22) Date of filing: 04.06.2019 (51) International Patent Classification (IPC): A61K 9 / 08 (2006.01) A61K 9 / 19 (2006.01) A61K 47 / 12 (2006.01) A61K 47 / 40 (2006.01) A61K 31 / 5377 (2006.01) A61P 35 / 00 (2006.01) A61K 9 / 00 (2006.01) (52) Cooperative Patent Classification (CPC): A61K 9 / 0019; A61K 9 / 08; A61K 9 / 19; A61K 31 / 5377; A61K 47 / 12; A61K 47 / 40; A61P 35 / 00 (84) Designated Contracting States: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (30) Priority: 07.06.2018 US 201862681722 P 02.11.2018 US 201862754651 P 24.01.2019 US 201962796133 P 02.05.2019 US 201962841882 P (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: 23176968.8 / 4 249 069 19742898.0 / 3 810 089 (71) Applicant: Pfizer Inc. New York, NY 10001‑2192 (US) (72) Inventors: • HUSSEY, James Joseph Sandwich, CT13 9NJ (GB) • BRIGHT, Andrew Gilbert Sandwich, CT13 9NJ (GB) (74) Representative: J A Kemp LLP 80 Turnmill Street London EC1M 5QU (GB) (54) 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 (57) The present invention relates to a pharmaceu- tical aqueous formulation comprising 1‑(4‑{[4‑(dimethy- lamino)piperidin‑1-yl]carbonyl}phenyl)‑3‑[4‑(4,6-dimor- pholin‑4-yl‑1,3,5-triazin‑2-yl)phenyl]urea, or a pharma- ceutically acceptable organic or inorganic acid salt there- of, a pharmaceutically acceptable organic or inorganic acid, a pharmaceutically acceptable beta‑ or gamma- cyclodextrin and water, that is a clear solution, with the proviso that the organic or inorganic acid (including a salt thereof) is not a sulphonic acid. Such a formulation is particularly suitable for intravenous or parenteral admin- istration to a patient. EP 4 64 9 94 0 A 3 Processed by Luminess, 75001 PARIS (FR) 2 EP 4 649 940 A3 5 10 15 20 25 30 35 40 45 50 55 3 EP 4 649 940 A3 5 10 15 20 25 30 35 40 45 50 55 4 EP 4 649 940 A3 5 10 15 20 25 30 35 40 45 50 55 5 EP 4 649 940 A3 5 10 15 20 25 30 35 40 45 50 55 摘 要 本发明涉及一种水性药物制剂，其包含 1‑(4‑{[4‑(二甲基氨基)哌啶‑1‑基]羰基} 苯基)‑3‑[4‑(4,6‑二吗啉‑4‑基‑1,3,5‑三嗪‑2‑基)苯基]脲或其药学上可接受的 有机或无机酸盐、药学上可接受的有机或无机酸、药学上可接受的β‑环糊精 或γ‑环糊精及水，其为澄清溶液，条件是所述有机或无机酸(包括其盐)不为 5 磺酸。此类制剂尤其适用于向患者静脉内或肠胃外给药。

Claims

1. A pharmaceutical aqueous formulation comprising: (i) Gedatolisib, or a pharmaceutically acceptable organic or inorganic acid salt thereof, with the proviso that the organic or inorganic acid salt is not a sulphonic acid; (ii) a pharmaceutically acceptable organic or inorganic acid, with the proviso that the organic or inorganic acid is not a sulphonic acid; (iii) a pharmaceutically acceptable beta- or gamma-cyclodextrin; and (iv) water, wherein sufficient of the pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution with no opalescence caused by chromonic liquid crystal formation.

2. The pharmaceutical aqueous formulation of claim 1, wherein: (a) the beta- or gamma-cyclodextrin is 2-hydroxypropyl-beta-cyclodextrin; or (b) the beta- or gamma-cyclodextrin is used in the formulation at an amount from 2 to 30% w / v, preferably wherein the beta- or gamma-cyclodextrin is used in the formulation at 5% w / v.

3. The pharmaceutical aqueous formulation of claim 1, wherein the organic or inorganic acid, or salt thereof, is lactic acid, or salt thereof.

4. The pharmaceutical aqueous formulation of claim 3, wherein the lactic acid concentration is from 10 to 200 mM, preferably wherein the lactic acid concentration is about 50 mM.

5. The pharmaceutical aqueous formulation of claim 3, wherein the beta-or gamma-cyclodextrin is 2-hydroxypropyl-beta-cyclodextrin.

6. The pharmaceutical aqueous formulation of claim 5, wherein 2-hydroxypropyl-beta-cyclodextrin is present at a concentration of 15 to 120 mg / ml.

7. The pharmaceutical aqueous formulation of claim 5, wherein gedatolisib, or a pharmaceutically acceptable organic or inorganic acid salt thereof, is present at a concentration of 6 to 30 mg / ml.

8. The pharmaceutical aqueous formulation of claim 1, wherein chromonic liquid crystal formation is assessed by Optical Polarized Microscopy (OPM).

9. A lyophilized formulation obtainable by freeze drying a formulation according to any one of the preceding claims.

10. The lyophilized formulation of claim 9, which further comprises a bulking agent, optionally wherein the bulking agent is selected from the group consisting of saccharides, sugar alcohols, amino acids and polymers, and preferably wherein the bulking agent is sucrose or mannitol.

11. A pharmaceutical aqueous solution formulation obtainable as a clear solution by reconstitution of the lyophilized formulation of claim 10 using water or an aqueous solution comprising a tonicity modifier.

12. The pharmaceutical aqueous solution formulation of claim 11, wherein the tonicity modifier is selected from the group consisting of glycerol, sorbitol, mannitol, sucrose, propylene glycol and dextrose.

13. A lyophilized formulation comprising: (i) Gedatolisib, or a pharmaceutically acceptable organic or inorganic acid salt thereof, with the proviso that the organic or inorganic acid salt is not a sulphonic acid; (ii) a pharmaceutically acceptable organic or inorganic acid, with the proviso that the organic or inorganic acid is not a sulphonic acid; and (iii) a pharmaceutically acceptable beta- or gamma-cyclodextrin; wherein sufficient of the pharmaceutically acceptable organic or inorganic acid and pharmaceutically acceptable beta- or gamma-cyclodextrin are present to provide a clear solution with no opalescence caused by chromonic liquid crystal formation upon reconstitution of the lyophilized formulation with water or an aqueous solution comprising a tonicity modifier.

14. The lyophilized formulation of claim 13, which further comprises a bulking agent, optionally wherein the bulking agent is selected from the group consisting of saccharides, sugar alcohols, amino acids and polymers, and preferably wherein the bulking agent is sucrose or mannitol.

15. The lyophilized formulation of claim 13, wherein the tonicity modifier is selected from the group consisting of glycerol, sorbitol, mannitol, sucrose, propylene glycol and dextrose.

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