WO2016097949A1 - Formulations of a pi3k/mtor-inhibitor for intravenous administration - Google Patents

Formulations of a pi3k/mtor-inhibitor for intravenous administration Download PDF

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Publication number
WO2016097949A1
WO2016097949A1 PCT/IB2015/059515 IB2015059515W WO2016097949A1 WO 2016097949 A1 WO2016097949 A1 WO 2016097949A1 IB 2015059515 W IB2015059515 W IB 2015059515W WO 2016097949 A1 WO2016097949 A1 WO 2016097949A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
dimethylamino
piperidin
dimorpholin
triazin
Prior art date
Application number
PCT/IB2015/059515
Other languages
French (fr)
Inventor
Kevin Richard Back
Michael Cram
Aidan James Harper
W. James Huang
Jonathan Richard Lillis
Timothy Michael Lukas
Sumit Luthra
Original Assignee
Pfizer Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to LTEPPCT/IB2015/059515T priority Critical patent/LT3233054T/en
Priority to BR112017010841-0A priority patent/BR112017010841B1/en
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to US15/534,999 priority patent/US10172942B2/en
Priority to RU2017119282A priority patent/RU2672875C1/en
Priority to AU2015365497A priority patent/AU2015365497B2/en
Priority to CN201580068063.3A priority patent/CN107205923B/en
Priority to EP15813578.0A priority patent/EP3233054B1/en
Priority to SI201531687T priority patent/SI3233054T1/en
Priority to HRP20211446TT priority patent/HRP20211446T1/en
Priority to KR1020177016417A priority patent/KR102016822B1/en
Priority to DK15813578.0T priority patent/DK3233054T3/en
Priority to MX2017008072A priority patent/MX2017008072A/en
Priority to NZ731518A priority patent/NZ731518A/en
Priority to PL15813578T priority patent/PL3233054T3/en
Priority to RS20211128A priority patent/RS62337B1/en
Priority to SG11201703826TA priority patent/SG11201703826TA/en
Priority to ES15813578T priority patent/ES2881214T3/en
Publication of WO2016097949A1 publication Critical patent/WO2016097949A1/en
Priority to IL252158A priority patent/IL252158B/en
Priority to ZA201703764A priority patent/ZA201703764B/en
Priority to US16/189,009 priority patent/US10660959B2/en
Priority to CY20211100851T priority patent/CY1124527T1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • 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 salt thereof.
  • 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 salt thereof, that is a clear solution.
  • 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 salt thereof, that is a clear solution.
  • a pharmaceutically acceptable salt thereof that is a clear solution.
  • the compound is an inhibitor of PI3 kinase and mTOR that is useful for the treatment of cancer.
  • 4-yl-1 ,3,5-triazin-2-yl)phenyl]urea may 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.
  • RH Relative Humidity
  • 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.
  • the formulation is suitable for intravenous administration of 1 -(4-
  • an intravenous formulation of any drug is a solution to facilitate safe and effective administration to a patient. It must be particle-free, and not form a gel or suspension. A clear, aqueous solution is preferred.
  • a clear solution is defined as a visually clear solution 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 vessels may occur. Accordingly, in view of the qualitative nature of the visual test, the term "essentially free from any visible particulates" is usually applied when no visible particulate matter is observed.
  • Particulate matter may be defined as follows:
  • ⁇ particulates with a definite shape or characteristic can be described as glasslike, metallic-looking, etc.
  • the visual inspection can be conducted in accordance with the method defined in European Pharmacopoeia Method 2.9.20 entitled " Particulate
  • Figure 2 "Figure 2.9.20.-1 " shown in Figure 2) consists of a viewing station comprising:
  • an adjustable lampholder fitted with a suitable, shaded, white-light source and with a suitable light diffuser (a viewing illuminator containing two 13 Watt 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.
  • the Method 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. "
  • Such a formulation can be directly administered to the patient (in order to avoid degradation occurring), intravenously or parenterally, preferably with the addition of a tonicity modifier.
  • a formulation optionally containing a bulking agent and/or tonicity modifier, may be first freeze-dried to prepare a lyophilised solid composition that is chemically stable on storage for preferably at least 2 years, 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 invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 6mg/ml and sufficient lactic acid is present to provide a clear solution.
  • the concentration of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea in the formulation of the invention may be from 1 to 5.5 mg/ml, from 2 to 5.5 mg/ml, or from 3 to 5.5mg/ml (calculated as the named free base),
  • the invention provides a pharmaceutical aqueous solution formulation 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 2.5 to 5.5mg/ml.
  • the invention provides a pharmaceutical aqueous solution formulation wherein 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml.
  • lactic acid when the free base of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is used, above 2.5 mole equivalents of lactic acid are present in the formulation of the invention. More preferably, from 3 to 10, from above 2.5 to 8.0, or from 3.5 to 4.5 mole equivalents of lactic acid are present in the formulation of the invention. Most preferably, about 4.1 mole equivalents of lactic acid are present in the formulation of the invention.
  • the invention provides a pharmaceutical aqueous solution formulation 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 5.0 to 5.5mg/ml and at least 2.5 mole equivalents of lactic acid are present.
  • the invention provides a pharmaceutical aqueous solution formulation wherein 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml and at least 2.5 mole equivalents of lactic acid are present.
  • the invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin- 4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a
  • the formulation of the invention may be prepared using 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 free base or using a lactic acid salt of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea.
  • the invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea lactate, lactic acid and water, wherein 1-(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml, and at least 1 .5 mole equivalents of lactic acid are present
  • DL-lactic acid D-lactic acid or L-lactic acid, or any combination thereof, may be used in the formulation of the invention.
  • DL-lactic acid is used, preferably, the pH of the formulation of the invention is not greater than 3.7. More preferably, the pH of the formulation of the invention is from 3.0 to 3.7, from 3.3 to 3.6, or from 3.4 to 3.5.
  • the present invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of up to 5.5 mg/ml, and above 2.5 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed with a pH of no greater than 3.7.
  • the present invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml, and about 4.1 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed with a pH of no greater than 3.7.
  • a crystalline form of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea L-lactate may be used to prepare the formulation of the invention.
  • the invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid and water, wherein 1 -(4- ⁇ [4-(dimethylamino)piperidin- 1 -yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a clear solution,
  • the invention provides a pharmaceutical aqueous solution formulation 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 3.0 to 3.5mg/ml.
  • the invention provides a pharmaceutical aqueous solution formulation wherein at least 5 mole equivalents of orthophosphoric acid are used.
  • the invention provides a pharmaceutical aqueous solution formulation wherein from 5 to 7 mole equivalents of orthophosphoric acid are used.
  • the present invention provides a pharmaceutical aqueous solution formulation comprising 1-(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid and water, wherein 1-(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4mg/ml, from 5 to 7 mole equivalents of orthophophoric acid are present and in an amount sufficient to ensure a clear solution is formed.
  • the pH of the formulation prepared is from 2-2.5 prior to
  • the pH is then preferably adjusted to from 3.0-4.5 for intravenous administration.
  • a bulking agent is preferably 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 used when the total mass of solutes in the formulation is less than 2g/100ml. Bulking agents may also be added to achieve isotonicity with blood.
  • the bulking agent may be selected from a saccharide, sugar alcohol, amino acid or polymer, or be a mixture of two or more of any thereof.
  • the bulking agent is a sugar or sugar alcohol, or a mixture thereof.
  • the sugar is sucrose.
  • the sugar alcohol is mannitol.
  • Reconstitution of the lyophilized solid composition may 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 tonicity modifier may then be added prior to use.
  • Constitution of the lyophilized 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.
  • a tonicity modifier must 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.
  • Suitable tonicity modifiers are non-ionic tonicity modifiers such as glycerol, sorbitol, mannitol, sucrose, propylene glycol or dextrose, or a mixture of any 2 or more thereof.
  • the non-ionic tonicity modifier is dextrose, sucrose or mannitol, or is a mixture of any 2 or more thereof.
  • Aqueous pharmaceutical formulations that are suitable for intravenous administration generally have a pH of from 3 to 9.
  • the formulations of the invention that are to be intravenously administered preferably have a pH of from 3 to 4.5.
  • 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 treated may 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.
  • 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 100-400mg/ml per week.
  • the solution was sterile filtered through an in-line 0.45 pm clarification filter and 0.22 pm filter assembly. This solution was then filled into 50 ml_ vials with a target fill volume of 20.8 ml_ for each vial.
  • the vials were each partially stoppered (not sealed) with a 20mm Gray Lyo D777-1 V10-F597W FluroTec Siliconised (trade mark) stopper.
  • the freeze dryer was back-filled with sterile filtered nitrogen to a set point of ca. 700mbar (70,000 Pascals), and the vials were fully closed using the stoppers. The freeze dryer was then vented to atmospheric pressure using sterile filtered air and the vials were unloaded from the freeze dryer.
  • Each vial contained the freeze dried (lyophilised) formulation as a white solid.
  • EXAMPLE 3 Reconstitution of a 5mq/ml pharmaceutical aqueous solution formulation comprising 1 -(4- ⁇ r4-(dimethylamino)piperidin-1 -yl1carbonyl)phenyl)-3-r4-(4,6-dimorpholin-4-yl- 1 ,3,5-thazin-2-yl)phenyl1urea, DL-lactic acid and mannitol from a lyophilised solid composition
  • the vials of lyophilised solid composition samples prepared in Example 2(b) were reconstituted as follows.
  • One of the reconstituted vials was visually inspected using a method based on that of European Pharmacopoeia Method 2.9.20 described above. The method is designed to observe the presence of any visible particles.
  • the solution in the vial was assessed for the presence of sub-visible particles using a HIAC apparatus (trade mark) by using a sub-visible particulate determination method that is based on that defined in United States Pharmacopoeia 36 ⁇ 788> Method 1 ("Light Obscuration Particle Count Test').
  • Method 1 Light Obscuration Particle Count Test'
  • the results must comply with the criteria for "Test 1 . B" for USP 36 ⁇ 788> Method 1 as these define the widest possible acceptable limits for sub-visible particulate matter.
  • This Test states as follows: "Test 1.B (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of less than 100 mL) -The preparation complies with the test if the average number of particles present in the units tested does not exceed 6000 per container equal to or greater than 10 pm and does not exceed 600 per container equal to or greater than 25 pm".
  • 1 ,3,5-triazin-2-yl)phenyl]urea (52mg) was weighed into a 2ml vial.
  • the slurry was heated to 60°C at a rate of 5°C/minute, held at 60°C for 20min. and then cooled at 0.1 °C/minute to 5°C where it was held until it was isolated (24 hours after the start of the heating step).
  • the slurry was filtered through a 0.2 pm nylon centrifuge filter to isolate the crystalline title compound.
  • Citric Acid at pH 2.94 13.3mM Citric Acid at pH 2.94
  • 5.47772g of Citric Acid Anhydrous was added to approximately 75ml_ of WFI.
  • 1.42293g of Sodium Citrate Dihydrate was added to this solution. This was then made to 1 L volume in a volumetric flask using WFI. pH was then recorded.
  • Acid at pH 1.79 0.38864g of Maleic Acid was dissolved in approximately 75ml_ of WFI. This was then made up to 100ml_ volume in a volumetric flask using WFI. pH was then recorded. Acid at pH 2.46 (9) 0.44667g of Malic Acid was dissolved in approximately 75ml_ of WFI. This was then made to 100ml_ volume in a volumetric flask using WFI. pH was then recorded.
  • Acid* was dispensed into a 100ml_ volumetric flask and made up to volume using WFI. pH was then recorded.
  • the stability testing was conducted using three ca. 3mg/ml samples of 1 -(4- ⁇ [4- (dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea for each acid buffer prepared above.
  • orthophosphoric acid would not be suitable for the preparation of pharmaceutical aqueous solution formulations for intravenous administration to a patient at a required API (active pharmaceutical ingredient) concentration.
  • API active pharmaceutical ingredient
  • the stability testing was conducted using three ca. 3mg/ml samples of 1 -(4- ⁇ [4- (dimethylamino)piperidin-l -yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea for each acid buffer prepared above.
  • Citric Acid at pH 2.98 13.3mM Citric Acid at pH 2.98
  • 0.27346g of Citric Acid Anhydrous was dissolved in approximately 40ml_ of WFI.
  • 0.07284g of Sodium Citrate Dihydrate was also added to this solution. This was then dispensed into a 50ml_ volumetric flask and made to volume using WFI. pH was then recorded.
  • the stability testing was conducted using three ca. 4mg/ml samples of 1 -(4- ⁇ [4- (dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea for each acid buffer prepared above.
  • the buffer solutions are prepared using WFI in 10ml (*20ml where indicated in the Table below) volumetric flasks using the following DL-lactic acid weights (** 90% W W DL-LACTIC ACID IN WATER):
  • Samples 1 - 1 1 were placed on a roller bed at room temperature and at 50rpm for ca. 21 .5 hours.
  • Samples 12 and 13 were placed on a roller bed at room temperature and at 50rpm for ca. 23 hours.
  • Samples 14 and 15 were placed on a roller bed at room temperature and at 50rpm for ca. 25 hours.
  • the solution concentration of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea must be less than 6mg/ml and more than 2.5 mole equivalents of DL-lactic acid must be used in the formulation.
  • Samples 1 -1 1 were stored at room temperature without rolling for further time to provide a total experimental period of ca. 72 hours. It was observed that some samples became a solution at the end of the total 72 hour period that were not in solution after the initial ca. 21 .5 hour rolling period.
  • Samples 14 and 15 were stored with rolling at room temperature for further time to provide a total experimental period of ca. 73 hours.
  • a clear solution is also achievable using a solution concentration of 3mg/ml of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea where above 2.5 mole equivalents of DL-lactic acid are used in the formulation.
  • the results above for Samples 14 and 15 show that clear solutions are achievable at a solution
  • a ca. 33.3mM aqueous orthophosphoric acid solution was prepared as follows. 0.32569g of orthophosphoric acid was dispensed into ca. 80mL of water for irrigation. This was made to 100mL volume using water for irrigation in a volumetric flask and the pH was recorded as 1 .92. A 3mg/ml_ concentration of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)- 3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea was desired and this had to take account of a drug potency of 97.1 %.
  • the 3 samples were therefore each diluted to 0.5mg/ml_, 0.1 mg/ml_ and 0.05mg/ml_ to identify if the pH increased to a suitable pH for intravenous administration.
  • the diluted samples were placed on a roller bed overnight in order to reach equilibrium. The pH was also measured. The pH of the samples was as follows:
  • Each of the samples was visually assessed using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background.
  • the sample was also tested by illumination using a narrow (Tyndall) beam light source and then visually inspected from a direction perpendicular to the light beam in order to identify undissolved solid particles. Each sample was observed to be a visually clear solution.
  • Lactic acid is therefore generally more suitable than orthophosphoric acid for the preparation of an aqueous solution formulation for intravenous administration of 1 -(4- ⁇ [4- (dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea according to the invention. 5. Investigation regarding 3mq/ml, 4mq/ml and 5mq/ml aqueous
  • API Three concentrations of API (3, 4 and 5mg/ml_) were desired which had to be corrected to take account of an API potency of 97.1 %.
  • the API weights were determined according to the following calculations.
  • the samples were placed on a roller bed at room temperature and visually assessed using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background.
  • the sample was also tested by illumination using a narrow (Tyndall) beam light source and then visually inspected from a direction perpendicular to the light beam in order to identify undissolved solid particles.
  • the visual analysis was carried out at 24 hour, 48 hour, 72 hour and 6 day periods.
  • the pH of the samples was assessed as follows:
  • orthophosphoric acid dispensed into ca. 75 mL of water for irrigation. This was made to 100 mL volume using water for irrigation in a volumetric flask and the pH was recorded as 1 .94. 3 and 3.5 mg/mL formulations of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea was desired and this had to take account of a drug potency of 97.1 %.
  • the 3mg/ml aqueous formulation used contained ca. 6.8 mole equivalents of orthophosphoric acid.
  • the samples were placed on a roller bed at room temperature for 15 hours.
  • Lactic acid is therefore preferable for the preparation of a clear, particle-free aqueous solution formulation of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea that is suitable for intravenous or parenteral administration.
  • the powder X-ray diffraction (PXRD) analysis was carried out on a Bruker D4 (trade mark) diffractometer using copper radiation (wavelength: 1 .5406A).
  • the tube voltage and amperage were set to 35 kV and 40 mA, respectively.
  • the divergence slit used was v6 and the scattering slit was set at 0.499 mm.
  • a variable receiving slit was used.
  • Diffracted radiation was detected by a Vantec detector.
  • a theta-two theta continuous scan at 5.4 min (0.2 sec/0.018° step) from 2.0 to 55 ° 2 ⁇ was used.
  • a corundum standard was analyzed to check the instrument alignment. The data were collected and analysed using Bruker AXS software.
  • the samples were prepared by placing them on a silicon wafer.
  • DIFFRAC.EVA V3.1 software was used to visualize and evaluate the PXRD spectra.
  • the PXRD data files (.raw) were not processed prior to peak searching.
  • a threshold value of 1.3 and a width value of 0.3 were used to make the preliminary peak assignments.
  • the output of automated assignments was visually checked to ensure validity and adjustments manually made if necessary.
  • peaks were manually assigned within the spectra, if appropriate. A peak at 28.1 ° 2-theta that related to the mounting medium was manually removed from the list.
  • the sample is typically placed onto a flat silicon plate.
  • the sample powder is pressed by a glass slide or equivalent to ensure a random surface and proper sample height.
  • the sample holder is then placed into the instrument.
  • the incident X-ray beam is directed at the sample, initially at a small angle relative to the plane of the holder, and then moved through an arc that continuously increases the angle between the incident beam and the plane of the holder.
  • X-ray powder analyses result from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors (e.g. flat sample errors), (c) calibration errors, (d) operator errors (including those errors present when determining the peak locations), and (e) the nature of the material (e.g. preferred orientation and transparency errors). Calibration errors and sample height errors often result in a shift of all the peaks in the same direction. Small differences in sample height when using a flat holder will lead to large displacements in the PXRD peak positions.
  • this correction factor will bring the measured peak positions from the Bruker into agreement with the expected peak positions and may be in the range of from 0 to 0.2 degree 2-theta.
  • This crystalline form of 1 -(4- ⁇ [4-(dimethylamino)piperidin-1 - yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea L-lactate is distinguished from other known (semi-crystalline) forms of this salt by having characterizing peaks at about 6.5, 15.9, 20.9, 22.1 and 23.1 degrees 2-theta (+/- 0.2 degrees 2-theta).
  • Samples of a lyophilised solid formulation prepared in accordance with the method of Example 2 in 50ml_ clear vials were analysed for chemical degradation after storage at 25°C/60% Relative Humidity (RH) and 40°C/75% RH at a variety of different timepoints. Several samples were evaluated for each condition to allow representative results at the selected timepoints. The 40°C/75% RH samples were tested after 6 months.
  • RH Relative Humidity
  • the 25°C/60% RH samples were tested after 6 months, 12 months, 24 months and 36 months.
  • the samples were tested for chemical purity using High Performance Liquid
  • HPLC Chromatography
  • Sample solvent Add 3 mL of 0.1 N aqueous hydrochloric acid into a 1000 mL volumetric flask and dilute to set volume with the Diluent (Acetonitrile/water, 1 : 1 v/v). Mix well.
  • Standard and Check standard preparations • Accurately prepare two solutions of ca. 2 mg/mL (+/- 10%) of 1 -(4- ⁇ [4- (dimethylamino)piperidin-1 -yl]carbonyl ⁇ phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1 ,3,5-triazin-2-yl)phenyl]urea Reference Standard in Sample solvent, and record the concentrations accurately of both. These are the Standard and Check standard solutions. Produce Standard and Check standard
  • Example 2 by adding 20 mL of water to each vial, shaking the vial to dissolve the solid and wait for the bubbles to disappear. Transfer the solution into a l OOOmL volumetric flask. Rinse each vial at least twice with Diluent and transfer the washings into the volumetric flask. Dilute to the set volume with Diluent.
  • Liquid chromatographic system e.g. Waters 2695 (trade mark) or Agilent 1 100 (trade mark) machine
  • test samples are 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 also measure the retention times and peak area of any peaks present in the sample injection that do not appear in the blank injection.
  • Degradants 3, 5 and 6 were identified as process related impurities which did not change on stability, and so were not reported at the 36 month timepoint.
  • samples of a lyophilised solid formulation prepared in accordance with the method of Example 2 in a 50ml_ clear vial are chemically stable for at least 36 months at 25°C/60% RH and for at least 6 months at 40°C/75% RH.

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Abstract

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

Description

FORMULATIONS OF A PI3K/MTOR-INHIBITOR FOR INTRAVENOUS ADMINISTRATION
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 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 salt thereof, that is a clear solution. Such a formulation is particularly suitable for intravenous administration to a patient.
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 in
WO2009/143313. The compound is an inhibitor of PI3 kinase and mTOR that is useful for the treatment of cancer.
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.
1 -(4-{[4-(Dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin- 4-yl-1 ,3,5-triazin-2-yl)phenyl]urea has the chemical structure:
Figure imgf000002_0001
1 -(4-{[4-(dimethylamino)pipehdin-1 -yl]
carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1 ,3,5-triazin-2-yl)phenyl]urea 1 -(4-{[4-(Dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-
4-yl-1 ,3,5-triazin-2-yl)phenyl]urea may 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.
There is a need to develop a pharmaceutically acceptable formulation of 1 -(4-
{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea that is (a) chemically stable on storage (e.g. at 25°C and 60% RH), and/or (b) that will facilitate effective intravenous (or parenteral) administration of the drug to a mammal, including a human being.
Preferably, the formulation is suitable for intravenous administration of 1 -(4-
{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea in view of the particular pharmacokinetic and bioavailability characteristics of this drug.
It is essential that an intravenous formulation of any drug is a solution to facilitate safe and effective administration to a patient. It must be particle-free, and not form a gel or suspension. A clear, aqueous solution is preferred.
A clear solution is defined as a visually clear solution 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 vessels may occur. Accordingly, in view of the qualitative nature of the visual test, the term "essentially free from any visible particulates" is usually applied when no visible particulate matter is observed.
Particulate matter may be defined as follows:
· speck - discrete particle whose shape cannot be determined without
magnification
• smoke or swirl - fine particles that look like smoke or a tornado and usually originate from the sample 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 glasslike, metallic-looking, etc. The visual inspection can be conducted in accordance with the method defined in European Pharmacopoeia Method 2.9.20 entitled " Particulate
contamination: visible particles". 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. Other validated methods may be also be used.
In European Pharmacopoeia Method 2.9.20 the apparatus (see
"Figure 2.9.20.-1 " shown in Figure 2) consists of a viewing station comprising:
· a matt black panel of appropriate size held in a vertical position
• a non-glare white panel of appropriate size held in a vertical position next to the black panel
• an adjustable lampholder fitted with a suitable, shaded, white-light source and with a suitable light diffuser (a viewing illuminator containing two 13 Watt 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. The Method 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. "
It has now been surprisingly found that the technical problem has been solved by a pharmaceutical aqueous solution formulation comprising
1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1 ,3,5-triazin-2-yl)phenyl]urea, 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
1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1 ,3,5-triazin-2-yl)phenyl]urea, or a phosphate salt thereof, orthophosphoric acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4mg/ml and sufficient orthophosphoric acid is present to provide a clear solution (hereafter "the formulation of the invention").
Such a formulation 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 to prepare a lyophilised solid composition that is chemically stable on storage for preferably at least 2 years, 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.
It has been found that the use of alternative acids to the lactic acid or orthophosphoric acid used in the formulation of the invention, at the preferred concentration of from 2.5-5.5mg/ml of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, results in cloudy formulations containing particulate matter or which gel, and does not lead to the essentially clear, particle-free solutions required for intravenous (or parenteral) administration to a patient.
In respect of the formulations comprising lactic acid:
it has been found that at solution concentrations of 1 -(4-{[4-
(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-
1 ,3,5-triazin-2-yl)phenyl]urea of 6mg/ml or above, the necessary clear solutions at the pH required for intravenous administration to a patient are not obtained, or are not obtained consistently.
preferably the invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 6mg/ml and sufficient lactic acid is present to provide a clear solution.
the concentration of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea in the formulation of the invention may be from 1 to 5.5 mg/ml, from 2 to 5.5 mg/ml, or from 3 to 5.5mg/ml (calculated as the named free base),
preferably, the invention provides a pharmaceutical aqueous solution formulation 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 2.5 to 5.5mg/ml.
preferably, the invention provides a pharmaceutical aqueous solution formulation wherein 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml.
preferably, when the free base of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is used, above 2.5 mole equivalents of lactic acid are present in the formulation of the invention. More preferably, from 3 to 10, from above 2.5 to 8.0, or from 3.5 to 4.5 mole equivalents of lactic acid are present in the formulation of the invention. Most preferably, about 4.1 mole equivalents of lactic acid are present in the formulation of the invention.
preferably, when the free base of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is used, the invention provides a pharmaceutical aqueous solution formulation 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 5.0 to 5.5mg/ml and at least 2.5 mole equivalents of lactic acid are present.
preferably, when the free base of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is used, the invention provides a pharmaceutical aqueous solution formulation wherein 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml and at least 2.5 mole equivalents of lactic acid are present.
preferably, when the free base of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is used, the invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin- 4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml, and at least 2.5 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed,
it should be noted that 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea forms a 1 : 1 (mole equivalent) lactate salt with lactic acid. The formulation of the invention may be prepared using 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 free base or using a lactic acid salt of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea. When the lactic acid salt is used, preferably above 1.5 mole equivalents of lactic acid are used to achieve the presence of the preferred lower limit of above 2.5 mole equivalents of lactic acid in the formulation of the invention, preferably, the invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea lactate, lactic acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml, and at least 1 .5 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed.
DL-lactic acid, D-lactic acid or L-lactic acid, or any combination thereof, may be used in the formulation of the invention. Preferably, DL-lactic acid is used, preferably, the pH of the formulation of the invention is not greater than 3.7. More preferably, the pH of the formulation of the invention is from 3.0 to 3.7, from 3.3 to 3.6, or from 3.4 to 3.5.
in a preferred embodiment, the present invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of up to 5.5 mg/ml, and above 2.5 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed with a pH of no greater than 3.7.
in a preferred embodiment, the present invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml, and about 4.1 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed with a pH of no greater than 3.7.
a crystalline form of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea L-lactate may be used to prepare the formulation of the invention. Preferably, the crystalline form of
1 - (4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin- 4-yl-1 ,3,5-triazin-2-yl)phenyl]urea L-lactate used has a PXRD pattern
(measured using a Bruker D4 diffractometer and copper K-alpha radiation) with major peaks at about 16.2, 17.3, 18.4, 18.9, 19.9, 20.9 and 23.1 degrees
2- theta (+/- 0.2 degrees 2-theta). This crystalline form of 1-(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholi
1 ,3,5-triazin-2-yl)phenyl]urea L-lactate is distinguished from other known forms of this salt by having characterizing peaks at about 6.5, 15.9, 20.9, 22.1 and 23.1 degrees 2-theta (+/- 0.2 degrees 2-theta).
In respect of the formulations comprising orthophosphoric acid:
preferably, the invention provides a pharmaceutical aqueous solution formulation comprising 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin- 1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a clear solution,
preferably, the invention provides a pharmaceutical aqueous solution formulation 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 3.0 to 3.5mg/ml.
preferably, the invention provides a pharmaceutical aqueous solution formulation wherein at least 5 mole equivalents of orthophosphoric acid are used.
preferably, the invention provides a pharmaceutical aqueous solution formulation wherein from 5 to 7 mole equivalents of orthophosphoric acid are used.
in a preferred embodiment the present invention provides a pharmaceutical aqueous solution formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid and water, wherein 1-(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4mg/ml, from 5 to 7 mole equivalents of orthophophoric acid are present and in an amount sufficient to ensure a clear solution is formed. • preferably, the pH of the formulation prepared is from 2-2.5 prior to
intravenous administration. The pH is then preferably adjusted to from 3.0-4.5 for intravenous administration.
• if a phosphate salt of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)- 3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is used, this is preferably prepared using orthophosphoric acid.
If the formulation of the invention is to be freeze-dried to provide a lyophilised solid composition, a bulking agent is preferably 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 used when the total mass of solutes in the formulation is less than 2g/100ml. Bulking agents may also be added to achieve isotonicity with blood. The bulking agent may be selected from a saccharide, sugar alcohol, amino acid or polymer, or be a mixture of two or more 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.
Reconstitution of the lyophilized solid composition may 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 tonicity modifier may then be added prior to use.
Constitution of the lyophilized 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.
A tonicity modifier must 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.
Suitable tonicity modifiers are non-ionic tonicity modifiers such as glycerol, 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.
Aqueous pharmaceutical formulations that are suitable for intravenous administration generally have a pH of from 3 to 9. The formulations of the invention that are to be intravenously administered preferably have a pH of from 3 to 4.5.
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 treated may 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.
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 100-400mg/ml per week.
The following Examples illustrate the preparation of the formulations of the invention.
EXAMPLES EXAMPLE 1
Preparation of a pharmaceutical aqueous solution formulation comprising 5mg/ml 1 - (4-{[4-(dimethylamino)piperidin-1 -yl1carbonyl)phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1 ,3,5-thazin-2-yl)phenyl1urea and DL-lactic acid
D, L-lactic acid (334 mg) was dissolved in water for irrigation to make a solution with a total volume of 100 ml. 1 -(4-{[4-(Dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea (200mg) was dissolved in 37 ml of this lactic acid solution, mixing with an Ultra Turrax T25 (trade mark)
homogeniser for 120 minutes and sonicating the solution for 10 minutes in an ultrasonic bath. The mixture was then stirred overnight with a magnetic stirrer to provide a clear solution. This was made up to 40ml volume with the lactic acid solution using a volumetric flask. The solution was filtered using a 0.2 pm nylon filter into a clean 50 ml vial in a laminar air flow (LAF) cabinet. The first 5 ml of filtered solution was used to wet the filter and was discarded as unrepresentative of the filtered solution. The vial was crimped and sealed using clean lyo-stoppers and flip- off caps. The solution was inspected visually and was found to be a clear, colourless solution. EXAMPLE 2
Preparation of (a) a 5mq/ml pharmaceutical aqueous solution formulation comprising 1 -(4-{[4-(dimethylamino)piperidin-1 -yl1carbonyl)phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1 ,3,5-thazin-2-yl)phenyl1urea, DL-lactic acid and mannitol; and (b) Preparation of a lyophilised solid composition thereof (a) 36, 100g of water for injection was weighed into a vessel. 125.82g of DL- Lactic acid (90.6% purity, parenteral grade) was slowly added and the mixture was stirred until the lactic acid dissolved. 195.3g of 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1 ,3,5-triazin-2-yl)phenyl]urea was slowly added and the mixture was stirred until the material dissolved. 1900g of mannitol powder (parenteral) was gradually added and the mixture was stirred until the material dissolved. Water for injection was added to make the solution up to a total weight of 38,760g and the solution was stirred for a further 10 minutes. The pH was checked and found to be 3.4 with a solution temperature of 29.3°C. The solution was sterile filtered through an in-line 0.45 pm clarification filter and 0.22 pm filter assembly. This solution was then filled into 50 ml_ vials with a target fill volume of 20.8 ml_ for each vial. The vials were each partially stoppered (not sealed) with a 20mm Gray Lyo D777-1 V10-F597W FluroTec Siliconised (trade mark) stopper.
(b) These vials were then loaded into stainless steel trays and inserted into a LSL1000 (trade mark) freeze dryer. The shelf temperature was set at 5°C. The freeze drying cycle was run using the method below.
Pressure
Temperature Time mbar
Treatment Step Rate/Hold (°C) (min) (Pascals)
Loading 5 atmospheric
Stabilisation 1 hold 5 120 atmospheric
Freezing 2 rate -25 300 atmospheric
3 hold -25 180 atmospheric
4 rate -12 130 atmospheric
5 hold -12 180 atmospheric 6 rate -40 93 atmospheric
7 hold -40 240 atmospheric
8 hold -40 60 atmospheric
Evacuation 9 hold -40 30 0.200 (20)
Primary Drying 10 rate 10 100 0.200 (20)
1 1 hold 10 1440 0.200 (20)
Secondary 12 rate 40 60 0.200 (20)
Drying
13 hold 40 360 0.200 (20)
14 rate 25 30 0.200 (20)
15 hold 25 30 0.200 (20)
16 rate 25 10 0.200 (20)
The freeze dryer was back-filled with sterile filtered nitrogen to a set point of ca. 700mbar (70,000 Pascals), and the vials were fully closed using the stoppers. The freeze dryer was then vented to atmospheric pressure using sterile filtered air and the vials were unloaded from the freeze dryer.
Each vial contained the freeze dried (lyophilised) formulation as a white solid.
EXAMPLE 3 Reconstitution of a 5mq/ml pharmaceutical aqueous solution formulation comprising 1 -(4-{r4-(dimethylamino)piperidin-1 -yl1carbonyl)phenyl)-3-r4-(4,6-dimorpholin-4-yl- 1 ,3,5-thazin-2-yl)phenyl1urea, DL-lactic acid and mannitol from a lyophilised solid composition The vials of lyophilised solid composition samples prepared in Example 2(b) were reconstituted as follows.
Approximately 25ml of water for injection was placed into a syringe and a 0.2 micron PVDF filter membrane was attached to the syringe. Approximately 5ml of the water was filtered through the membrane and discarded. 20ml of the water remaining in the syringe was then filtered into the 50ml vial containing the lyophilised composition as prepared in Example 2(b). The mixture was swirled in the vial until a clear, colourless solution was achieved.
The reconstituted solution was analysed as follows:
(a) pH
The pH of the solution in the vial was measured as pH =3.52 at 23.2 degrees °C.
(b) Visual appearance of Reconstituted Solution
One of the reconstituted vials was visually inspected using a method based on that of European Pharmacopoeia Method 2.9.20 described above. The method is designed to observe the presence of any visible particles.
By this method the solution in the vial was visually inspected in a Verivide DCAC60 (trade mark) light cabinet using a light meter reading of 3250 lux against a matt black panel and a white panel.
The result showed a clear, colourless solution, free from particulate matter, had been achieved on reconstitution.
(c) Analysis for sub-visible particles
The solution in the vial was assessed for the presence of sub-visible particles using a HIAC apparatus (trade mark) by using a sub-visible particulate determination method that is based on that defined in United States Pharmacopoeia 36 <788> Method 1 ("Light Obscuration Particle Count Test'). In order for a solution to be suitable for parenteral or intravenous administration the results must comply with the criteria for "Test 1 . B" for USP 36 <788> Method 1 as these define the widest possible acceptable limits for sub-visible particulate matter. This Test states as follows: "Test 1.B (Solutions for parenteral infusion or solutions for injection supplied in containers with a nominal content of less than 100 mL) -The preparation complies with the test if the average number of particles present in the units tested does not exceed 6000 per container equal to or greater than 10 pm and does not exceed 600 per container equal to or greater than 25 pm".
By this method, firstly, 10 vial solution samples were pooled. Four samples of not less than 5ml_ each were removed from the pooled solution and, for each sample, the number of particles equal to or greater than 10 pm and 25 pm were counted using a HIAC HRLD 400 (trade mark) sensor. The result obtained for the first sample was disregarded. For each of the remaining three samples, the mean number of particles per container was calculated and compared with the
requirements of USP 36 <788> Test 1 .B. These samples each met the acceptance criteria of USP 36 <788> Test 1 .B for a solution to be suitable for parenteral or intravenous administration
EXAMPLE 4
Preparation of a crystalline form of 1 -(4-{r4-(dimethylamino)piperidin-1 - yl1carbonyl)phenyl)-3-r4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl1urea L-lactate
Preparation A:
1 -(4-{[4-(Dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1 ,3,5-triazin-2-yl)phenyl]urea (52mg) was weighed into a 2ml vial. A 22 mg/ml solution of L-lactic acid in 98:2 v/v ethyl acetate:dimethylformamide (0.5ml) was added to the vial. This slurry was stirred at about 23°C for 24 hours. The slurry was then filtered through a 0.2 pm nylon centrifuge filter to isolate the crystalline title compound.
The product was analysed by PXRD (see "Investigation 7" below) using a Bruker D4 (trade mark) diffractometer and copper K-alpha radiation and gave a pattern that is shown in FIGURE 1 . Preparation B:
1 -(4-{[4-(Dimethylamino)piperidin-1 ^
1 ,3,5-triazin-2-yl)phenyl]urea (52mg) was weighed into a 2ml vial. A 22 mg/ml solution of L-lactic acid in 98:2 v/v ethyl acetate:dimethylformamide (0.5ml) was added to the vial. The slurry was heated to 60°C at a rate of 5°C/minute, held at 60°C for 20min. and then cooled at 0.1 °C/minute to 5°C where it was held until it was isolated (24 hours after the start of the heating step). The slurry was filtered through a 0.2 pm nylon centrifuge filter to isolate the crystalline title compound.
The product was analysed by PXRD (see "Investigation 7" below) using a Bruker D4 diffractometer and copper K-alpha radiation and gave a pattern consistent with that shown in FIGURE 1.
The following investigations were conducted in respect of the present invention.
INVESTIGATIONS
1. Investigation regarding 3mq/ml aqueous formulations of 1-(4- 4- (dimethylamino)piperidin-1-vncarbonyl)phenyl)-3-r4-(4.6-dimorpholin-4- yl-1,3,5-triazin-2-yl)phenvnurea with various acids
Procedure Nine individual acidic buffer solutions were prepared as follows in order to use ca. 6.8 mole equivalents of each acid (except where indicated):
Buffer (Buffer Number) Method
33.3mM Citric Acid at pH 2.94 (1) 5.47772g of Citric Acid Anhydrous was added to approximately 75ml_ of WFI. 1.42293g of Sodium Citrate Dihydrate was added to this solution. This was then made to 1 L volume in a volumetric flask using WFI. pH was then recorded.
33.3mM Succinic Acid at pH 2.77 (2) 0.39386g of Succinic Acid was added to approximately 80ml_ of WFI. This was then made to 100ml_ volume in a volumetric flask using WFI. pH was then recorded.
33.3mM Acetic Acid at pH 3.25 (3) 1.96522g of Glacial Acetic Acid was added to approximately 75ml_ of WFI. 0.077013g of Sodium Acetate Trihydrate was added to this solution. This was then made to 1 L volume in a volumetric flask using WFI. pH was then recorded.
phoric Acid at pH 1.91 3.26683g of Orthophosphoric Acid was (4) added to approximately 500ml_ of WFI.
This was then made to 1 L volume in a volumetric flask using WFI. pH was then recorded.
ine at pH 6.06 (5) 2.50191 g of Glycine was added to
approximately 500ml_ of WFI. This was then made to 1 L volume in a volumetric flask using WFI. pH was then recorded.c Acid at pH 2.22 (6) 0.50018g of Tartaric Acid was added to approximately 75ml_ of WFI. This was then made to 100ml_ volume in a volumetric flask using WFI. pH was then recorded. Acid at pH 2.47 (7) 0.43090g of Racemic Mixture DL Lactic.8 mole equivalents of Acid* was dissolved in approximately acid) 75ml_ of WFI. This was then made to
100ml_ volume in a volumetric flask using WFI. pH was then recorded.
Acid at pH 1.79 (8) 0.38864g of Maleic Acid was dissolved in approximately 75ml_ of WFI. This was then made up to 100ml_ volume in a volumetric flask using WFI. pH was then recorded. Acid at pH 2.46 (9) 0.44667g of Malic Acid was dissolved in approximately 75ml_ of WFI. This was then made to 100ml_ volume in a volumetric flask using WFI. pH was then recorded.
33mM DL-Lactic Acid at pH 2.60 (10) 0.33915g of Racemic Mixture DL Lactic
Acid* was dispensed into a 100ml_ volumetric flask and made up to volume using WFI. pH was then recorded.
(WFI = water for irrigation) (*90% w/w DL-Lactic acid in water)
The stability testing was conducted using three ca. 3mg/ml samples of 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea for each acid buffer prepared above. These samples were prepared using a target weight of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea of 15.45mg (due to 97.1 % API Activity) by weighing the required quantity into each vial as follows:
Figure imgf000020_0001
5mL of the respective buffer was introduced to the weighed sample in the vials and the vials were each closed by a crimped cap then sealed with a protective film. The vials were placed on a roller bed in an oven at 25°C for 5 days. Results At the end of the 5 day period the pH of each sample was measured and a visual observation of each sample was made using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow (Tyndall) beam light source and then visually inspected from a direction
perpendicular to the light beam in order to identify undissolved solid particles.
Six vials were found to have fallen off the roller during the course of the experiment meaning the exact time those vials actually rolled is unknown. These samples are marked in the "pH results" and "visual observations" tables below with an asterix (*). pH results after 5 days at 25°C
Buffer number N=1 N=2 N=3
1 (Citric Acid) 3.02 3.01 3.01
2 (Succinic Acid) 3.14 3.14 3.15
3 (Acetic Acid) 3.86 3.87 3.88
4 (Orthophosphoric Acid) 2.01 2.07 2.04
5 (Glycine) 6.45 6.71 6.51
6 (Tartaric Acid) 2.54* 2.37* 2.38*
7 (DL-Lactic Acid) 2.91 * 2.91 2.91
8 (Maleic Acid) 1 .91 1 .87* 1 .90
9 (Malic Acid) 2.71 2.70* 2.70
10 (DL-Lactic Acid) 3.07 3.21 3.27 Visual Observations of samples after 5 days at 25°C
Figure imgf000022_0001
Conclusion
The results show that the 3mg/ml samples containing 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea and DL - lactic acid achieved a clear solution after 5 days at 25°C. All the other samples except one (orthophosphoric acid - N=2 sample) failed to achieve a clear solution. As such, acids other than DL-lactic acid and
orthophosphoric acid would not be suitable for the preparation of pharmaceutical aqueous solution formulations for intravenous administration to a patient at a required API (active pharmaceutical ingredient) concentration. 2. Investigation regarding 3mq/ml and 4mg/ml aqueous formulations of 1 - (4-fr4-(dimethylamino)piperidin-1 -vncarbonyl>phenyl)-3-r4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenvnurea with various acids Procedure
(a) Four individual acidic buffer solutions were prepared as follows for use in the 3mg/ml formulations, in order to use ca. 6.8 mole equivalents of the respective acid:
Figure imgf000023_0001
(WFI = water for irrigation)
The stability testing was conducted using three ca. 3mg/ml samples of 1 -(4-{[4- (dimethylamino)piperidin-l -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea for each acid buffer prepared above. These samples were prepared using a target weight of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea of 5.45mg (due to 97.1 % API Activity) by weighing the required quantity into each vial s follows:
Figure imgf000024_0001
(b) Individual acidic buffer solutions were prepared as follows for use in the
4mg/ml formulations, in order to use ca. 5.1 mole equivalents of the respective acid (except where indicated):
Buffer (Buffer Number) Method
33.3mM Citric Acid at pH 2.98 (1) 0.27346g of Citric Acid Anhydrous was dissolved in approximately 40ml_ of WFI. 0.07284g of Sodium Citrate Dihydrate was also added to this solution. This was then dispensed into a 50ml_ volumetric flask and made to volume using WFI. pH was then recorded.
33.3mM Succinic Acid at pH 2.79 (2) 0.20084g of Succinic Acid was dissolved in approximately 40ml_ of WFI. This was dispensed into a 50ml_ volumetric flask and made to volume using WFI. pH was then recorded.
33.3mM Acetic Acid at pH 3.35 (3) 0.1021 g of Glacial Acetic Acid was
dissolved in approximately 40ml_ of WFI. 0.00528g of Sodium Acetate Trihydrate was also added to this solution. This was then dispensed into a 50ml_ volumetric flask and made to volume using WFI. pH was then recorded.
33.3mM Orthophosphoric Acid at pH 0.16909g of Orthophosphoric Acid was 1.87 (4) dissolved in approximately 40ml_ of WFI.
This was then dispensed into a 50ml_ volumetric flask and made to volume using WFI. pH was then recorded.
33.3mM Tartaric Acid at pH 2.28 (5) 0.25180g of (D)-Tartaric Acid was dissolved in approximately 40ml_ of WFI.
This was then dispensed into a 50ml_ volumetric flask and made to volume using WFI. pH was then recorded.
33.3mM Hydrochloric Acid at pH 1.51 6.7ml_ of 1 M aqueous HCI was dispensed (6) using a positive displacement pipette into a 200ml_ volumetric flask, this was then made to volume with WFI and then using a positive displacement pipette, an extra 1 ml_ of WFI was added to reach the correct molarity. The pH was then recorded.
43mM (DL)-Lactic Acid at pH 2.53 (7) 0.21400g of (DL)-Lactic Acid* was
(in order to use 6.6 mole equivalents of dissolved in approximately 40ml_ of WFI. acid) This was then dispensed into a 50ml_ volumetric flask and made to volume using WFI. pH was then recorded.
3.5mM Maleic Acid at pH 2.55 (8) 0.02057g of Maleic Acid was dissolved in
(in order to use 0.5 mole equivalents of approximately 40ml_ of WFI. This was then acid) dispensed into a 50ml_ volumetric flask and made to volume using WFI. pH was then recorded.
3.5mM Malic Acid at pH 3.08 (9) 0.02357g of Malic Acid was dissolved in
(in order to use 0.5 mole equivalents of approximately 40ml_ of WFI. This was then acid) dispensed into a 50ml_ volumetric flask and was made to volume using WFI. pH was then recorded.
33.3mM (D)-Lactic Acid at pH 2.68 (10) 100mg of (D)-Lactic Acid was dissolved in
33.3ml_ of WFI in a volumetric flask. pH was then recorded.
33.3mM (L)-Lactic Acid at pH 2.72 (11) 153.65mg of (L)-Lactic Acid was dissolved in 40ml_ of WFI. This was then poured into a 50ml_ volumetric flask and made to volume using WFI. pH was then recorded.
33.3mM (DL)-Lactic Acid at pH 2.60 0.33915g of (DL)-Lactic Acid* was
(12) dispensed into a 100ml_ volumetric flask.
This was then made to 100ml_ volume with WFI. pH was then recorded.
33.3mM Maleic Acid at pH 1.72 (13) 0.19385g of Maleic Acid was added to approximately 40ml_ of WFI. This was poured into a 50ml_ Volumetric flask then made to volume with WFI. pH was then recorded.
33.3mM Malic Acid at pH 2.30 (14) 0.22332g of Malic Acid was added to
approximately 40ml_ of WFI. This was poured into a 50ml_ Volumetric flask then made to volume with WFI. pH was then recorded.
(WFI=water for irrigation) (*90% w/w DL-Lactic acid in water)
The stability testing was conducted using three ca. 4mg/ml samples of 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea for each acid buffer prepared above. These samples were prepared using a target weight of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea of 20.60mg (due to 97.1 % API Activity) by weighing the required quantity into each vial as follows:
Figure imgf000026_0001
For the formulations of both (a) and (b) above, 5ml_ of the respective buffer was introduced to the weighed sample in the vial and the vials were each closed by a crimped cap and sealed with a protective film. The vials were placed on a roller bed in an oven at 25°C for 5 days. Results
At the end of the 5 day period the pH of each sample was measured and a visual observation of each sample was made made using a light box as described in
European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow (Tyndall) beam light source and then visually inspected from a direction perpendicular to the light beam in order to identify undissolved solid particles. pH after 5 days at 25°C
3mq/mL
Figure imgf000027_0001
4mg/mL
Buffer Initial pH N=1 N=2 N=3
33.3mM Citric 2.98 3.07 3.09 3.08
Acid
33.3mM Succinic 2.79 3.19 3.17 3.15
Acid
33.3mM Acetic 3.35 4.07 4.09 4.08
Acid
33.3mM 1 .87 2.09 2.06 2.05
Orthophosphoric Acid
33.3mM Tartaric 2.28 2.41 2.42 2.42
Acid
33.3mM 1.51 1 .63 1.62 1.65
Hydrochloric Acid
43mM (DL)-Lactic 2.53 3.07 3.05 3.04
Acid
3.5mM Maleic 2.55 4.70 4.66 4.66
Acid
3.5mM Malic Acid 3.08 5.14 5.1 1 5.1 1
33.3mM (D)- 2.68 3.27 3.31 3.34
Lactic Acid
33.3mM (L)- 2.72 3.36 3.37 3.38
Lactic Acid
33.3mM (DL)- 2.60 3.23 3.23 3.28
Lactic Acid
33.3mM Maleic 1.72 2.03 2.04 2.05
Acid
33.3mM Malic 2.30 2.70 2.74 2.73
Acid
Visual Observations of samples after 5 days at 25°C
3mq/mL
Figure imgf000028_0001
4mq/mL
Buffer N=1 N=2 N=3
33.3mM Citric Acid Haze Present Haze Present Haze Present 33.3mM Succinic Haze Present Haze Present Haze Present
Acid
33.3mM Acetic Acid Not in Solution Not in Solution Not in Solution
33.3mM Gelling Occurred Gelling Occurred Gelling Occurred
Orthophosphonc Acid
33.3mM Tartaric Acid Haze Present Haze Present Haze Present
33.3mM Hydrochloric Possible Gel/Haze Possible Gel/Haze Possible Gel/Haze
Acid Present Present Present
43mM (DL)-Lactic Clear Clear Clear
Acid
3.5mM Maleic Acid Possible Gel/Haze Possible Gel/Haze Possible Gel/Haze
Present Present Present
3.5mM Malic Acid Haze Present Haze Present Haze Present
33.3mM (D)-Lactic Clear Clear Clear
Acid
33.3mM (L)-Lactic Clear Clear Clear
Acid
33.3mM (DL)-Lactic Clear Clear Clear
Acid
33.3mM Maleic Acid Haze Present Haze Present Haze Present
33.3mM Malic Acid Haze Present Haze Present Haze Present
Conclusion
The results show that the 3mg/ml and 4mg/ml samples containing 1 -(4-{[4- (dimethylamino)piperidin-l -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea and D-lactic acid, L-lactic acid or DL-lactic acid achieved a clear solution after 5 days at 25°C.
The results show that the 3mg/ml samples containing 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea and orthophosphonc acid also achieved a clear solution after 5 days at 25°C.
All the other samples failed achieve a clear solution and acids other than DL-lactic acid, D-lactic acid, L-lactic acid and orthophosphonc acid would not be suitable for the preparation of pharmaceutical aqueous solution formulations for intravenous administration to a patient at a required API concentration. 3. Investigation regarding aqueous formulations of 1-(4-(Γ4-
(dimethylamino)piperidin-1 -yl1carbonyl>phenyl)-3-r4-(4,6-dimorpholin-4- yl-1 ,3,5-triazin-2-yl)phenvnurea with DL-lactic acid at varying H and concentration
Procedure
(a) Buffer solutions for use in the preparation of 3mg/ml, 5mg/ml, 5.5mg/ml, 6mg/ml and 6.5mg/ml formulations of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea were prepared according to the following calculations (WFI = water for irrigation) (* 90% w/w DL-LACTIC ACID IN WATER). · 3mg/mL @ 0.9 Mole Equivalence at 10mL Scale equals 4.39mg of DL-Lactic Acid* in 10mL WFI. (1)
• 3mg/mL @ 2.25 Mole Equivalence at 10mL Scale equals 10.98mg of DL- Lactic Acid* in 10mL WFI. (2)
• 3mg/mL @ 3.7 Mole Equivalence at 10mL Scale equals 17.99mg of DL-Lactic Acid* in 10mL WFI. (3)
• 5mg/mL @ 0.9 Mole Equivalence at 10mL Scale equals 7.32mg of DL-Lactic Acid* in 10mL WFI. (4)
• 5mg/mL @ 2.25 Mole Equivalence at 10mL Scale equals 18.29mg of DL- Lactic Acid* in 10mL WFI. (5)
• 5mg/mL @ 3.7 Mole Equivalence at 10mL Scale equals 30mg of DL-Lactic Acid* in 10mL WFI. (6)
• 5mg/mL @ 7.2 Mole Equivalence at 10mL Scale equals 58.54mg of DL-Lactic Acid* in 10mL WFI. (7)
· 5mg/mL @ 10.8 Mole Equivalence at 10mL Scale equals 87.80mg of DL- Lactic Acid* in 10mL WFI. (8) 5.5mg/ml_ @ 2.25 Mole Equivalence at 10ml_ Scale equals 20.12mg of DL- Lactic Acid* in 10mL WFI. (9)
5.5mg/mL @ 3.7 Mole Equivalence at 10mL Scale equals 33mg of DL-Lactic Acid* in 10mL WFI. (10)
5.5mg/mL @ 10.8 Mole Equivalence at 10mL Scale equals 96.58mg of DL- Lactic Acid* in 10mL WFI. (11)
6mg/mL @ 3.7 Mole Equivalence at 10mL Scale equals 36mg of DL-Lactic Acid* in 10mL WFI. (12)
6mg/mL @ 3.7 Mole Equivalence at 20mL Scale equals 72mg of DL-Lactic Acid* in 20mL WFI. (14)
6.5mg/mL @ 3.7 Mole Equivalence at 10mL Scale equals 39mg of DL-Lactic Acid* in 10mL WFI. (13)
6.5mg/mL @ 3.7 Mole Equivalence at 20mL Scale equals 78mg of DL-Lactic Acid* in 10mL WFI. (15)
The buffer solutions are prepared using WFI in 10ml (*20ml where indicated in the Table below) volumetric flasks using the following DL-lactic acid weights (** 90% W W DL-LACTIC ACID IN WATER):
Buffer Weight** (mg) Actual mole PH
number equivalence
1 3.91 0.8 3.14
2 12.12 2.5 2.86
3 18.16 3.7 2.69
4 6.97 0.9 2.99
5 19.07 2.3 2.68
6 30.80 3.8 2.55 7 57.10 7.0 2.41
8 87.82 10.8 2.30
9 20.36 2.3 2.67
10 33.37 3.7 2.56
11 100.33 1 1 .2 2.27
12 35.93 3.6 2.55
13 41 .84 3.9 2.50
14 70.9* 3.6 2.50
15 78.6* 3.7 2.45
(b) The following quantities of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea were weighed into vials (n.b. 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea has an activity of 97.1 % and the target weights below were corrected for this activity). re. Buffer Target Weight Actual Weight
number (mg) (mg)
1 15.45 15.53
2 15.45 15.52
3 15.45 15.57
4 25.75 25.68
5 25.75 25.70
6 25.75 25.76
7 25.75 25.82
8 25.75 25.77
9 28.32 28.38
10 28.32 28.41 11 28.32 28.34
12 30.90 31 .22
13 33.47 33.61
14 30.90 N=1 30.83
N=2 30.98
N=3 30.81
15 33.47 N=1 33.49
N=2 33.35
N=3 33.38
5mL of the corresponding DL-lactic acid buffer was added to the API in the vial and each vial was then closed with a crimped cap and sealed using protective film. Samples 1 - 1 1 were placed on a roller bed at room temperature and at 50rpm for ca. 21 .5 hours.
Samples 12 and 13 were placed on a roller bed at room temperature and at 50rpm for ca. 23 hours.
Samples 14 and 15 were placed on a roller bed at room temperature and at 50rpm for ca. 25 hours.
Results after ca. 21 .5 / 23 / 25 hour periods
At the end of the specified rolling period the pH of each sample was measured and a visual observation of each sample was made made using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow (Tyndall) beam light source and then visually inspected from a direction perpendicular to the light beam in order to identify undissolved solid particles. Sample # PH
1 4.09
2 3.71
3 3.47
4 4.08
5 3.75
6 3.37
7 3.03
8 2.83
9 3.81
10 3.48
11 2.81
12 3.31
13 3.24
14 N=1 3.27
N=2 3.28
N=3 3.28
15 N=1 3.26
N=2 3.26
N=3 3.27
Visual assessment
Sample # Visual Appearance
1 Not in Solution
2 Not in Solution 3 Clear
4 Not in Solution
5 Not in Solution
6 Clear
7 Clear
8 Clear
9 Not in Solution
10 Clear
11 Clear
12 Haze Present
13 Haze Present
14 N=1 Clear
N=2 Clear
N=3 Clear
15 N=1 Clear
N=2 Clear
N=3 Clear
The following observations were made:
• Samples 7, 8 & 1 1 appeared to have become solutions within 2 hours of being placed on the roller bed
· Sample 6 appeared to have become a solution within 4 hours of being placed on the roller bed
• Samples 3 and 10 appeared to have become a solution within 20 hours of being placed on the roller bed. Conclusion
After the ca. 24 hour period it can be concluded that to achieve a clear solution the solution concentration of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea must be less than 6mg/ml and more than 2.5 mole equivalents of DL-lactic acid must be used in the formulation. However, the results above for Samples 14 and 15 show that clear solutions are achievable at a solution concentration of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea of both 6mg/ml and 6.5mg/ml with 3.6 and 3.7 mole equivalents, respectively, of DL-lactic acid. These results for Samples 14 and 15, when compared with those for Samples 12 and 13, reflect the fact a metastable zone likely exists in which both clear and non-clear solutions may result.
Results after 72 hour period
After the ca. 21 .5 hour rolling periods above, Samples 1 -1 1 were stored at room temperature without rolling for further time to provide a total experimental period of ca. 72 hours. It was observed that some samples became a solution at the end of the total 72 hour period that were not in solution after the initial ca. 21 .5 hour rolling period.
After the ca. 25 hour rolling periods above, Samples 14 and 15 were stored with rolling at room temperature for further time to provide a total experimental period of ca. 73 hours.
These samples were visually assessed made using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow (Tyndall) beam light source and then visually inspected from a direction perpendicular to the light beam in order to identify undissolved solid particles. The pH was also measured. The results were as follows:
(i) Visual assessment after 72 hours Sample # Visual Appearance
1 Not in Solution
2 Haze Present
3 Clear
4 Not in Solution
5 Clear
6 Clear
7 Clear
8 Clear
9 Clear
10 Clear
11 Clear
14 N=1 Clear
N=2 Clear
N=3 Clear
15 N=1 Clear
N=2 Clear
N=3 Clear
(ii) Comparison of pH results and visual assessments after ca. 24 hour and 72 hour periods
PH Visual Assessment
Target /
Sample Concentration Actual Buffer ca. 24 72
24 hours 72 hours Number (mg/mL) Mole PH hours hours
Equivalence
Not in Not in
1 3 0.9 / 0.8 3.14 4.09 4.12
Solution Solution
2 3 2.25 / 2.5 2.86 3.71 7.31 Not in Haze Solution Present
3 3.7/3.7 2.69 3.47 3.41 Clear Clear
Not in Not in
5 0.9/0.9 2.99 4.08 4.11
Solution Solution
Not in
5 2.25/2.3 2.68 3.75 3.74 Clear
Solution
5 3.7/3.8 2.55 3.37 3.35 Clear Clear
5 7.2/7.0 2.41 3.03 2.98 Clear Clear
5 10.8/10.8 2.3 2.83 2.78 Clear Clear
Not in
5.5 2.25/2.3 2.67 3.81 3.75 Clear
Solution
5.5 3.7/3.7 2.56 3.48 3.41 Clear Clear
5.5 10.8/11.2 2.27 2.81 2.75 Clear Clear
6.0 3.7/3.6 2.55 3.31 Haze
present
6.5 3.7/3.9 2.50 3.24 Haze
present
6.0 3.7/3.6 2.50 N=1 N=1 N=1 N=1
3.27, 3.26, Clear, Clear, N=2 N=2 N=2 N=2 3.28, 3.24, Clear, Clear, N=3 N=3 N=3 N=3 3.28 3.27 Clear Clear
6.5 3.7/3.7 2.45 N=1 N=1 N=1 N=1
3.26, 3.25, Clear, Clear, N=2 N=2 N=2 N=2 3.26, 3.26, Clear, Clear, N=3 N=3 N=3 N=3 3.27 3.29 Clear Clear Conclusion
After the total 72 hour experimental period it may be concluded that a clear solution is achievable using a solution concentration of 5 and 5.5mg/ml of 1 -(4-{[4- (dimethylamino)piperidin-l -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea where at least 2.3 mole equivalents of DL-lactic acid are used in the formulation. A clear solution is also achievable using a solution concentration of 3mg/ml of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea where above 2.5 mole equivalents of DL-lactic acid are used in the formulation. The results above for Samples 14 and 15 show that clear solutions are achievable at a solution
concentration of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea of both 6mg/ml and 6.5mg/ml with 3.6 and 3.7 mole equivalents, respectively, of DL-lactic acid. These results for Samples 14 and 15, when compared with those for Samples 12 and 13, reflect the fact a metastable zone likely exists in which both clear and non-clear solutions may result.
4. Investigation regarding 3mq/ml aqueous formulations of 1-(4-IT4-
(dimethylamino)piperidin-1 -yl1carbonyl>phenyl)-3-r4-(4,6-dimorpholin-4- yl-1 ,3,5-triazin-2-yl)phenvnurea with 6.8 mole eguivalents of
orthophosphoric acid Procedure
A ca. 33.3mM aqueous orthophosphoric acid solution was prepared as follows. 0.32569g of orthophosphoric acid was dispensed into ca. 80mL of water for irrigation. This was made to 100mL volume using water for irrigation in a volumetric flask and the pH was recorded as 1 .92. A 3mg/ml_ concentration of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)- 3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea was desired and this had to take account of a drug potency of 97.1 %. A scale of 10mL was decided upon and therefore the target weight of 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea was 30.9mg. Three samples of API were prepared using the following weights in each 20ml_ vial:
Figure imgf000040_0001
10ml_ of the orthophosphoric acid buffer prepared above was dispensed, using an air displacement pipette, into each vial. The vials were each closed with a crimped cap and sealed with protective film. The samples were placed on a roller bed at room temperature for ca. 19 hours.
These samples were visually assessed using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow (Tyndall) beam light source and then visually inspected from a direction
perpendicular to the light beam in order to identify undissolved solid particles. The pH was also measured. The results were as follows:
Visual Final pH
Assessment
N=1 Clear 2.15
N=2 Clear 2.15 N=3 Clear 2.17
Dilutions
Although clear, particle-free solutions had been obtained by the above method, the pH of each sample is too low to be preferred for intravenous
administration for which a pH of from 3 to 4.5 is preferred.
The 3 samples were therefore each diluted to 0.5mg/ml_, 0.1 mg/ml_ and 0.05mg/ml_ to identify if the pH increased to a suitable pH for intravenous administration. The diluted samples were placed on a roller bed overnight in order to reach equilibrium. The pH was also measured. The pH of the samples was as follows:
0.5mg/ml_
Figure imgf000041_0001
Each of the samples was visually assessed using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow (Tyndall) beam light source and then visually inspected from a direction perpendicular to the light beam in order to identify undissolved solid particles. Each sample was observed to be a visually clear solution.
Conclusion
The results show that it is possible to formulate a clear, particle-free 3mg/ml aqueous solution formulation of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea with 6.8 mole equivalents of orthophosphoric acid. However, the pH of this formulation, or a reconstituted formulation thereof, would not be suitable for intravenous
administration and therefore it would have to subsequently diluted below 0.5mg/ml_ to achieve a solution pH suitable for intravenous administration.
When these results are compared to the results obtained for the lactic acid formulations above, the pH and 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea concentrations achievable are lower when using orthophosphoric acid. Lactic acid is therefore generally more suitable than orthophosphoric acid for the preparation of an aqueous solution formulation for intravenous administration of 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea according to the invention. 5. Investigation regarding 3mq/ml, 4mq/ml and 5mq/ml aqueous
formulations of 1 -(4-f r4-(dimethylamino)piperidin-1 -vncarbonvDphenyl)- 3-r4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenvnurea with acetic acid
Procedure
In order to prepare a 33.3mM acetic acid solution 0.2071 g of glacial acetic acid was dispensed into a 250ml_ glass beaker and approximately 80ml_ of WFI (water for irrigation) was added.
0.0138g of sodium acetate trihydrate was added and dissolved into solution. The solution was made to 100ml_ volume in a volumetric flask using WFI and the pH was recorded as 3.35.
Three concentrations of API (3, 4 and 5mg/ml_) were desired which had to be corrected to take account of an API potency of 97.1 %. The API weights were determined according to the following calculations.
• 30mg active is 30.9mg 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea
• 40mg active is 41 .2mg 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea · 50mg active is 51 .49mg 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea
The following weights were dispensed into 20ml_ glass vials:
Figure imgf000043_0001
10mL of the acetic acid buffer prepared above was introduced into each of the weighed samples. The vials were each closed with a crimped cap and sealed with protective film.
The samples were placed on a roller bed at room temperature and visually assessed using a light box as described in European Pharmacopoeia Method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow (Tyndall) beam light source and then visually inspected from a direction perpendicular to the light beam in order to identify undissolved solid particles. The visual analysis was carried out at 24 hour, 48 hour, 72 hour and 6 day periods.
Results
No sample had achieved a clear solution after any of these 24 hour, 48 hour, 72 hour and 6 day periods.
The pH of the samples was assessed as follows:
(a) pH Check after 48 hours
Buffer initial pH = 3.35
(i) re. 3mq/mL samples
Figure imgf000044_0001
(ii) re. 4mq/mL samples
N=1 3.94
N=2 3.95
N=3 3.95 (iii) re. 5mq/mL samples
Figure imgf000045_0001
(b) pH Check after 6 days (i) re. 3mq/mL samples
Figure imgf000045_0002
(ii) re. 4mq/mL samples
Figure imgf000045_0003
(Hi) re. 5mq/mL samples
Figure imgf000045_0004
Conclusion The results show that at 3, 4 and 5 mg/ml concentrations, 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea does not produce a clear solution using 33.3 mM acetic acid. The 3mg/ml aqueous formulation used contained ca. 6.8 mole equivalents of acetic acid. The 4mg/ml aqueous formulation used contained ca. 5.1 mole equivalents of acetic acid. The 5mg/ml aqueous formulation used contained ca. 4.1 mole
equivalents of acetic acid.
6. Investigation regarding 3 and 3.5mq/ml aqueous formulations of 1-(4-IT4-
(dimethylamino)piperidin-1-yl1carbonyl>phenyl)-3-r4-(4,6-dimorpholin-4- yl-1,3,5-triazin-2-yl)phenvnurea with orthophosphoric acid A 33.3 mM aqueous orthophosphoric acid solution was prepared as follows.
0.32767 g of orthophosphoric acid was dispensed into ca. 75 mL of water for irrigation. This was made to 100 mL volume using water for irrigation in a volumetric flask and the pH was recorded as 1 .94. 3 and 3.5 mg/mL formulations of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea was desired and this had to take account of a drug potency of 97.1 %.
The 3mg/ml aqueous formulation used contained ca. 6.8 mole equivalents of orthophosphoric acid. The 3.5mg/ml aqueous formulation used contained ca. 5.9 mole equivalents of orthophosphoric acid.
A scale of 5 mL was decided upon and therefore the target weight of 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5- triazin-2-yl)phenyl]urea was 15.5 mg for the 3 mg/mL formulation and 18.0 mg for the 3.5 mg/mL formulation. Three samples were prepared for each formulation using the following weights in each 20mL vial: 3 mg/mL 3.5 mg/mL
N=1 15.48 mg 18.32 mg
N=2 16.15 mg 18.02 mg
N=3 15.89 mg 18.28 mg
5 mL of the orthophosphonc acid buffer prepared above was dispensed, using an air displacement pipette, into each vial. The vials were each closed with a crimped cap and sealed with protective film.
The samples were placed on a roller bed at room temperature for 15 hours.
These samples were visually assessed using a light box as described in European Pharmacopoeia method 2.9.20 (above), inspecting the samples against a black and a white background. The sample was also tested by illumination using a narrow (Tyndall) beam light source and then visually inspected from a direction
perpendicular to the light beam in order to identify undissolved solid particles. All solutions were observed to be visually clear. The pH was also measured. The results were as follows (n.b the ingoing pH of the 33.3 mM orthophosphonc acid was pH = 1 .94)
3 mg/mL
N=1 2.02
N=2 2.03
N=3 2.05
3.5 mg/mL
N=1 2.09
N=2 2.07
N=3 2.07 Conclusion
The results show that it is possible to formulate a clear, particle-free 3.0 or 3.5 mg/ml_ aqueous solution formulation of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea with 5.9 mole equivalents of orthophosphoric acid.
However, the pH readings demonstrate that dilution would be required to provide a suitable pH to allow direct intravenous or parenteral administration of these formulations.
When these results are compared to the results obtained for the lactic acid formulations above, the pH and 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea concentrations achievable are lower when using orthophosphoric acid. Lactic acid is therefore preferable for the preparation of a clear, particle-free aqueous solution formulation of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea that is suitable for intravenous or parenteral administration.
7. Characterisation of the crystalline form of 1-(4-IT4-
(dimethylamino)piperidin-1-vncarbonyl>phenyl)-3-r4-(4,6- dimorpholin-4-yl-1,3,5-triazin-2-yl)phenvnurea L-lactate
PXRD analysis
The powder X-ray diffraction (PXRD) analysis was carried out on a Bruker D4 (trade mark) diffractometer using copper radiation (wavelength: 1 .5406A). The tube voltage and amperage were set to 35 kV and 40 mA, respectively. The divergence slit used was v6 and the scattering slit was set at 0.499 mm. A variable receiving slit was used. Diffracted radiation was detected by a Vantec detector. A theta-two theta continuous scan at 5.4 min (0.2 sec/0.018° step) from 2.0 to 55 ° 2Θ was used. A corundum standard was analyzed to check the instrument alignment. The data were collected and analysed using Bruker AXS software. The samples were prepared by placing them on a silicon wafer. DIFFRAC.EVA V3.1 software was used to visualize and evaluate the PXRD spectra. The PXRD data files (.raw) were not processed prior to peak searching. Generally, a threshold value of 1.3 and a width value of 0.3 were used to make the preliminary peak assignments. The output of automated assignments was visually checked to ensure validity and adjustments manually made if necessary. Additionally, peaks were manually assigned within the spectra, if appropriate. A peak at 28.1 ° 2-theta that related to the mounting medium was manually removed from the list.
To perform an X-ray diffraction measurement using the Bragg-Brentano geometry on the Bruker instrument used for measurements reported herein, the sample is typically placed onto a flat silicon plate. The sample powder is pressed by a glass slide or equivalent to ensure a random surface and proper sample height. The sample holder is then placed into the instrument. The incident X-ray beam is directed at the sample, initially at a small angle relative to the plane of the holder, and then moved through an arc that continuously increases the angle between the incident beam and the plane of the holder. The measurement differences
associated with such X-ray powder analyses result from a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument errors (e.g. flat sample errors), (c) calibration errors, (d) operator errors (including those errors present when determining the peak locations), and (e) the nature of the material (e.g. preferred orientation and transparency errors). Calibration errors and sample height errors often result in a shift of all the peaks in the same direction. Small differences in sample height when using a flat holder will lead to large displacements in the PXRD peak positions. A systematic study showed that, using a Shimadzu XRD-6000 in the typical Bragg-Brentano configuration, a sample height difference of 1 mm leads to peak shifts as high as 1 degree 2-theta (Chen et al.; J Pharmaceutical and Biomedical Analysis, 2001 ; 26,63). These shifts can be identified from the X-ray diffractogram and can be eliminated by compensating for the shift (applying a systematic correction factor to all peak position values) or recalibrating the instrument. As mentioned above, it is possible to rectify
measurements from the various machines by applying a systematic correction factor to bring the peak positions into agreement. In general, this correction factor will bring the measured peak positions from the Bruker into agreement with the expected peak positions and may be in the range of from 0 to 0.2 degree 2-theta.
The PXRD pattern of the crystalline form of 1 -(4-{[4-(dimethylamino)piperidin- 1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea L- lactate of Example 4, Preparation A, is provided in FIGURE 1 and is characterized by the following peak listing that is expressed in terms of the degree 2Θ (+/- 0.2 degrees 2-theta) and relative intensity (of > 2.5 %) as measured on a Bruker D4 diffractometer with copper K-alpha (CuKa) radiation:
Angle Relative
(degree 2Θ) intensity (%) *
6.5 5.9
9.2 9.7
1 1 .0 13.2
13.0 15.8
13.3 4.3
13.7 2.9
15.6 9.4
15.9 17.2
16.2 28.8
17.0 17.7
17.3 43.9
18.4 46
18.9 51 .3
19.1 20
19.9 54.6 20.9 67.1
22.1 19.5
22.5 8.4
22.9 10.3
23.1 100
24.2 2.6
25.0 18.1
25.6 15.8
26.3 4.8
26.6 10.2
28.2 9.8
28.5 10.8
29.2 2.7
30.3 4.3
30.7 4.2
35.1 2.9
(*The relative intensities may change depending on the crystal size and morphology)
This crystalline form of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea L-lactate is distinguished from other known (semi-crystalline) forms of this salt by having characterizing peaks at about 6.5, 15.9, 20.9, 22.1 and 23.1 degrees 2-theta (+/- 0.2 degrees 2-theta).
7. Chemical stability of a lyophilised solid formulation of the invention
Samples of a lyophilised solid formulation prepared in accordance with the method of Example 2 in 50ml_ clear vials were analysed for chemical degradation after storage at 25°C/60% Relative Humidity (RH) and 40°C/75% RH at a variety of different timepoints. Several samples were evaluated for each condition to allow representative results at the selected timepoints. The 40°C/75% RH samples were tested after 6 months.
The 25°C/60% RH samples were tested after 6 months, 12 months, 24 months and 36 months. The samples were tested for chemical purity using High Performance Liquid
Chromatography (HPLC) using the following methodology in order to measure any degradation during the period of testing.
HPLC method
The solutions, samples and standards for use in the HPLC method are prepared as below:
• Reference Standard: 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea with a known potency value.
• Diluent: Acetonitrile/Water (1 : 1 v/v).
• Mobile Phase A: 10mM aqueous ammonium bicarbonate buffer solution with pH adjusted to 9.8 with aqueous ammonium hydroxide solution
• Mobile Phase B: Acetonitrile
· Sample solvent: Add 3 mL of 0.1 N aqueous hydrochloric acid into a 1000 mL volumetric flask and dilute to set volume with the Diluent (Acetonitrile/water, 1 : 1 v/v). Mix well.
Note: larger or smaller volumes of solutions may be prepared using the appropriate ratio of components.
Standard and Check standard preparations: • Accurately prepare two solutions of ca. 2 mg/mL (+/- 10%) of 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1 ,3,5-triazin-2-yl)phenyl]urea Reference Standard in Sample solvent, and record the concentrations accurately of both. These are the Standard and Check standard solutions. Produce Standard and Check standard
preparations by accurately diluting these solutions to a concentration of around 2 microgram/mL of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea using the Diluent.
Sensitivity solution:
• Accurately dilute the Standard preparation to a concentration of
approximately 0.06 microgram/mL of 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea using the Diluent.
Sample preparation:
• Reconstitute two lyophilised solid formulation vials of 1 -(4-{[4- (dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl- 1 ,3,5-triazin-2-yl)phenyl]urea (prepared in accordance with the method of
Example 2) by adding 20 mL of water to each vial, shaking the vial to dissolve the solid and wait for the bubbles to disappear. Transfer the solution into a l OOOmL volumetric flask. Rinse each vial at least twice with Diluent and transfer the washings into the volumetric flask. Dilute to the set volume with Diluent.
Chromatographic conditions:
• Liquid chromatographic system - e.g. Waters 2695 (trade mark) or Agilent 1 100 (trade mark) machine
· Column: Waters Xbridge C18 (trade mark), 15 cm x 4.6 mm, 3.5 pm or
equivalent • Column Temperature: 40°C
• Injection Volume: 20 μΙ_
• Flow Rate: 1.0 ml_ /min.
• Detection: UV at 303 nm
· Run Time: 60 minutes
• Mobile Phase A
• Mobile Phase B
• Linear Gradient Table:
Figure imgf000054_0001
Explanatory notes
Prepare the HPLC machine by pumping Mobile Phase B through the column until a stable baseline is obtained (this usually takes around 30 minutes).
Re-equilibrate the chromatographic system with Mobile Phase A (usually 10-15 minutes) before running the injection sequence.
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.
The following criteria must be satisfied on initial HPLC 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 # of Injections Solution Criteria Blank 1 Diluent Chromatogram similar to
Figures 3 and 4
Signal to Noise 1 Sensitivity European
Solution Pharmacopoeia
(EP)/United States Pharmacopoeia (USP) Signal to Noise > 10
Repeatability 5 Standard Relative Standard
preparation Deviation < 5.0%
Retention time 1* 28-36 minutes
Efficiency Plate number for 1 -(4- (Plate)** {[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 Asymmetry 0.9 < T≤2.0 for 1 -(4-{[4- or (dimethylamino)piperidin- 1 -yl]carbonyl}phenyl)-3- [4-(4,6-dimorpholin-4-yl- 1 ,3,5-triazin-2- yl)phenyl]urea peak
*Use average of all system suitability (repeatability) injections.
**Refer to United States Pharmacopoeia (USP) calculation equations for Efficiency and Peak Asymmetry. 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 ± 5% of the standard preparation.
After the system suitability has been demonstrated, inject the blank solution, standard preparation and prepared test samples, followed by an injection of the standard preparation, according to the chromatographic conditions above. 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, also measure the retention times and peak area of any peaks present in the sample injection that do not appear in the blank injection. Do not integrate gradient artifacts, if present. Compare the 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 % degradants and report the individual degradant peaks which are at or above 0.05%. Unknown degradants should be reported individually by their relative retention time. Known degradants should be reported individually by name. The results are summarised in the tables below.
Key
• NMT = Not More Than.
· NR = Not Reported.
• RRT = Relative Retention Time
• All % are w/w
Degradant 1
Figure imgf000057_0001
Figure imgf000057_0002
Degradants 3, 4, 5 and 6
These were each characterised by their RRT only.
25°C/60% RH
Timepoint Acceptance Initial 6 12 24 36
criteria months months months months Degradant 1 NMT 1.1 % 0.74% 0.77% 0.77% 0.79% 0.87%
Degradant 2 NMT 0.5% NMT NMT NMT NMT NMT
0.05% 0.05% 0.05% 0.05% 0.05%
Degradant 3 NMT 0.5% 0.10% 0.09% 0.10% 0.08% NR* RRT 0.86 each
Degradant 4 NMT 0.5% NMT NMT 0.06% NMT NMT RRT 1.05 each 0.05% 0.05% 0.05% 0.05%
Degradant 5 NMT 0.5% NMT NMT 0.07% 0.06% NR* RRT 1.15 each 0.05% 0.05%
Degradant 6 NMT 0.5% 0.12% 0.12% 0.1 1 % 0.12% NR* RRT 1.42 each
Total NMT 3.0% 0.96% 0.98% 1.1% 1.1% 0.87%*
Degradants
• Degradants 3, 5 and 6 were identified as process related impurities which did not change on stability, and so were not reported at the 36 month timepoint.
40°C/75% RH
Timepoint Acceptance Initial 6 months
criteria
Degradant 1 NMT 1.1 % 0.74% 0.80%
Degradant 2 NMT 0.5% NMT NMT 0.05%
0.05%
Degradant 3 NMT 0.5% 0.10% 0.09%
RRT 0.86 each
Degradant 6 NMT 0.5% 0.12% 0.12%
RRT 1.42 each
Total NMT 3.0% 0.96% 1.0%
Degradants Conclusion
The results show that samples of a lyophilised solid formulation prepared in accordance with the method of Example 2 in a 50ml_ clear vial are chemically stable for at least 36 months at 25°C/60% RH and for at least 6 months at 40°C/75% RH.

Claims

1. A pharmaceutical aqueous solution formulation comprising
1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin- 4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, 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
1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin- 4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, or a phosphate salt thereof,
orthophosphoric acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin- 1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4mg/ml and sufficient orthophosphoric acid is present to provide a clear solution.
2. A pharmaceutical aqueous solution formulation as claimed in claim 1
comprising 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, or a 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.
3. A pharmaceutical aqueous solution formulation as claimed in claim 1 or 2 comprising 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, 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.
4. A pharmaceutical aqueous solution formulation as claimed in any one of claims 1 to 3 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 2.5 to 5.5mg/ml.
5. A pharmaceutical aqueous solution formulation as claimed in any one of claims 1 to 4 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 5.0 to 5.5mg/ml and at least 2.5 mole equivalents of lactic acid are present.
6. A pharmaceutical aqueous solution formulation as claimed in claim 4 wherein 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-
4- yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml.
7. A pharmaceutical aqueous solution formulation as claimed in claim 6 wherein 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin- 4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml and at least 2.5 mole equivalents of lactic acid are present.
8. A pharmaceutical aqueous solution formulation as claimed in any one of claims 1 to 3 comprising 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin-1 - yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml, and at least 2.5 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed.
9. A pharmaceutical aqueous solution formulation as claimed in claim 1 or 2 comprising 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea lactate, lactic acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml, and at least 1.5 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed.
10. A pharmaceutical aqueous solution formulation as claimed in claim 8
comprising 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, lactic acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin- 4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of about 5mg/ml, and about 4.1 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed with a pH of no greater than 3.7.
1 1 . A pharmaceutical aqueous solution formulation as claimed in claim 1 or 2 comprising 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, 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 from 2.5 to 5.5mg/ml, and from above 2.5 to 8.0 mole equivalents of lactic acid are present and in an amount sufficient to ensure a clear solution is formed.
12. A pharmaceutical aqueous solution formulation as claimed in any one of claims 1 to 1 1 wherein DL-lactic acid, L-lactic acid or D-lactic acid is used.
13. A pharmaceutical aqueous solution formulation as claimed in any one of claims 1 to 12 wherein DL-lactic acid is used.
14. A pharmaceutical aqueous solution formulation as claimed in claim 1 comprising 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, or a phosphate salt thereof, orthophosphoric acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin- 1 -yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a clear solution.
15. A pharmaceutical aqueous solution formulation as claimed in claim 1 or 14 comprising 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4-(4,6- dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea, orthophosphoric acid and water, wherein 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3-[4- (4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 4 mg/ml and sufficient orthophosphoric acid is present to provide a clear solution.
16. A pharmaceutical aqueous solution formulation as claimed in claim 15
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 3.0 to 3.5mg/ml.
17. A pharmaceutical aqueous solution formulation as claimed in claim 15 or 16 wherein at least 5 mole equivalents of orthophosphoric acid are used.
18. A pharmaceutical aqueous solution formulation as claimed in claim 17
wherein from 5 to 7 mole equivalents of orthophosphoric acid are used.
19. A lyophilised formulation obtainable by freeze drying a formulation as
claimed in any one of claims 1 to 18.
20. A lyophilised formulation as claimed in claim 19 obtainable by freeze drying a formulation as claimed in any one of claims 1 to 18 additionally containing a bulking agent.
21 . A lyophilised formulation as claimed in claim 20 wherein the bulking agent is mannitol.
22. A pharmaceutical aqueous solution formulation obtainable as a clear solution by reconstitution or constitution of a lyophilized formulation as claimed in any one of claims 19 to 21 using water or an aqueous solution comprising a tonicity modifier.
23. A pharmaceutical aqueous solution formulation as claimed in claim 22
wherein the tonicity modifier is dextrose, sucrose or mannitol, or is a mixture of any 2 or more thereof.
24. A pharmaceutical aqueous solution formulation as claimed in any one of claims 1 to 18, or 22 or 23, that is adjusted, as necessary, to have a pH suitable for intravenous or parenteral administration.
25. A pharmaceutical aqueous solution formulation as claimed in claim 24
wherein the pH is from 3 to 4.5.
26. A formulation as claimed in any one of claims 1 to 25 for use in the treatment of cancer.
27. 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 claims 1 to 25.
28. A crystalline form of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)-3- [4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea L-lactate characterized by a PXRD pattern measured using a Bruker D4 diffractometer and copper K- alpha radiation with major peaks at about 16.2, 17.3, 18.4, 18.9, 19.9, 20.9 and 23.1 degrees 2-theta (+/- 0.2 degrees 2-theta).
29. A crystalline form of 1 -(4-{[4-(dimethylamino)piperidin-1 -yl]carbonyl}phenyl)- 3-[4-(4,6-dimorpholin-4-yl-1 ,3,5-triazin-2-yl)phenyl]urea L-lactate
characterized by a PXRD pattern measured using a Bruker D4 diffractometer and copper K-alpha radiation with characterising peaks at about 6.5, 15.9, 20.9, 22.1 and 23.1 degrees 2-theta (+/- 0.2 degrees 2-theta).
30. A crystalline form as claimed in claim 28 or 29 for use in the preparation of a formulation as claimed in any one of claims 1 , 2 or 9.
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US11541058B2 (en) 2017-08-25 2023-01-03 Pfizer Inc. 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
WO2019234632A1 (en) 2018-06-07 2019-12-12 Pfizer Inc. 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
TWI696469B (en) * 2018-06-07 2020-06-21 美商輝瑞大藥廠 Formulation
RU2772287C1 (en) * 2018-06-07 2022-05-18 Пфайзер Инк. Aqueous composition containing 1-(4-{[4-(dimethylamino)piperidine-1-yl]carbonyl} phenyl)-3-[4-(4,6- dimorpholine-4-yl-1,3,5-triazine-2-yl)phenyl]urea
AU2019283550B2 (en) * 2018-06-07 2022-06-16 Pfizer Inc. 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
EP4249069A2 (en) 2018-06-07 2023-09-27 Pfizer Inc. 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
EP4249069A3 (en) * 2018-06-07 2023-11-29 Pfizer Inc. 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
AU2022211854B2 (en) * 2018-06-07 2024-01-04 Pfizer Inc. 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
US12109308B2 (en) 2018-06-07 2024-10-08 Pfizer Inc. Aqueous formulation comprising 1-(4-{[4-(dimethylamino)piperidin-1-yljcarbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea
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