QTX125 Drug Formulation

Abstract

The present invention relates to compounds of formula I, and compounds of formula II, 1 -H or Independently selected from JPEG2025511030000050.jpg12170: R 2 does not exist or C 1-4 Alkyl; Q is -H, -SO3 - , -OH, -C(O)R 3 or -C(OH)R 3 2 groups; and R 3 are independently -H or C 1-4 the molar ratio of the compound of formula I to the compound of formula II is 1:50 to 1:2; and the pH of the pharmaceutical formulation is between pH 7 and pH 8. JPEG2025511030000051.jpg126170

Description

[Technical field]

[0001] Technical Field The present invention relates generally to the fields of medicine and pharmacology, and more particularly to pharmaceutical formulations comprising certain histone deacetylase inhibitors and cyclodextrin or derivatives thereof. The present invention also relates to the use of such formulations in the treatment of, for example, cancer or autoimmune diseases. [Background technology]

[0002] Background Histone deacetylases (HDACs) Histone deacetylases (HDACs) are important proteins involved in the pathogenesis of cancer (see PA Marks et al. Nature Rev. Cancer 2001, 1, 194; JE Bolden et al. Nature Rev. Drug Discov. 2006, 5, 769; P. Gallinari et al. Cell Res. 2007, 17, 195; KB Glaser Biochem. Pharmacol. 2007, 74, 659; L. Pan et al. Cell. Mol. Immunol. 2007, 4, 337; M. Haberland et al. Nature Rev. Genetics 2009, 10, 32; Y. Zhang et al. Curr. Med. Chem. 2008, 15, 2840; S. Ropero, M. Esteller Mol. Oncol. 2007, 1, 2840). 19) and other diseases, such as those related to the central nervous system, autoimmune diseases (see AG Kazantsev, LM Thompson Nature Rev. Drug Discov. 2006, 7, 854).

[0003] Several families of HDAC inhibitors (HDACi) have been designed and their general structures can be found in different reviews (see A. Villar-Garea, M. Esteller Int. J. Cancer 2004, 112, 171; TA Miller et al. J. Med. Chem. 2003, 46, 5097; T. Suzuki, N. Miyata Curr. Med. Chem. 2005, 12, 2867; M. Paris et al. J. Med. Chem. 2008, 51, 1505). The general structure of these inhibitors consists of a ring structure, a spacer and a chelating group that can bind to the Zn(II) cation in the active center of different HDAC isoforms belonging to class I (HDAC1, HDAC2, HDAC3 and HDAC8), class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10) and class IV (HDAC11).

[0004] The mechanism of action of HDAC inhibitors is explained by their antagonistic properties against histone deacetylases, which are involved in the control of processes related to apoptosis, cell proliferation, tumor progression, cancer metastasis, cell adhesion, etc. These properties are achieved by preventing HDACs from binding to their natural ligands, which are cytoplasmic proteins such as histones or tubulin, as well as by inhibiting their normal catalytic activation, i.e., deacetylation of ε-N-acetyl lysine residues present in these proteins.

[0005] Despite having a similar mode of inhibition, occasionally some selectivity has been observed in the inhibition of different HDAC isoforms (see JC Wong et al. J. Am. Chem. Soc. 2003, 125, 5586; G. Estiu et al. J. Med. Chem. 2008, 51, 2898). The selectivity mentioned is of therapeutic interest (see KV Butler, AP Kozikowski Curr. Pharm. Design 2008, 14, 505; TC Karagiannis, A. El-Osta Leukemia 2007, 21, 61).

[0006] HDAC inhibitors One important class of HDAC inhibitors are trisubstituted pyrrole derivatives linked to chelating groups via aromatic and heteroaromatic groups, as described, for example, in WO 2011 / 039353. These compounds have been shown to be effective in the treatment of cancer (see WO 2011 / 039353).

[0007] Furthermore, these compounds have been shown to be effective in treating several autoimmune diseases, for example, they have been shown to be effective in animal models of autoimmune hepatitis and autoimmune encephalomyelitis (see WO2018 / 087082).

[0008] A particularly promising compound is 3-(3-furyl)-N-{4-[(hydroxyamino)carbonyl]benzyl}-5-(4-hydroxyphenyl)-1H-pyrrole-2-carboxamide (referred to herein as QTX125).

[0009] [ka]

[0010] QTX125 is a highly selective and potent HDAC6 inhibitor. It has shown high antitumor efficacy in xenograft mouse models of mantle cell lymphoma (see Perez-Salvia, M. et al haematologica 2018; 103:e540), lung cancer and pancreatic cancer. QTX125 has also shown high efficacy in two different mouse models of multiple sclerosis (see WO 2018 / 087082).

[0011] However, hydroxamic acids such as QTX125 are known to have very low solubility in water (see Patre, S. et al. 2011 International Conference on Environment and BioScience IPCBEE vol.21 (2011)), and high pH is usually required to dissolve QTX125 in aqueous solutions. QTX125 has also been demonstrated to be physically and chemically unstable in solution.

[0012] For injectable formulations of QTX125, it is desirable for the solubility in the formulation to be 7.5 mg / mL or greater at physiological pH (i.e., pH 7 to pH 8). This is particularly important from the standpoint of avoiding pain at the injection site, as compositions at particularly high or particularly low pH tend to be painful. Without being bound by theory, it is believed that formulations for infusion administration should be closer to the physiological pH range (pH 7-8), and formulations for bolus administration should be pH 4-8 for buffered solutions and pH 3-9 for unbuffered solutions. Injectable formulations should also be stable over long periods of time from manufacture to administration, and have low toxicity.

[0013] As a result, there remains a need in the art to provide pharmaceutical formulations that contain high concentrations of dissolved QTX125 at physiological pH, which are stable and have low toxicity.

[0014] Numerous patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which it pertains. Full citations for these publications are provided herein. Each of these publications is herein incorporated by reference in its entirety into this disclosure. Summary of the Invention

[0015] Summary of the Invention The present inventors have developed a pharmaceutical formulation which helps to solve the practical problems mentioned above.

[0016] Thus, in a first aspect, the present invention provides a method for producing a composition comprising: - a compound of formula I,

[0017] [ka]

[0018] and a compound of formula II,

[0019] [ka]

[0020] (In the formula, each R 1 is independently selected from the following groups: -H or

[0021] [ka]

[0022] R 2 does not exist or is C 1-4 is alkyl; Q is selected from the following groups: -H, -SO3 - , -OH, -C(O)R 3 or -C(OH)R 3 2; and R 3 are independently -H or C 1-4alkyl; The injectable pharmaceutical formulation is provided, wherein the molar ratio of the compound of formula I to the compound of formula II is 1:50 to 1:2; and the pH of the pharmaceutical formulation is between pH7 and pH8.

[0023] Preferably, the present invention relates to a compound of formula I

[0024] [ka]

[0025] and β-cyclodextrin sulfobutyl ether (SBβCD), The injectable aqueous pharmaceutical formulation relates to a molar ratio of the compound of formula I to β-cyclodextrin sulfobutyl ether of 1:50 to 1:2, and the pH of the pharmaceutical formulation is between pH7 and pH8.

[0026] In a second aspect, the present invention provides a method for producing a method for treating a cancer cell comprising: - a compound of formula I,

[0027] [ka]

[0028] and a compound of formula II,

[0029] [ka]

[0030] (In the formula, each R 1 is independently selected from the following groups: -H or

[0031] [ka]

[0032] R 2 does not exist or C 1-4 is alkyl; Q is selected from the following groups: -H, -SO3 - , -OH, -C(O)R 3 or -C(OH)R 3 2, and R 3 are independently -H or C 1-4 For the injectable aqueous pharmaceutical formulation comprising a cyclic alkyl group, the pharmaceutical formulation comprises: Step 1: preparing a mixture comprising water, a compound of formula I and a compound of formula II, wherein the molar ratio of the compound of formula I to the compound of formula II is 1:50 to 1:2; and Step 2: adding an acid to reduce the pH of the mixture to a value between pH 7 and pH 8.

[0033] In a further aspect, the present invention relates to a dry pharmaceutical formulation obtainable by drying the aqueous pharmaceutical formulation according to the present invention, preferably a dry pharmaceutical formulation obtainable by lyophilizing the aqueous pharmaceutical formulation according to the present invention.

[0034] In a further aspect, the present invention relates to a kit for use in reconstituting a dosage form comprising said dry pharmaceutical formulation and pharma- ceutical acceptable grade water, buffer or saline.

[0035] In a further aspect, the present invention relates to an aqueous pharmaceutical formulation or a dry pharmaceutical formulation as described herein for use in the manufacture of a medicament.

[0036] In a further aspect, the present invention relates to the aqueous or dry pharmaceutical formulation described herein for use in the manufacture of a medicament for the treatment of cancer or an autoimmune disease.

[0037] In a further aspect, the present invention relates to a liquid pharmaceutical formulation obtained by reconstituting the aqueous or dry pharmaceutical formulation described herein, for use as a medicament.

[0038] In a further aspect, the present invention relates to a liquid pharmaceutical formulation obtainable by reconstituting the aqueous pharmaceutical formulation or the formulation described herein for use in the treatment of cancer or an autoimmune disease.

[0039] In a further aspect, the present invention relates to a method of treatment comprising administering to a patient a liquid pharmaceutical formulation obtained by reconstituting the aqueous or dry pharmaceutical formulation described herein.

[0040] In a further aspect, the present invention relates to a method for treating cancer or an autoimmune disease comprising administering to a patient a liquid pharmaceutical formulation obtained by reconstituting the aqueous or dry pharmaceutical formulation described herein.

[0041] As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention also pertain to other aspects of the invention.

[0042] Detailed Description definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs.Methods and materials are described herein for use in this disclosure, but other suitable methods and materials known in the art can also be used.Materials, methods, and examples are illustrative only and are not intended to be limiting.All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety.In case of discrepancy, the present specification, including definitions, will prevail.

[0043] The term "about" preceding a stated value indicates that the value may have an uncertainty of ±20%, preferably ±10%, ±5%, ±2%, ±1% of the stated value.

[0044] The term "C1-C4 alkyl" refers to a straight or branched hydrocarbon chain consisting of carbon and hydrogen atoms, containing no unsaturation, having from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms ("C1-C3 alkyl"), attached to the remainder of the molecule through a single bond, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, and the like.

[0045] The term "room temperature" refers to the ambient temperature in a typical laboratory, typically between 20°C and 30°C, preferably around 25°C, at atmospheric pressure.

[0046] The term "dry" refers to a formulation that has been subjected to drying. Optionally, a dry formulation may refer to a solid material having a residual moisture content of less than 10%, preferably less than 8%, preferably less than 5%, preferably from about 0.1% to about 5%. Residual moisture content may be determined using Karl Fischer titration.

[0047] The terms "lyophilised" or "freeze-dried" refer to materials obtained and / or resulting from lyophilising a liquid formulation, i.e., materials resulting from a drying procedure in which the material to be dried is first frozen and then sublimated under vacuum to remove the ice or freezing solvent.

[0048] The term "reconstituted" refers to contacting a dry (lyophilized) formulation with a pharma- ceutically acceptable liquid, such as pharma- ceutically acceptable grade water (preferably sterile), a pharma- ceutically acceptable buffer or saline solution, to convert the powder (or solid compound) into either a suspension or a solution that can be administered to a patient by injection. The term "reconstituted dry pharmaceutical formulation" relates to a liquid pharmaceutical formulation obtained by reconstituting a dry pharmaceutical formulation according to the invention in a pharma- ceutically acceptable liquid.

[0049] The term "injection" refers to any form of injection known to those skilled in the art, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal. Injection can refer to a bolus (discrete) administration as well as an infusion process (e.g., continuous administration).

[0050] The term "pharmaceutical acceptable salt" refers to a salt that, when administered to a recipient, can provide (directly or indirectly) a compound described herein. "Pharmaceutically acceptable" preferably refers to compositions and molecular entities that are physiologically acceptable and do not normally produce allergic reactions or similar undesirable reactions, such as stomach upset, dizziness, or the like, when administered to humans or animals. Preferably, the term "pharmaceutical acceptable" means approved by a state or federal regulatory agency or included in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, particularly humans.

[0051] The term "treatment" or "treating" refers to the administration of a compound or pharmaceutical composition of the present invention to ameliorate or eliminate a disease or one or more symptoms associated with a disease. The term "prevention" or "preventing" includes reducing the risk of the appearance or development of a disease.

[0052] Unless otherwise specified, "%" refers to weight-%.

[0053] The present invention has many advantageous features, including the following:

[0054] Firstly, the aqueous pharmaceutical formulation according to the present invention means that the compound QTX125 can be dissolved at a concentration of 7.5 mg / mL or more in a formulation between pH 7 and pH 8 suitable for injection.

[0055] Second, the liquid pharmaceutical formulation according to the present invention is non-toxic in mammals at dosages up to 200 mg / kg, and is therefore suitable for use in therapeutic methods in mammals, such as methods for treating cancer.

[0056] Third, the aqueous pharmaceutical formulation according to the present invention is stable for extended periods of time, for example up to 3 months at 5° C. The aqueous pharmaceutical formulation can also be lyophilized without incurring loss of activity of the formulation upon reconstitution.

[0057] Fourth, the dried (lyophilized) pharmaceutical formulations according to the present invention exhibit high stability over a period of at least three months at room temperature, which may obviate the need for cold chain transportation of these formulations. These formulations are also stable, providing a pH value between pH 7 and pH 8 once reconstituted, even after long-term storage.

[0058] Compounds of Formula I One aspect of the present invention focuses on providing an aqueous pharmaceutical formulation having a high dissolved concentration of the compound of formula I (QTX125).

[0059] The aqueous pharmaceutical formulation: - a compound of formula I,

[0060] [ka]

[0061] and a compound of formula II,

[0062] [ka]

[0063] (In the formula, each R 1 is independently selected from the following groups: -H or

[0064] [ka]

[0065] R 2 does not exist or C 1-4 is alkyl; Q is selected from the following groups: -H, -SO3 - , -OH, -C(O)R 3 or -C(OH)R 3 2; and R 3 are independently -H or C 1-4 alkyl); the molar ratio of the compound of formula I to the compound of formula II is 1:50 to 1:2; and the pH of the pharmaceutical formulation is between pH7 and pH8.

[0066] Preferably, the concentration of the compound of formula I dissolved in the aqueous pharmaceutical formulation is 7.5 mg / mL or more, more preferably 8 mg / mL or more, more preferably 8.5 mg / mL or more, more preferably 9 mg / mL or more and most preferably 9.5 mg / mL or more.

[0067] The concentration of dissolved QTX125 in the formulation may be determined using HPLC as described in the Experimental section below.

[0068] The maximum concentration of dissolved QTX 125 is limited only by the maximum achievable solubility value of QTX 125. Optionally, the maximum concentration of QTX 125 in solution is 50 mg / mL, or 20 mg / mL, or 15 mg / mL.

[0069] The compounds of formula I may be incorporated into aqueous pharmaceutical formulations in the form of a salt (preferably as a pharma- ceutically acceptable salt), as a solvate, as a free base, as a neutral compound, or as a prodrug.

[0070] Salts can be prepared by methods known in the art. For example, pharma-ceutically acceptable salts may be synthesized from the parent compound containing a basic residue by conventional chemical methods. In general, such salts are prepared, for example, by reacting the free base form of the compound with a suitable base or acid in water or in an organic solvent or in a mixture of both. In general, non-aqueous solvents such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Acid addition salts include mineral acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and organic acid addition salts such as acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate. Base addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminum and lithium salts, as well as organic salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkyleneethanolamine, triethanolamine, glucamine and basic salts of amino acids.

[0071] Compound of Formula II The aqueous pharmaceutical formulation according to the present invention further comprises a compound of formula II

[0072] [ka]

[0073] (In the formula, each R 1 is independently selected from the following groups: -H or

[0074] [ka]

[0075] R 2 does not exist or C 1-4 is alkyl; Q is selected from the following groups: -H, -SO3 -, -OH, -C(O)R 3 or -C(OH)R 3 2; and R 3 are independently -H or C 1-4 alkyl).

[0076] The compound of formula II is a β-cyclodextrin backbone in which the hydroxy groups of β-cyclodextrin may be substituted with a number of different functional groups (as described above). Cyclodextrins are cyclic oligosaccharides with a toroidal structure, embracing a hydrophobic / lipophilic central cavity and a hydrophilic outer surface. β-cyclodextrin is a cyclodextrin consisting of seven glucopyranose units.

[0077] Many different types of β-cyclodextrin and its derivatives have been deemed safe for use as pharmaceutical excipients, for example, 2-hydroxypropyl-β-cyclodextrin has been demonstrated to be well tolerated in a range of animal species such as rats, mice and dogs (S. Gould et al., Food and Chemical Technology, 43, 1451-1459, 2005), and β-cyclodextrin sulfobutyl ether (SBβCD) had no observable effects in acute toxicity studies and showed no negative kidney histopathology in mice (Rajewski, RA, 1990. Development and evaluation of the usefulness and parenteral safety of modified cyclodextrins. Lawrence, KS, USA, Univ. Kansas, 251 pp).

[0078] Without being bound by theory, it is believed that cyclodextrins interact with QTX125 compounds to form water-soluble complexes, for example, by incorporating the QTX125 molecule into its hydrophobic central cavity.

[0079] The compound of formula II is preferably β-cyclodextrin (naturally occurring β-cyclodextrin), (C 1-4 alkyl)-β-cyclodextrin, (C 1-4 alkyl)-β-cyclodextrin, (hydroxy-C 1-4 (alkyl)-β-cyclodextrin, C 1-4 Alkyl-carboxylalkyl-β-cyclodextrin and C 1-4 Alkyl-(hydroxy-C 1-4 The sulfobutyl ethers of alkyl)-β-cyclodextrins are selected from the group consisting of sulfobutyl ethers of alkyl (alkyl)-β-cyclodextrins.

[0080] More preferably, the compound of formula II is β-cyclodextrin, (C 1-4 alkyl)-β-cyclodextrin, (hydroxy-C 1-4 alkyl)-β-cyclodextrin and (C 1-4 The sulfobutyl ethers of alkyl)-β-cyclodextrins are selected from the group consisting of sulfobutyl ethers of alkyl (alkyl)-β-cyclodextrins.

[0081] More preferably, the compound of formula II is (hydroxy-C 1-4 alkyl)-β-cyclodextrin and (C 1-4 The sulfobutyl ethers of alkyl)-β-cyclodextrins are selected from the group consisting of sulfobutyl ethers of alkyl (alkyl)-β-cyclodextrins.

[0082] More preferably, the compound of formula II is hydroxypropyl β-cyclodextrin or β-cyclodextrin sulfobutyl ether (SBβCD).

[0083] Most preferably, the compound of formula II is β-cyclodextrin sulfobutyl ether (SBβCD).

[0084] Alternatively, the present invention may include more than one compound according to Formula II, for example a formulation according to the present invention may include both hydroxypropyl beta cyclodextrin and beta-cyclodextrin sulfobutyl ether (SBβCD).

[0085] The compound of formula II may be incorporated as a free base or as a salt form, such as a sodium or potassium salt.

[0086] As will be appreciated by those of skill in the art, the average substitution pattern of a cyclodextrin such as SBβCD may vary. SBβCD may have an average of 2-8 hydroxy groups substituted with sulfobutyl ether moieties, preferably 5-7 hydroxy groups substituted with sulfobutyl ether moieties.

[0087] The average molecular weight of the compound of formula II varies with the degree of substitution. The average molecular weight of commercial preparations of β-cyclodextrin sulfobutyl ether (SBβCD) may vary from 1451 to 2242 g / mol.

[0088] Molar ratio of components In the aqueous pharmaceutical formulation according to the invention, the molar ratio of the compound of formula I to the compound of formula II is from 1:50 to 1:2.

[0089] Preferably, the molar ratio of the compound of formula I to the compound of formula II is from 1:40 to 1:2, preferably from 1:30 to 1:2, preferably from 1:25 to 1:2, preferably from 1:20 to 1:2, preferably from 1:15 to 1:2, preferably from 1:10 to 1:2, preferably from 1:9 to 1:2, preferably from 1:8 to 1:2, preferably from 1:6 to 1:2, more preferably from 1:4.5 to 1:2, and most preferably about 1:2.7.

[0090] In certain embodiments, the molar ratio of the compound of formula I to the compound of formula II is from 1:50 to 1:2.3.

[0091] Preferably, the molar ratio of the compound of formula I to the compound of formula II is from 1:40 to 1:2.3, preferably from 1:30 to 1:2.3, preferably from 1:25 to 1:2.3, preferably from 1:20 to 1:2.3, preferably from 1:15 to 1:2.3, preferably from 1:10 to 1:2.3, preferably from 1:9 to 1:2.3, preferably from 1:8 to 1:2.3, preferably from 1:6 to 1:2.3, more preferably from 1:4.5 to 1:2.3, most preferably about 1:2.7.

[0092] In certain preferred embodiments, the molar ratio of the compound of formula I to the compound of formula II is from 1:50 to 1:2.5.

[0093] Preferably, the molar ratio of the compound of formula I to the compound of formula II is from 1:40 to 1:2.5, preferably from 1:30 to 1:2.5, preferably from 1:25 to 1:2.5, preferably from 1:20 to 1:2.5, preferably from 1:15 to 1:2.5, preferably from 1:10 to 1:2.5, preferably from 1:9 to 1:2.5, preferably from 1:8 to 1:2.5, preferably between 1:6 and 1:2.5, more preferably from 1:4.5 to 1:2.5, most preferably about 1:2.7.

[0094] The concentration of a compound of Formula II (eg, β-cyclodextrin sulfobutyl ether) in solution may be determined using HPLC / MS based on comparison of peak areas to a calibration curve of known compounds.

[0095] Other additional ingredients Optionally, the aqueous pharmaceutical formulation further comprises one or more other pharma- ceutically acceptable components well known to those skilled in the art, including, but not limited to, pharma- ceutically acceptable carriers, diluents, excipients, adjuvants, buffers, pH adjusting agents, preservatives, antioxidants, bacteriostats, stabilizers, suspending agents, solubilizing agents, surfactants (e.g., wetting agents), colorants, and isotonic solutes (i.e., those that render the formulation isotonic with the blood or other relevant bodily fluids of the intended recipient). Suitable carriers, diluents, excipients, and the like can be found in standard pharmaceutical texts. For example, Handbook of Pharmaceutical Additives , 2nd Edition (eds. M. Ash and I. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences , 18th edition, Mack Publishing Company, Easton, Pa., 1990; Handbook of Pharmaceutical Excipients , 2nd edition, 1994.

[0096] Optionally, the aqueous pharmaceutical formulation according to the invention further comprises a buffer (i.e. the formulation further comprises a buffer salt dissolved therein). Optionally, the buffer may be selected from the group: MES, Bis-Tris, ADA, ACES, PIPES, MOPSO, BES, MOPS, TES, HEPES, DIPSO, MOBS, TAPSO, Tris-HCl, HEPPSO, POPSO, TEA, EPPS, Tricine, Gly-Gly, Bicine, HEPBS, TAPS, AMPD, TABS, AMPSO, CHES, CAPSO, APS, CHAPS, CABS, phosphate and histidine or a combination of the above.

[0097] Without being bound by theory, it is believed that the use of a buffer may help stabilize the composition at physiological pH.

[0098] The concentration of the buffer salt in the aqueous pharmaceutical formulation may range from 1 mM to 1 M, preferably from 1 mM to 100 mM, preferably from 5 mM to 50 mM, preferably from 5 mM to 20 mM.

[0099] The aqueous pharmaceutical formulation may also include counterions and salts, such as sodium counterions, chloride ions or NaCl that are dissolved in the solution.

[0100] The aqueous pharmaceutical formulation may also contain other active agents, such as other therapeutic or prophylactic agents.

[0101] Optionally, the aqueous pharmaceutical formulation according to the present invention is substantially free of meglumine.

[0102] Optionally, the aqueous pharmaceutical formulation comprises: -water - optionally a buffer salt or dissolved salt such as NaCl; - a compound of formula I

[0103] [ka]

[0104] and - a compound of formula II,

[0105] [ka]

[0106] (In the formula, each R 1 is independently selected from the following groups: -H or

[0107] [ka]

[0108] R 2 does not exist or C 1-4 Alkyl; Q is selected from the following groups: -H, -SO3 - , -OH, -C(O)R 3 or -C(OH)R 3 2; and R3 are independently -H or C 1-4 alkyl); the molar ratio of the compound of formula I to the compound of formula II is 1:50 to 1:2; and The pH of the pharmaceutical formulation is between pH 7 and pH 8.

[0109] Aqueous pharmaceutical composition Preferably, the aqueous pharmaceutical formulation of the present invention comprises: Step 1: preparing a mixture comprising water, a compound of formula I and a compound of formula II, wherein the molar ratio of the compound of formula I to the compound of formula II is 1:50 to 1:2; Step 2: Adding an acid to reduce the pH of the mixture to a value between pH 7 and pH 8: The method is obtained by a method comprising the steps of:

[0110] Preferably, step 1 is carried out at a pH of at least 9. This pH may be established using any pharma- ceutically acceptable base, such as sodium hydroxide.

[0111] Preferably, step 1 is carried out at a pH of 10 or above, preferably a pH of 10.5 or above, preferably a pH of 10.7 or above, preferably a pH of 11 or above.

[0112] 1-Hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclylic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamine Any pharma- ceutically acceptable acid may be used to lower the pH in step 2, such as glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and / or undecylenic acid.

[0113] In the sense of the present invention, an aqueous pharmaceutical formulation may also refer to a reconstituted liquid pharmaceutical formulation obtained by reconstituting a dry pharmaceutical formulation according to the present invention (as described below) in water, buffer or salt of pharma- ceutical acceptable grade.

[0114] dry form The present invention also relates to a dry pharmaceutical formulation obtainable by drying the aqueous pharmaceutical formulation according to the present invention.

[0115] Without wishing to be bound by any theory, it is believed that drying the aqueous formulation according to the present invention can increase the stability of the compound (QTX125) and ensure that the pH of the liquid pharmaceutical composition upon reconstitution is between pH 7 and pH 8.

[0116] The dry pharmaceutical composition according to the present invention comprises a compound of formula I and a compound of formula II in a molar ratio of from 1:50 to 1:2.

[0117] The drying step can be accomplished by any drying method known to those skilled in the art, such as freeze-drying or spray-drying, etc. Preferably, the drying step is carried out by freeze-drying the aqueous pharmaceutical formulation according to the present invention.

[0118] Preferably, the dry pharmaceutical formulation comprises: Step 1: preparing a mixture comprising water, a compound of formula I and a compound of formula II, wherein the molar ratio of the compound of formula I to the compound of formula II is 1:50 to 1:2; Step 2: Adding an acid to reduce the pH of the mixture to a value between pH 7 and pH 8; Step 3: Drying the solution The method is obtained by a method comprising the steps of:

[0119] Preferably, step 1 is carried out at a pH of 9 or above, preferably a pH of 10 or above, preferably a pH of 10.5 or above, preferably a pH of 10.7 or above, preferably a pH of 11 or above.

[0120] Without wishing to be bound by any theory, it is believed that by dissolving the compound of formula I at high pH, ​​the compound of formula I becomes trapped in the cavity of the compound of formula II (β-cyclodextrin). The compound of formula I remains trapped in the cavity during steps 2 and 3, which means that when the solution is reconstituted, the compound of formula I is soluble in aqueous solution at physiological pH.

[0121] The dry pharmaceutical formulation may be reconstituted into an aqueous pharmaceutical formulation according to the invention by reconstituting the formulation in pharma- ceutical acceptable grade water, buffer or saline to obtain an aqueous pharmaceutical formulation.

[0122] Alternatively, drying the pharmaceutical composition can include: Step 1: preparing a mixture comprising water, a compound of formula I and a compound of formula II, wherein the molar ratio of the compound of formula I to the compound of formula II is 1:50 to 1:2; Step 2: Drying the solution It may be obtained by a method comprising:

[0123] In this case, the reconstitution step is preferably carried out with an acidic solution to ensure that the resulting solution has a suitable pH for injection.

[0124] Preparation of the Composition The present invention also relates to a method for producing an aqueous pharmaceutical formulation according to the present invention, said method comprising: Step 1: preparing a mixture comprising water, a compound of formula I and a compound of formula II; Step 2: Adding an acid to lower the pH of the mixture to a value between pH 7 and pH 8. The process includes the steps of:

[0125] Preferably, step 1 is carried out at a pH of 9 or above, preferably a pH of 10 or above, preferably a pH of 10.5 or above, preferably a pH of 10.7 or above, preferably a pH of 11 or above.

[0126] Preferably, the concentration of the compound of formula II in step 1 is from 10 mg / mL to 2000 mg / mL, more preferably from 50 mg / mL to 1500 mg / mL, and most preferably from 100 mg / mL to 1000 mg / mL.

[0127] Preferably, step 1 comprises: Step 1a: preparing a mixture comprising water and a compound of formula II; Step 1b: Adding a base to the mixture to ensure that the mixture has a pH of 9 or greater, preferably 10 or greater; preferably a pH of 11 or greater. Step 1c: Adding a compound of formula I Includes.

[0128] Preferably, during step 1, the mixture is stirred using a stirring device until all of the compound of formula I is dissolved. The stirring device used is not particularly limited, and suitable stirring devices include a vortex mixer, a magnetic stirrer, a helix mixer, or a paddle stirrer.

[0129] Preferably, the mixture is stirred for at least 40 minutes in step 1. Without wishing to be bound by any theory, it is believed that this is the time necessary to ensure that the QTX125 molecules enter the cavities in the cyclodextrin and release any intramolecular non-covalent interactions.

[0130] Optionally, when the method comprises steps 1a, 1b and 1c, the mixture may be stirred for at least 20 minutes in step 1a, at least 15 minutes in step 1b, and at least 40 minutes in step 1c.

[0131] Preferably, step 2 also involves diluting the mixture with a diluent, such as water.

[0132] Preferably, following step 2, the mixture is filtered, for example through a 0.45 μm or 0.2 μm filter.

[0133] Also, the method is: Step 1: preparing a mixture comprising water, a compound of formula I and a compound of formula II; Step 2: Adding an acid to reduce the pH of the mixture to a value between pH 7 and pH 8; Step 3: Drying the mixture The present invention may also relate to a method for producing a dry pharmaceutical formulation, comprising the steps of:

[0134] The preferred embodiments for steps 1 and 2 described for the process for producing the liquid pharmaceutical formulation according to the present invention also apply to the process for producing the dry pharmaceutical formulation.

[0135] Preferably, the drying in step 3 is carried out by lyophilizing the pharmaceutical formulation.

[0136] Optionally, the method may include a step 4 of storing the dried pharmaceutical formulation at room temperature for a period of at least 3 months.

[0137] The present invention also relates to an aqueous pharmaceutical formulation or a dry pharmaceutical formulation obtainable by the above process.

[0138] Medical uses, treatment methods In a further aspect, the present invention relates to the aqueous pharmaceutical formulation or the dry pharmaceutical formulation according to the invention for use in the manufacture of a medicament.

[0139] Preferably, the present invention relates to an aqueous or dry pharmaceutical formulation according to the present invention for use in the manufacture of a medicament for the treatment of cancer.

[0140] Alternatively, the present invention relates to the aqueous pharmaceutical formulation or the dry pharmaceutical formulation according to the present invention for use in the manufacture of a medicament for the treatment of an autoimmune disease.

[0141] In a further aspect, the present invention relates to a liquid pharmaceutical formulation obtainable by reconstituting the aqueous or dry pharmaceutical formulation according to the invention for use as a medicament.

[0142] Preferably, the present invention relates to a liquid pharmaceutical formulation obtainable by reconstituting the aqueous or dry pharmaceutical formulation according to the present invention for use in the treatment of cancer.

[0143] Alternatively, the present invention relates to a liquid pharmaceutical formulation obtainable by reconstituting the aqueous or dry pharmaceutical formulation according to the present invention for use in the treatment of an autoimmune disease.

[0144] In a further aspect, the present invention relates to a method of treatment comprising administering to a patient in need of such treatment a liquid pharmaceutical formulation obtained by reconstituting the aqueous or dry pharmaceutical formulation according to the invention.

[0145] Preferably, the present invention relates to a method for treating cancer comprising administering to a patient in need of cancer treatment a liquid pharmaceutical formulation obtained by reconstituting the aqueous or dry pharmaceutical formulation according to the present invention.

[0146] Alternatively, the present invention relates to a method for treating an autoimmune disease, comprising administering to a patient in need of such treatment a liquid pharmaceutical formulation obtained by reconstituting the aqueous or dry pharmaceutical formulation according to the present invention.

[0147] Preferably, the cancer is selected from breast cancer, chronic myeloid (or myeloid) leukemia (CML), colon cancer, lymphoma (such as non-Hodgkin's lymphoma), fibrosarcoma, gastric cancer, glioblastoma, renal cancer, liver cancer, lung cancer, melanoma, nasopharyngeal cancer, oral cancer, orthotopic multiple myeloma, osteosarcoma, ovarian cancer, pancreatic cancer, and prostate cancer.

[0148] Preferably, the autoimmune disease is selected from autoimmune hepatitis; inflammatory demyelinating diseases of the central nervous system; systemic lupus erythematosus; acute anterior uveitis; Sjogren's syndrome; rheumatoid arthritis; type 1 diabetes; Graves' disease; and inflammatory bowel disease.

[0149] Inflammatory demyelinating diseases of the central nervous system are diseases in which the myelin supporting cells and / or myelin layer of the central nervous system, such as oligodendrocytes, are destroyed. Demyelination causes disruption of nerve signals between the brain and other parts of the body, ultimately resulting in a variety of signs and symptoms, including physical, mental, and sometimes psychiatric problems.

[0150] Specific and non-limiting examples of inflammatory demyelinating diseases include multiple sclerosis (MS) (such as relapsing MS, progressive MS, and optic spinal MS); neuromyelitis optica; acute desseminating encephalomyelitis; acute hemorrhagic leukoencephalitis; Baroconcentric sclerosis; Schilder's disease; Marburg MS; oncolytic MS; sporadic sclerosis; optic neuritis; transverse myelitis; Susac syndrome; age-related white matter lesions; myalgic encephalomyelitis; Guillain-Barre syndrome; progressive inflammatory neuropathy; leukodystrophies such as adrenoleukodystrophy and adrenomyeloneuropathy.Preferably, the autoimmune disease is multiple sclerosis or acute desseminating encephalomyelitis.The autoimmune disease is more particularly acute desseminating encephalomyelitis, or more preferably and most preferably, multiple sclerosis.

[0151] Preferably, the autoimmune disease is selected from autoimmune hepatitis and inflammatory demyelinating diseases of the central nervous system.

[0152] In a particularly preferred embodiment, the autoimmune disease is an inflammatory demyelinating disease of the central nervous system, as described above.

[0153] In another particularly preferred embodiment, the autoimmune disease is autoimmune hepatitis.

[0154] The present inventors have found that, unlike other histone deacetylase inhibitors, QTX125 advantageously shows no evidence of genotoxicity, particularly clastogenicity or agenicity.Similarly, QTX125 has unexpectedly been observed to have improved pharmacokinetic properties, particularly a high half-life and volume of distribution, compared to other histone deacetylase inhibitors.

[0155] Administration Preferably, the aqueous pharmaceutical formulation according to the invention (or the liquid pharmaceutical formulation obtained by reconstituting the dry pharmaceutical formulation according to the invention) is administered by injection. The pharmaceutical formulation may be administered by infusion (continuous) as well as by bolus (separate) administration.

[0156] Methods of administration by injection may be, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intravesical, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid and intrasternal injection.

[0157] Preferably, the administration is by intravenous infusion or intravenous injection (bolus administration), more preferably by intravenous infusion.

[0158] Subjects / Medications The subject of administration can be any animal. Preferably, the subject is a mammal, such as a rat, mouse, cat, dog, horse, pig, sheep, cow, primate, or human. Preferably, the subject is a human patient.

[0159] Generally, the effective amount of the compound of formula I to be administered will depend on a variety of factors, such as the severity of the disorder being treated and the weight of the subject. The active compound is usually administered one or more times per day, for example, once, twice, three or four times per day, with typical total daily doses ranging from 0.01 to 1,000 mg / kg / day.

[0160] Preferably, the compound of formula I is administered to a human patient at a dose of from 0.5 to 50 mg / kg, preferably from 0.5 to 30 mg / kg, preferably from 1 to 20 mg / kg, more preferably from 5 to 10 mg / kg.

[0161] Preferably, the compound of formula I is administered to a human patient in a dosage of from 25 mg to 4500 mg, preferably from 50 mg to 3000 mg, preferably from 250 mg to 1500 mg per day.

[0162] The compounds of the present invention can be used together with at least one other drug to provide a combination therapy, which can be part of the same composition or provided as separate compositions and can be administered at the same or different times.

[0163] kit Another aspect of the invention relates to a kit comprising pharma- ceutical acceptable grade water, buffer or saline for use in the reconstitution of the dried (preferably lyophilized) pharmaceutical formulations and dosage forms according to the invention. Preferably, the pharmaceutical composition is provided in a suitable container and / or in suitable packaging.

[0164] The kit may also include one or more delivery systems, such as syringes and needles, for delivering or administering the pharmaceutical compositions provided therein. The kit may also include instructions for use (e.g., instructions for treating a subject).

[0165] Preferably, the kit also includes instructions for use, e.g., written instructions on how to administer the composition (e.g., injection procedures). Most preferably, the kit includes written instructions on how to prepare a suitable pharmaceutical formulation from a dry pharmaceutical formulation (e.g., how to reconstitute the formulation), and how to subsequently administer the reconstituted pharmaceutical formulation.

[0166] As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention.

[0167] Preferred Embodiments Particularly preferred embodiments include: A compound of formula I dissolved in a concentration of 9 mg / mL or greater; and -β-Cyclodextrin sulfobutyl ether: The injectable aqueous pharmaceutical formulation has a molar ratio of the compound of formula I to β-cyclodextrin sulfobutyl ether of from 1:15 to 1:2.3.

[0168] Preferably, the molar ratio of the compound of formula I to β-cyclodextrin sulfobutyl ether is from 1:4.5 to 1:2.3.

[0169] Preferably, the aqueous pharmaceutical composition comprises: Step 1: preparing a mixture comprising water, a compound of formula I, and β-cyclodextrin sulfobutyl ether, wherein the molar ratio of the compound of formula I to β-cyclodextrin sulfobutyl ether is 1:15 to 1:2.3, and optionally the pH of the mixture is pH 9 or higher; Step 2: Adding an acid to lower the pH of the mixture to a value between pH 7 and pH 8. The method is obtained by a method comprising the steps of:

[0170] In a further preferred embodiment, the present invention provides: A compound of formula I dissolved in a concentration of 9 mg / mL or greater; and - a compound of formula II (wherein the molar ratio of the compound of formula I to the compound of formula II is from 1:15 to 1:2.3). A dry pharmaceutical formulation obtained by freeze-drying an aqueous pharmaceutical formulation comprising: The dry pharmaceutical preparation is: Step 1: preparing a mixture containing water, a compound of formula I and a compound of formula II (the molar ratio of the compound of formula I to the compound of formula II is 1:50 to 1:2.3, and the pH of the mixture is 9 or more, preferably 10.5 or more); Step 2: Adding an acid to reduce the pH of the mixture to a value between pH 7 and pH 8; Step 3: Lyophilizing the Pharmaceutical Formulation The method is obtained by a method comprising the steps of:

[0171] Preferably, the compound of formula II is β-cyclodextrin sulfobutyl ether (SBβCD).

[0172] Preferably, the pH of the mixture in step 1 is greater than or equal to pH 10.7.

[0173] In a further preferred embodiment, the present invention relates to kits comprising pharma- ceutical acceptable grade water, buffer or saline for use in the reconstitution of the above-mentioned lyophilized pharmaceutical formulations and dosage forms.

[0174] In a further preferred embodiment, the present invention relates to the use of a pharmaceutical formulation or a lyophilized formulation as described above in the manufacture of a medicament.

[0175] Preferably, the medicament is for the treatment of cancer or an autoimmune disease.

[0176] More preferably, the medicament is for treating cancer. EXAMPLES

[0177] Working Example In order to better understand the nature of the present invention, some illustrative examples are now described.

[0178] The scope of the invention is not limited to the examples provided below, which merely demonstrate the effectiveness of the invention.

[0179] The experimental results of WO 2011 / 039353 are incorporated herein by reference.

[0180] Experiment 1 - Formulation development This example illustrates a compound of formula I

[0181] [ka]

[0182] This figure shows how the solubility of various aqueous formulations containing (3-(3-furyl)-N-{4-[(hydroxyamino)carbonyl]benzyl}-5-(4-hydroxyphenyl)-1H-pyrrole-2-carboxamide (QTX125)) changes depending on the aqueous formulation.

[0183] Excipients Parenteral grade excipients were used in the formulation development of Example 1. Details of the excipients are summarized in Table 1 below.

[0184] [Table 1]

[0185] The 0.2 μm filters were PDVF filters manufactured by Merck; The 0.45 μm filters were nylon syringe filters manufactured by Merck.

[0186] Solubility Test Procedure The solubility tests in this application were performed as follows: - Required amount of excipients was weighed into vials. - Diluents / co-solvents were added as per the respective test composition. - The contents were vortexed until dissolved. - The required amount of QTX125 was weighed and added to the above mixture and vortexed for 10-15 min. - The formulation was made up to volume with diluent. - The above solution was mixed for 24 hours at room temperature using a bottle roller.

[0187] Abbreviation The following abbreviations were used in Example 1:

[0188] JPEG2025511030000020.jpg75170

[0189] Example 1.1 - pH Adjustment In this example, the effect of pH adjustment was investigated, and the results are shown in Table 2.

[0190] [Table 2]

[0191] From this data, it was observed that QTX125 formed a cloudy suspension. The pH achieved with all basifying agents used in this study was greater than 10, which is not suitable for parenteral administration (without being bound by theory, it is believed that a pH that is too high would be painful upon administration). Therefore, a pH adjustment approach alone would not help to solubilize QTX125 within the physiological pH range.

[0192] Example 1.2 - Co-solvents In this example, the effect of co-solvents on the solubility of QTX125 was investigated, and the results are shown in Table 3.

[0193] [Table 3]

[0194] QTX125 remains undissolved or forms a cloudy suspension in all studies using different solvent compositions at the maximum tolerated dose. The use of a co-solvent approach is not sufficient to solubilize QTX125.

[0195] Example 1.3 - Cyclodextrin In this example, the effect of using a formulation containing cyclodextrin was investigated, and the results are shown in Table 4.

[0196] [Table 4]

[0197] HPβCD forms a cloudy suspension with a solubility of 0.14 mg / mL after 24 h. In conclusion, HPβCD alone does not help solubilize QTX125.

[0198] Example 1.4 - Cosolvents and Microemulsions In this example, the effect of using a co-solvent and a microemulsion was investigated, and the results are shown in Table 5.

[0199] [Table 5]

[0200] It was observed that the pH of the drug solution was within the required range and achieved a solubility of up to 9.85 mg / mL. However, it was observed that this solution was not stable and the emulsion broke after 24 hours. This means that it is not suitable for the development of pharmaceutical formulations where it is important that QTX125 remains in solution during long-term storage. To check the reproducibility of T24, T31 study was performed using the same drug and excipient concentrations and the same manufacturing procedures as T24. However, the results varied from study to study, indicating that the same level of solubility could not be reproducibly obtained using this approach. It is therefore concluded that this approach is not suitable for the development of an IV formulation of QTX125.

[0201] Example 1.5 - Basifying Agents and Co-Solvents In this example, the effect of using a basifying agent and a co-solvent was investigated, and the results are shown in Table 6.

[0202] [Table 6]

[0203] Example 1.6 - pH Adjustment and Cyclodextrin In this example, the effects of pH adjustment and using cyclodextrin were investigated, and the results are shown in Table 7.

[0204] [Table 7-1]

[0205] [Table 7-2]

[0206] [Table 7-3]

[0207] [Table 7-4]

[0208] Example 1.7 - pH Adjustment and Lyophilization In this example, the effect of using pH adjustment and lyophilization was investigated, and the results are shown in Table 8.

[0209] The samples were prepared as described in the Solubility Test Procedure section above, and the solutions were then lyophilized, then reconstituted in 10 mL of water to determine the solubility of QTX125.

[0210] [Table 8]

[0211] Example 1.8 - pH Adjustment, Co-solvents and Cyclodextrins In this example, the effects of pH adjustment, co-solvents and using cyclodextrin were investigated, and the results are shown in Table 9.

[0212] [Table 9]

[0213] Example 1.9 - Co-solvents and Cyclodextrins In this example, the effect of using a co-solvent and cyclodextrin was investigated, and the results are shown in Table 10.

[0214] [Table 10]

[0215] Experiment 2 - Stability and freeze-drying studies This study will explore the development of a robust and stable intravenous formulation of QTX125. The study will assess the long-term stability of such a formulation.

[0216] material The materials used in Example 2 are shown in Table 11.

[0217] [Table 11]

[0218] HPLC measurement method The required parameters for the HPLC method used to determine the concentration of QTX125 in solution are given below.

[0219] JPEG2025511030000034.jpg41170

[0220] JPEG2025511030000035.jpg30170

[0221] JPEG2025511030000036.jpg122170

[0222] HPLC quantification of the percentage of QTX125 in the following solutions was determined using the protocol above. The QTX125 peak was seen at a retention time of approximately 24.1 min.

[0223] The assay (% LC) was determined by comparing the area of ​​the QTX125 peak with a calibration curve determined by running samples of known concentrations of QTX125 (standard) on the HPLC.

[0224] QTX125% was calculated based on the area of ​​the QTX125 peak compared to the sum of all peak areas in the chromatogram.

[0225] The percentage of impurities (% w / w) was calculated based on the area normalization method, which is based on the relative area of ​​the impurity peaks (i.e., peaks eluting at retention times other than 24.1 min) compared to the sum of all peak areas in the chromatogram.

[0226] Example 2.1-1: 2.7 Liquid Injection Formulation Manufacturing Process The liquid injectable formulation used in Example 2.1 was manufactured in a batch size of 400 mL as follows: -30% v / v water based on the total volume of the formulation was added to the beaker; - The required amount of SBβCD was added to the beaker and stirred for 20 minutes to dissolve. The pH of the solution was checked. -20mL of 1.0N NaOH (equivalent to 5% v / v NaOH) was added to the solution (800mg sodium hydroxide) and mixed by stirring for 15 minutes. The pH of the solution was checked. -Appropriate amount of QTX125 was added to the solution and dissolved by stirring at room temperature for 40 minutes. The pH of the solution was checked and adjusted to pH 7.3 with 0.25N HCl solution. - The volume of the bulk solution was made up to 100% v / v of the total batch size with Water for Injection and stirred for 15 minutes. The pH of the solution was checked. -The solution was filtered through a 0.2 μm PVDF filter membrane (Merck).

[0227] For the liquid formulation with a drug to SBβCD ratio of 1:2.7, stability results after 1 month (1M), 2 months (2M), and 3 months (3M) of storage at 5±3° C., 25° C. and 60% relative humidity (25° C. / 60% RH), and 40° C. and 75% relative humidity (40° C. / 75% RH) are shown in Table 12.

[0228] [Table 12]

[0229] Precipitation was observed in samples stored at 25°C / 60% RH and 40°C / 75% RH. A decrease in pH was observed in samples at 25°C / 60% RH and 40°C / 75% RH. The formulation appears to be stable for up to 3 months at 2-8°C, but was found to be unstable at 25°C / 60% RH and 40°C / 75% RH. This is evident from the solution depiction, decrease in pH and increase in total impurities.

[0230] Example 2.2-1: 5.4 Liquid Injection Formulation Samples were prepared as described above for Example 2.1. Stability results for the liquid formulation with a drug to SBβCD ratio of 1:5.4 after 1 month (1M), 2 months (2M) and 3 months (3M) of storage at 5±3° C., 25° C. and 60% relative humidity (25° C. / 60% RH), and 40° C. and 75% relative humidity (40° C. / 75% RH) are shown in Table 13.

[0231] [Table 13]

[0232] Example 2.3 - 1:2.7 Liquid Injection with Buffer Manufacturing Process The liquid injectable formulation used in Example 2.3 was manufactured in a batch size of 400 mL as follows: -30% v / v water based on the total volume of the formulation was added to the beaker; - The required amount of SBβCD was added to the beaker and stirred for 20 minutes to dissolve. The pH of the solution was checked. -10 mL of 1.0 N NaOH (2.5% v / v NaOH) was added to the solution (400 mg sodium hydroxide) and mixed by stirring for 15 minutes. The pH of the solution was checked. -Appropriate amount of QTX125 was added to the solution and dissolved by stirring at room temperature for 40 minutes. The pH of the solution was checked and adjusted to pH 7.3 with 0.25N HCl solution. - 120 mL of 0.2 N monosodium phosphate solution (30% v / v) was added to the mixture and mixed for 15 minutes. The pH of the solution was checked. - The volume of the bulk solution was made up to 100% v / v of the total batch size with Water for Injection and stirred for 15 minutes. The pH of the solution was checked. -The solution was filtered through a 0.2 μm PVDF filter membrane (Merck).

[0233] For the liquid formulation with a 1:2.7 ratio of drug to SBβCD in buffer, stability results after 1 month (1M), 2 months (2M), and 3 months (3M) of storage at 5±3° C., 25° C. and 60% relative humidity (25° C. / 60% RH), and 40° C. and 75% relative humidity (40° C. / 75% RH) are shown in Table 14.

[0234] [Table 14]

[0235] Lumps were observed in the 2-month and 3-month and later samples; therefore, these samples were not tested.

[0236] Example 2.4-1: 2.7 Freeze-dried product Samples were prepared as in Example 2.1 above, filled into 20 mL / 20 mm amber USP Type I vials, semi-stoppered with 20 mm rubber stoppers, and loaded into the freeze dryer.

[0237] The freeze-drying process was carried out using the following program, as shown in Table 15.

[0238] [Table 15]

[0239] For the reconstituted lyophilized formulation with a drug to SBβCD ratio of 1:4, stability results after 1 month (1M), 2 months (2M), and 3 months (3M) of storage at 5±3° C., 25° C. and 60% relative humidity (25° C. / 60% RH), and 40° C. and 75% relative humidity (40° C. / 75% RH) are shown in Table 16.

[0240] [Table 16]

[0241] No changes were observed in the test parameters. The drug product in the form of a lyophilized cake was found to be stable up to three months under all three conditions (2°C-8°C, 25°C / 60% RH and 40°C / 75% RH).

[0242] Conclusion of Example 2 In conclusion, the lyophilized drug products are relatively more stable than the ready-to-use injectable forms. A summary of the observations from each of Examples 2.1-2.4 is shown in Table 17 below.

[0243] [Table 17]

[0244] Example 3 - Tolerance of the new formulation in Sprague Dawley rats The objective of this study was to evaluate mammalian (male Sprague Dawley rats) tolerance to different formulations of QTX125.

[0245] Formulations used in this example Formulation A: 5% v / v 1N NaOH + 13.9% SBβCD (Captisol) + pH adjusted to 7.2 with 0.25N HCl and / or 0.1 NaOH + water for injection qs

[0246] Formulation B: 20% PEG400 + 30% propylene glycol + 15% glycerol + 10% Tween80 + 25% water for injection qs

[0247] The study design of this study is summarized in Table 18 below.

[0248] [Table 18]

[0249] The formulations were prepared on the day of dosing and were administered to each group of animals as a 30-minute intravenous infusion via a femoral vein cannula using a Harvard pump infusion.

[0250] result Intravenous infusion of Formulation A (doses of 15, 30, 40, 60, 80, 120 and 200 mg / kg) was well tolerated in male Sprague Dawley rats.

[0251] A single intravenous injection of Formulation B (dose: 30 mg / kg) into male Sprague Dawley rats revealed that all animals died during the infusion period.

[0252] These results indicate that Formulation A is better tolerated than Formulation B in male Sprague Dawley rats.

Claims

1. An injectable aqueous pharmaceutical formulation comprising: a compound of formula I, 【Chemistry 1】 and a compound of formula II: 【Chemistry 2】 (In the formula, each R １ is independently selected from the following groups: —H or 【Chemistry 3】 R ２ does not exist or C １－４ is alkyl; Q is selected from the following groups: -H, -SO ３ － , -OH, -C(O)R ３ or -C(OH)R ３ ２ and R ３ are independently -H or C １－４ alkyl); the molar ratio of the compound of formula I to the compound of formula II is from 1:50 to 1:2; and The pH of the pharmaceutical formulation is between pH 7 and pH 8.

2. 2. The liquid pharmaceutical formulation according to claim 1, wherein the compound of formula I is dissolved at a concentration of 7.5 mg / mL or more.

3. 3. The formulation of claim 1 or 2, wherein the compound of formula I is dissolved in a concentration of at least 8 mg / mL, preferably at least 8.5 mg / mL, more preferably at least 9 mg / mL, even more preferably at least 9.5 mg / mL and optionally up to a maximum concentration of 20 mg / mL.

4. The compound of formula II is: β-cyclodextrin, (C １－４ alkyl)-β-cyclodextrin, (hydroxy-C １－４ 2. The aqueous pharmaceutical formulation according to any one of the preceding claims, wherein the cyclodextrin is selected from the group of (alkyl)-β-cyclodextrin and sulfobutyl ether of β-cyclodextrin.

5. 10. The method of claim 1, wherein the compound of formula II is hydroxypropyl beta-cyclodextrin or beta-cyclodextrin sulfobutyl ether (SBβCD).

6. 10. The method of claim 9, wherein the compound of formula II is β-cyclodextrin sulfobutyl ether (SBβCD).

7. 7. The aqueous pharmaceutical formulation according to any one of claims 1 to 6, wherein the molar ratio of the compound of formula I to the compound of formula II is from 1:40 to 1:2.5, preferably from 1:30 to 1:2.5, preferably from 1:25 to 1:2.5, preferably from 1:20 to 1:2.

5.

8. 8. The aqueous pharmaceutical formulation according to claim 7, wherein the molar ratio of the compound of formula I to the compound of formula II is from 1:15 to 1:2.5, preferably from 1:10 to 1:2.5, preferably from 1:9 to 1:2.5, preferably from 1:8 to 1:2.5, preferably from 1:6 to 1:2.5, more preferably from 1:4.5 to 1:2.

5.

9. - the compound of formula I is dissolved in a concentration of 9 mg / mL or more; - the compound of formula II is β-cyclodextrin sulfobutyl ether; and - the molar ratio of compound of formula I to β-cyclodextrin sulfobutyl ether is from 1:4.5 to 1:2.5;

10. 13. The injectable aqueous pharmaceutical formulation according to any one of the preceding claims, comprising: a compound of formula I, 【Chemistry 4】 and a compound of formula II: 【Chemistry 5】 (In the formula, each R １ is independently selected from the following groups: 【Chemistry 6】 R ２ does not exist or C １－４ Alkyl; Q is selected from the following groups: -H, -SO ３ － , -OH, -C(O)R ３ or -C(OH)R ３ ２ , and R ３ are independently -H or C １－４ alkyl); Step 1: preparing a mixture comprising water, a compound of formula I, and a compound of formula II, wherein the molar ratio of the compound of formula I to the compound of formula II is from 1:50 to 1:2; Step 2: adding an acid to reduce the pH of the mixture to a value between pH 7 and pH 8; optionally, step 1 is carried out at a pH of 9 or higher.

11. A dry pharmaceutical formulation obtainable by drying the aqueous pharmaceutical formulation according to any one of the preceding claims.

12. 12. The dry pharmaceutical formulation according to claim 11, obtained by freeze-drying the aqueous pharmaceutical formulation according to any one of claims 1 to 10.

13. 13. A kit comprising pharma-ceutical grade water, buffer or saline for use in the reconstitution of the dry pharmaceutical formulations and dosage forms according to claims 11 or 12.

14. Use of the aqueous pharmaceutical formulation according to any one of claims 1 to 10 or the dry pharmaceutical formulation according to claim 11 or 12 in the manufacture of a medicament.

15. Use of the aqueous pharmaceutical formulation according to any one of claims 1 to 10 or the dry pharmaceutical formulation according to claim 11 or 12 in the manufacture of a medicament for the treatment of cancer or an autoimmune disease.

16. A reconstituted liquid pharmaceutical formulation obtainable by reconstituting the aqueous pharmaceutical formulation according to any one of claims 1 to 10 or the dry pharmaceutical formulation according to claim 11 or 12 for use as a medicament.

17. A reconstituted liquid pharmaceutical formulation obtained by reconstituting the aqueous pharmaceutical formulation according to any one of claims 1 to 10 or the dry pharmaceutical formulation according to claim 11 or 12 for use as a pharmaceutical for treating cancer or an autoimmune disease.

18. A method of treatment comprising administering to a patient in need of such treatment a reconstituted liquid pharmaceutical formulation obtained by reconstituting the aqueous pharmaceutical formulation according to any one of claims 1 to 10 or the dry pharmaceutical formulation according to claim 11 or 12.

19. 18. The method of treatment of claim 17, wherein the method is a method for treating cancer or an autoimmune disease.

20. A method for producing the aqueous pharmaceutical formulation according to any one of claims 1 to 10 or the dry pharmaceutical formulation according to claim 11 or 12, comprising: Step 1: Preparing a mixture containing water, a compound of formula I, and a compound of formula II; Step 2: Adding an acid to lower the pH of the mixture to a value between pH 7 and pH 8.

21. 21. The method of claim 20, wherein step 1 is carried out at a pH of 9 or greater.

22. The method for producing a dried pharmaceutical formulation according to claim 20 or 21, further comprising a step of lyophilizing the liquid pharmaceutical formulation obtained after step 2.

23. The method according to any one of claims 20 to 22, wherein the method further comprises the step of storing the aqueous pharmaceutical formulation or the lyophilized or freeze-dried formulation at room temperature for a period of at least 3 months.

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