Pharmaceutical compositions comprising an antibiotic macrocyclic peptide

Abstract

The present invention relates to liquid and lyophilized pharmaceutical compositions comprising 4-[(11S,14S,17S)-14-(4-Aminobutyl)-11-(3-aminopropyl)-17-(1H-indol-3- ylmethyl)-16-methyl-12,15,18-trioxo-2-thia-4,10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-1(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (I), or a pharmaceutically acceptable salt thereof, to processes for their preparation, kits comprising them, and their use in medical treatment.

Description

[0001] Case P39012

[0002] PHARMACEUTICAL COMPOSITIONS COMPRISING AN ANTIBIOTIC MACROCYCLIC PEPTIDE

[0003] Field of the invention

[0004] The present invention relates to liquid and lyophilized pharmaceutical compositions comprising 4-[(l lS,14S,17S)-14-(4-Aminobutyl)-l 1 -(3 -aminopropyl)- 17-(lH-indol-3-ylmethyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19-pentazatricyclo[19.4.0.03,8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (I), or a pharmaceutically acceptable salt thereof, to processes for their preparation, kits comprising them, and their use in medical treatment.

[0005]

[0006] Background of the invention

[0007] The compound of formula (I) is a potent antibiotic with selective action against Acinetobacter baumannii (WO2019206853, C. Zampaloni etal., Nature 2024, https: / / doi.org / 10.1038 / s41586-023-06873-0). The compound of formula (I) is also known under the INN zosurabalpin (WHO Drug Information, Vol. 36, No. 2, 2022) and the lab code RO7223280.

[0008] WO2019206853 discloses a sterile aqueous solution comprising certain macrocyclic peptides, such as zosurabalpin, for intravenous administration. However, it has now been found that aqueous solutions of zosurabalpin are prone to degradation over time. Furthermore, aqueous solutions comprising zosurabalpin have been found to be prone to formation of visible particles.

[0009] In summary, there is a high unmet need for new pharmaceutical compositions comprising zosurabalpin that address, for example, the problems outlined above, in order to safely administer this new drug to patients in need.

[0010] CNE / 18.12.2025Summary of the Invention

[0011] It has now surprisingly been found that adding methionine to liquid formulations comprising zosurabalpin as API suppresses API degradation over time.

[0012] Thus, in a first aspect, the present invention relates to an aqueous pharmaceutical composition comprising:

[0013] (i) 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3- ylmethyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (I)

[0014]

[0015] or a pharmaceutically acceptable salt thereof, and

[0016] (ii) methionine.

[0017] Lyophilizates of the liquid formulations described herein have certain advantages that are described in more detail further below. Thus, in a further aspect, the present invention provides lyophilizates of the liquid formulations described herein. The present invention also provides pharmaceutical compositions that are obtained by reconstitution of the lyophilized formulations described herein.

[0018] In some instances, it may be required to dilute the liquid pharmaceutical compositions according to the invention. Such diluted pharmaceutical compositions are also within the ambit of the present invention.

[0019] In yet further aspects, the present invention provides processes for the preparation of the formulations described herein, kits comprising them, and their use in medical treatment, especially their use as antibiotics.Brief Description of the Figures

[0020] Figure 1 depicts degradation of the API over time in an aqueous solution with or without methionine as a stabilizer (experiment described in Example 4).

[0021] Definitions

[0022] The term “isotonic” as used herein refers to an aqueous pharmaceutical formulation having an osmolarity of approximately 300-312 mOsm / L, for example 306 mOsm / L.

[0023] The term “treatment” of a disease state as used herein includes inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

[0024] The term “therapeutically effective amount” denotes an amount of a pharmaceutical composition of the present invention that, when administered to a subject, (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. The therapeutically effective amount will vary depending on the disease state being treated, the severity of the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.

[0025] Detailed Description

[0026] Liquid Formulations

[0027] In a first aspect, the present invention provides an aqueous pharmaceutical composition comprising:

[0028] (i) 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3- ylmethyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (I)

[0029]

[0030] or a pharmaceutically acceptable salt thereof, and

[0031] (ii) methionine.

[0032] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, or about 25 mg / mL to about 50 mg / mL.

[0033] As mentioned above, aqueous solutions comprising zosurabalpin have been found to be prone to visible particle formation. Lowering the concentration of zosurabalpin in the formulation to about 25 mg / mL has been found to be an effective means to suppress the formation of visible particles. Thus, in a preferred embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 25 mg / mL.

[0034] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 50 mg / mL.

[0035] In one embodiment, methionine is at a concentration of about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, about 5 mM to about 20 mM, about 10 mM to about 40 mM, or about 20 mM to about 40 mM.

[0036] In one embodiment, methionine is at a concentration of about 20 mM to about 40 mM.

[0037] In a preferred embodiment, methionine is at a concentration of about 40 mM.

[0038] The pH of the aqueous pharmaceutical compositions according to the invention may be adjusted by adding hydrochloric acid to them. In some instances, this is required to solubilize the API. Inone embodiment, the pH of the composition is at about 4.8 to about 7.0, preferably about 4.8 to about 5.8.

[0039] In a preferred embodiment, the pH of the composition is at about 5.3.

[0040] It may be desired to modify the tonicity of the pharmaceutical formulations of the invention by adding sugars to them. Thus, in one embodiment, the composition further comprises a sugar.

[0041] In one embodiment, the sugar is at a concentration of about 80 mM to about 300 mM, about 90 mM to about 300 mM, about 100 mM to about 300 mM, about 110 mM to about 290 mM, about 120 mM to about 280 mM, about 130 mM to about 270 mM, about 140 mM to about 260 mM, about 150 mM to about 250 mM, about 160 mM to about 240 mM, about 170 mM to about 230 mM, about 180 mM to about 220 mM, or about 190 mM to about 220 mM.

[0042] In a preferred embodiment, the sugar is at a concentration of about 200 mM.

[0043] In one embodiment, the sugar is selected from the group consisting of: sucrose, mannitol, sorbitol, glycerol, dextran 40, and trehalose.

[0044] In a preferred embodiment, the sugar is trehalose.

[0045] In a preferred embodiment, the sugar is trehalose and is at a concentration of about 200 mM.

[0046] The tonicity of the pharmaceutical compositions of the invention may also be modified by adding sodium chloride to them. Thus, in one embodiment, the composition further comprises sodium chloride.

[0047] In one embodiment, the sodium chloride concentration is about 7.5 mg / mL.

[0048] In one embodiment, the pharmaceutical composition is isotonic.

[0049] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 25 mg / mL and methionine is at a concentration of about 40 mM.

[0050] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 25 mg / mL, methionine is at a concentration of about 40 mM and the pH of the pharmaceutical composition is at about 5.3.In one embodiment, the pharmaceutical composition is:

[0051]

[0052] In one embodiment, the pharmaceutical composition is:

[0053]

[0054] In one embodiment, the pharmaceutical composition is:

[0055]

[0056] Lyophilized Formulations

[0057] Lyophilized formulations may have certain advantages over the corresponding liquid formulations, for example in terms of increased shelflife and the possibility to reconstitute them in small volumes of liquids, suitable for administration to pediatric patients. Thus, in one aspect, the present invention provides a solid pharmaceutical composition that is obtained by lyophilization of certain aqueous pharmaceutical compositions described herein.

[0058] In one embodiment, the pharmaceutical composition is a lyophilized cake.

[0059] In one aspect, the present invention provides a pharmaceutical composition that is obtained by reconstitution of a lyophilized cake described herein with sterile water for injection (SWFI).In one embodiment, the final volume of the reconstituted composition is about 8 mL to about 35 mL.

[0060] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about

[0061] 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, or about 25 mg / mL to about 50 mg / mL.

[0062] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 12 mg / mL.

[0063] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 25 mg / mL.

[0064] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 50 mg / mL.

[0065] In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 100 mg / mL.

[0066] Diluted Formulations

[0067] The drug product is administered intravenously and it will typically be required to dilute the aqueous pharmaceutical compositions described herein prior to intravenous administration. Thus, in one aspect, the present invention provides a pharmaceutical composition for intravenous administration obtained by dilution of any of the aqueous pharmaceutical compositions described herein into SWFI to produce a diluted composition.

[0068] In one embodiment, the SWFI is contained in an IV bag.

[0069] In one embodiment, the final volume of the diluted composition is about 1 mL to about 500 mL.

[0070] In one embodiment, the SWFI comprises dextrose, preferably 5% wt / wt to 10% wt / wt of dextrose.

[0071] In one embodiment, the SWFI comprises sodium chloride, preferably 0.9% wt / wt of sodium chloride.In one embodiment, the concentration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the diluted composition is between about 1 mg / mL and about

[0072] 15 mg / mL, preferably about 12 mg / mL.

[0073] In one embodiment, the pharmaceutical composition is isotonic.

[0074] Using the Pharmaceutical Compositions

[0075] The aqueous pharmaceutical compositions of the invention are for administration by intravenous infusion to human patients. The lyophilized formulations of the invention need to be reconstituted in sterile water for injection (SWFI) before administration to patients. In some instances, the liquid formulations of the inventions may need to be diluted in SWFI prior to administration to patients, for example by adding them to an IV bag containing SWFI. The SWFI that is used for dilution / reconstitution may contain excipients like sodium chloride and / or dextrose. In some instances, the human patients are pediatric patients aged from birth to 18 years old.

[0076] In one aspect, the present invention provides a kit comprising a pharmaceutical composition described herein and instructions for use.

[0077] In one aspect, the present invention provides a pharmaceutical composition described herein for use as an antibiotic.

[0078] In one aspect, the present invention provides a pharmaceutical composition described herein for use in the treatment of an infection due to a pathogen from the Acinetobacter baumannii complex of pathogens.

[0079] In one aspect, the present invention provides a method for the treatment of an infection due to a pathogen from the Acinetobacter baumannii complex of pathogens in a human, which method comprises administering a therapeutically effective amount of a pharmaceutical composition described herein to said human.

[0080] In one aspect, the present invention provides the use of a pharmaceutical composition described herein for the treatment of an infection due to a pathogen from the Acinetobacter baumannii complex of pathogens.In one aspect, the present invention provides the use of a pharmaceutical composition described herein for the manufacture of a medicament for the treatment of an infection due to a pathogen from the Acinetobacter baumannii complex of pathogens.

[0081] In one embodiment, said pathogen from the Acinetobacter baumannii complex of pathogens is Acinetobacter baumannii.

[0082] In one embodiment, said pathogen from the Acinetobacter baumannii complex of pathogens is carbapanem-resistant, colistin-resistant and / or polymyxin B-resistant.

[0083] In one embodiment, said pathogen from the Acinetobacter baumannii complex of pathogens is carbapanem-resistant Acinetobacter baumannii (CRAB).

[0084] In one embodiment, said pathogen from the Acinetobacter baumannii complex of pathogens is colistin-resistant and / or polymyxin B-resistant CRAB.

[0085] In one embodiment, said infection is hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) and / or a bloodstream infection (BSI).

[0086] Numbered Clauses

[0087] The present invention is further described in the following numbered clauses:

[0088] 1. An aqueous pharmaceutical composition comprising:

[0089] (i) 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3- ylmethyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (I)

[0090]

[0091] or a pharmaceutically acceptable salt thereof, and(ii) methionine.

[0092] 2. The aqueous pharmaceutical composition according to clause 1, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about

[0093] 60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, or about 25 mg / mL to about 50 mg / mL.

[0094] 3. The aqueous pharmaceutical composition according to clause 2, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 25 mg / mL.

[0095] 4. The aqueous pharmaceutical composition according to clause 2, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 50 mg / mL.

[0096] 5. The aqueous pharmaceutical composition according to any one of clauses 1 to 4, wherein methionine is at a concentration of about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, about 5 mM to about 20 mM, about 10 mM to about 40 mM, or about 20 mM to about 40 mM.

[0097] 6. The aqueous pharmaceutical composition according to clause 5, wherein methionine is at a concentration of about 20 mM to about 40 mM.

[0098] 7. The aqueous pharmaceutical composition according to any one of clauses 1 to 6, wherein the pH of the composition is at about 4.8 to about 7.0.

[0099] 8. The aqueous pharmaceutical composition according to clause 7, wherein the pH of the composition is at about 5.3.

[0100] 9. The aqueous pharmaceutical composition according to any one of clauses 1 to 8, wherein the composition further comprises sodium chloride.

[0101] 10. The aqueous pharmaceutical composition according to clause 9, wherein the sodium chloride concentration is about 7.5 mg / mL.The aqueous pharmaceutical composition according to any one of clauses 1 to 10, wherein the composition further comprises a sugar.

[0102] The aqueous pharmaceutical composition according to clause 11, wherein the sugar is at a concentration of about 80 mM to about 300 mM, about 90 mM to about 300 mM, about 100 mM to about 300 mM, about 110 mM to about 290 mM, about 120 mM to about 280 mM, about 130 mM to about 270 mM, about 140 mM to about 260 mM, about 150 mM to about 250 mM, about 160 mM to about 240 mM, about 170 mM to about 230 mM, about 180 mM to about 220 mM, or about 190 mM to about 220 mM.

[0103] The aqueous pharmaceutical composition according to clause 12, wherein the sugar is at a concentration of about 200 mM.

[0104] The aqueous pharmaceutical composition according to any one of clauses 11 to 13, wherein the sugar is selected from the group consisting of: sucrose, mannitol, sorbitol, glycerol, dextran 40, and trehalose.

[0105] The aqueous pharmaceutical composition according to clause 14, wherein the sugar is trehalose.

[0106] A solid pharmaceutical composition that is obtained by lyophilization of an aqueous pharmaceutical composition according to any one of clauses 11 to 15.

[0107] The solid pharmaceutical composition according to clause 16, wherein the pharmaceutical composition is a lyophilized cake.

[0108] A pharmaceutical composition that is obtained by reconstitution of a lyophilized cake according to clause 17 with sterile water for injection (SWFI).

[0109] The pharmaceutical composition according to clause 18, wherein the final volume of the reconstituted composition is about 8 mL to about 35 mL.

[0110] The pharmaceutical composition according to clause 18 or 19, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, or about 25 mg / mL to about 50 mg / mL.

[0111] 21. The pharmaceutical composition according to clause 20, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 12 mg / mL.

[0112] 22. The pharmaceutical composition according to clause 20, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 25 mg / mL.

[0113] 23. The pharmaceutical composition according to clause 20, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 50 mg / mL.

[0114] 24. The pharmaceutical composition according to clause 20, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about

[0115] 100 mg / mL.

[0116] 25. A pharmaceutical composition for intravenous administration obtained by dilution of a pharmaceutical composition according to any one of 1 to 15 and 18 to 24 into SWFI to produce a diluted composition.

[0117] 26. The pharmaceutical composition according to clause 25, wherein the final volume of the diluted composition is about 1 mL to about 500 mL.

[0118] 27. The pharmaceutical composition according to any one of clauses 18 to 26, wherein the SWFI comprises dextrose, preferably 5% wt / wt to 10% wt / wt of dextrose.

[0119] 28. The pharmaceutical composition according to any one of clauses 18 to 26, wherein the SWFI comprises sodium chloride, preferably 0.9% wt / wt of sodium chloride.

[0120] 29. The pharmaceutical composition according to any one of clauses 25 to 28, wherein the concentration of the compound of formula (I), or a pharmaceutically acceptable salt thereof, in the diluted composition is between about 1 mg / mL and about 15 mg / mL, preferably about 12 mg / mL.

[0121] 30. The pharmaceutical composition according to any one of clauses 1 to 15 and 18 to 29, wherein the pharmaceutical composition is isotonic.31. A pharmaceutical composition according to any one of clauses 1 to 30 for use as an antibiotic.

[0122] 32. A kit comprising a pharmaceutical composition according to any one of clauses 1 to 30 and instructions for use.

[0123] 33. A pharmaceutical composition according to any one of clauses 1 to 30 for use in the treatment of an infection due to a pathogen from the Acinetobacter baumannii complex of pathogens.

[0124] 34. A method for the treatment of an infection due to a pathogen from the Acinetobacter baumannii complex of pathogens in a human, which method comprises administering a therapeutically effective amount of a pharmaceutical composition according to any one of clauses 1 to 30 to said human.

[0125] 35. The use of a pharmaceutical composition according to any one of clauses 1 to 30 for the treatment of an infection due to a pathogen from the Acinetobacter baumannii complex of pathogens.

[0126] 36. The use of a pharmaceutical composition according to any one of clauses 1 to 30 for the manufacture of a medicament for the treatment of an infection due to a pathogen from the Acinetobacter baumannii complex of pathogens.

[0127] Examples

[0128] The following examples are provided for illustration of the invention. They should not be considered as limiting the scope of the invention, but merely as being representative thereof.

[0129] The following abbreviations are used in the present text:

[0130] API Active pharmaceutical ingredient (RO7223280, zosurabalpin)

[0131] QS Quantum satisExample 1 — Liquid Formulation (25 mg / ml)

[0132]

[0133] RO7223280 and methionine were dissolved in water for injection to obtain the desired composition. The pH was adjusted to 5.3 by adding HC1.

[0134] Example 2 — Liquid Formulation (50mg / ml)

[0135]

[0136] RO7223280 and sodium chloride were dissolved in water for injection to obtain the desired composition prior to filling. The pH was adjusted to 6.8 by adding HC1.

[0137] Example 3 — Liquid (50mg / ml) and Lyophilized Formulations

[0138]

[0139] RO7223280, trehalose and methionine were dissolved in water for injection to obtain a 50 mg / mL liquid composition. The pH was then adjusted to 5.3 by adding HC1. Subsequently, the liquid composition was subjected to lyophilization.

[0140] The following additional liquid and lyophilized formulations were prepared in an analogous fashion:

[0141]

[0142]

[0143] Example 4 — Drug Product Degradation Over Time

[0144]

[0145] Formulation 6a

[0146] RO7223280 and methionine were dissolved in water for injection to obtain a 50 mg / mL liquid composition. The pH was then adjusted to 4.8 by adding HC1.

[0147] Formulation 6b

[0148] RO7223280 was dissolved in water for injection to obtain a 50 mg / mL liquid composition. The pH was then adjusted to 4.8 by adding HC1.Stress Test

[0149] The stress test was conducted by incubating formulations 6a and 6b (see table above) as is in a controlled stability chamber set to a temperature of 40°C. Samples were pulled after defined time intervals (e.g. 4 weeks, 8 weeks, 13 weeks and 30 weeks), as outlined in Table 1. To quantify degradation by HPLC analytics per Example 5, the drug product samples were diluted to a concentration of 1.0 mg / mL in the diluent (water / acetonitrile 8:2 + 0.1% TFA). An API solution in diluent (c = 1.0 mg / mL) served as external reference solution. Samples and references were stored at 2-8°C, protected from light.

[0150] Table 1 Analytical results for total degradation of temperature stress experiments with the drug product (RL = reporting limit). The same results are represented graphically in Figure 1.

[0151] <

[0152] <

[0153] <

[0154] <

[0155] <

[0156] <

[0157]

[0158] Example 5 —HPLC Conditions

[0159] The HPLC conditions used in the stress test of Example 4 were as follows:

[0160] Content and degradation were controlled using a reversed phase HPLC method (e.g. Agilent 1290 series with UV detection, quaternary or binary pump, autosampler). A Cl 8 column (e.g. Waters ACQUITY UPLC Peptide CSH C18 Column, 130 A, L = 100 mm, ID = 2.1 mm, particle size = 1.7 pm) was used as stationary phase. The column temperature was set to 40°C and the detection wavelength was 256 nm (band width = 4 nm). Water + 0.1% TFA served as mobile phaseA, acetonitrile + 0.1% TFA was used as mobile phase B. The flow rate was 0.4 mL / min. An injection volume of 1.5 pL was applied. The column back pressure was ca. 500 bar under initial conditions and the column was flushed with 1. Acetonitrile / water 1:1 and 2. Acetonitrile / water 8:2. A gradient program was used, as shown below:

[0161]

[0162] Data were acquired for 30 min.

[0163] Example 6 — Visible Particle Formation Assessment

[0164] As outlined above, aqueous solutions comprising zosurabalpin have been found to be prone to formation of visible particles due to self-association of zosurabalpin. One object of the present invention is to provide formulations that prevent zosurabalpin from forming visible particles or reduce its tendency to do so. Experimental procedures to study an API’s selfassociation mechanisms in solution are known in the art and include techniques such as measuring diffusion constants by NMR and measuring surface tensions and critical micelle concentrations.

Claims

Claims1. An aqueous pharmaceutical composition comprising:(i) 4-[(llS,14S,17S)-14-(4-Aminobutyl)-ll-(3-aminopropyl)-17-(lH-indol-3- ylmethyl)- 16-m ethyl- 12,15,18-trioxo-2-thia-4, 10,13,16,19- pentazatricyclo[19.4.0.03,8]pentacosa-l(25),3(8),4,6,21,23-hexaen-22-yl]benzoic acid (I)or a pharmaceutically acceptable salt thereof, and(ii) methionine.

2. The aqueous pharmaceutical composition according to claim 1, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, or about 25 mg / mL to about 50 mg / mL.

3. The aqueous pharmaceutical composition according to claim 1 or 2, wherein methionine is at a concentration of about 5 mM to about 50 mM, about 5 mM to about 40 mM, about 5 mM to about 30 mM, about 5 mM to about 20 mM, about 10 mM to about 40 mM, or about 20 mM to about 40 mM.

4. The aqueous pharmaceutical composition according to any one of claims 1 to 3, wherein the pH of the composition is at about 4.8 to about 7.0.

5. The aqueous pharmaceutical composition according to any one of claims 1 to 4, wherein the composition further comprises a sugar.

6. The aqueous pharmaceutical composition according to claim 5, wherein the sugar is at a concentration of about 80 mM to about 300 mM, about 90 mM to about 300 mM, about 100 mM to about 300 mM, about 110 mM to about 290 mM, about 120 mM to about 280 mM, about 130 mM to about 270 mM, about 140 mM to about 260 mM, about 150 mM to about 250 mM, about 160 mM to about 240 mM, about 170 mM to about 230 mM, about 180 mM to about 220 mM, or about 190 mM to about 220 mM.

7. The aqueous pharmaceutical composition according to claim 5 or 6, wherein the sugar is selected from the group consisting of: sucrose, mannitol, sorbitol, glycerol, dextran 40, and trehalose.

8. A lyophilized cake that is obtained by lyophilization of an aqueous pharmaceutical composition according to any one of claims 5 to 7.

9. A pharmaceutical composition that is obtained by reconstitution of a lyophilized cake according to claim 8 with sterile water for injection (SWFI).

10. The pharmaceutical composition according to claim 9, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is at a concentration of about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 20 mg / mL to about 50 mg / mL, or about 25 mg / mL to about 50 mg / mL.

11. A pharmaceutical composition for intravenous administration obtained by dilution of a pharmaceutical composition according to any one of claims 1 to 7 and 9 to 10 into SWFI to produce a diluted composition.

12. The pharmaceutical composition according to claim 11, wherein the SWFI comprises dextrose, preferably 5% wt / wt to 10% wt / wt of dextrose.

13. The pharmaceutical composition according to claim 11 or 12, wherein the SWFI comprises sodium chloride, preferably 0.9% wt / wt of sodium chloride.

14. The pharmaceutical composition according to any one of claims 11 to 13, wherein the concentration of the compound of formula (I), or a pharmaceutically acceptable saltthereof, in the diluted composition is between about 1 mg / mL and about 15 mg / mL, preferably about 12 mg / mL.

15. The pharmaceutical composition according to any one of claims 1 to 7 and 9 to 14, wherein the pharmaceutical composition is isotonic.

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