Fixed dosage antibiotic composition

Abstract

Provided herein are fixed dose combinations of dururobactam and sulbactam and their use in the treatment of one or more bacterial infections.

Description

Related Applications

[0001]

[0001] This application claims the benefit of priority based on U.S. Provisional Patent Application No. 63 / 139,363, filed on January 20, 2021, the entire content of which is incorporated herein by reference.

Background Art

[0002]

[0002] Acinetobacter baumannii is a Gram-negative opportunistic pathogen and one of the most common causes of nosocomial infections. A. baumannii is generally multidrug-resistant (MDR) at a rate of 50% - 60% in the United States and over 80% in parts of Europe and Asia. Severe infections caused by MDR A. baumannii isolates are associated with high morbidity rates, and the mortality rate can reach up to 50% or more.

[0003]

[0003] Prioritizing β-lactamase-mediated resistance, sulbactam (SUL) was one of the few antibiotics selected for the treatment of A. baumannii infections. Currently, the minimal treatment options still effective against A. baumannii infections have insufficient efficacy and tolerability, and the mortality rate approaches 50% in A. baumannii pneumonia and bloodstream infections.

[0004]

[0004] Durlobactam (DUR; also known as ETX2514) is a novel diazabicyclooctenone β-lactamase inhibitor (BLI) that exhibits potent inhibition of class A, C, and D β-lactamases (see, e.g., Nat Microbiol 2:17104.doi:10.1038 / nmicrobiol.2017.104). In vitro, dullobactam exhibits intrinsic antibacterial activity against some Enterobacteriaceae but does not have significant intrinsic activity against A. baumannii complex (ABC) isolates. Durlobactam restores the in vitro activity of sulbactam against members of A. baumannii, and a combination of sulbactam and dullobactam (SUL-DUR) is under development for the treatment of A. baumannii infections and other bacteria-associated infections.

[0005]

[0005] Durlovactam sodium is highly hygroscopic and has poor flow properties. As a result, the processing and administration of SUL-DUR combination therapy agents are not ideal. The procedure with SUL-DUR involves separately reconstituting two vials of sterile durlovactam sodium salt drug component in sterile water for injection and one vial of sterile sulbactam sodium salt drug component in sterile water for injection. A fixed amount is then transferred from each of the three vials to an intravenous infusion bag, and the resulting combination is then administered to the patient as needed. This cumbersome process not only increases the possibility of user error but also results in unnecessary chemical and medical waste. Therefore, a fixed-dose composition containing SUL-DUR is needed. [Overview of the Initiative]

[0006]

[0006] We have now found that co-freezing durlovactam sodium and sulbactam sodium together improves the flow properties of durlovactam sodium, making fixed dosage combinations of durlovactam-sulbactam possible. Initial attempts to formulate fixed dosages involved dry powder filling of both DUR sodium salt and SUL sodium salt into glass vials. Due to the hygroscopic and inadequate flow properties of DUR sodium salt, significant powder adhesion occurred to the filling equipment parts (see Figure 1). This drawback leads to unreliable and inconsistent product dosing. However, when DUR sodium salt and SUL sodium salt were co-freezed, powder adhesion was essentially eliminated. This result is not only achievable for fixed dosage combinations of durlovactam-sulbactam, but is also remarkable considering the relative differences between calculated flow parameters such as the Hausner ratio and compression index (also known as the Carr index) compared to DUR sodium salt alone. See, for example, the Examples section below.

[0007]

[0007] Accordingly, a co-freezyo-dried fixed-dose combination of durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof is disclosed herein. The disclosed fixed-dose combination has been found to have good stability and to have shown little change in assay values ​​and nominal impurity increases over 3 months at 5°C. See, for example, Table 3. Similar results were observed at 25°C / RH60%. See, for example, Table 4.

[0008]

[0008] Also disclosed are pharmaceutically acceptable solutions comprising a co-freely dried fixed-dose combination of durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof. Such solutions include, for example, the disclosed co-freely dried fixed-dose combination reconstituted with a solvent for administration (e.g., water for injection).

[0009]

[0009] Also disclosed herein are split-fill fixed-dose combinations of lyophilized durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof, wherein the sulbactam or a salt thereof and the lyophilized durlovactam or a salt thereof are sequentially filled.

[0010]

[0010] The use of the disclosed fixed-dose combinations or reconstituted solutions for treating bacterial infections is also disclosed.

[0011] Packaged pharmaceutical kits containing the disclosed fixed-dose combinations or reconstituted solutions are also disclosed.

[0011]

[0012] Methods for preparing co-freely dried fixed-dose combinations of SUL-DUR or their reconstituted solutions are further described. [Brief explanation of the drawing]

[0012] [Figure 1]

[0013] This figure shows the DUR sodium salt powder residue observed in the central suction and feeding chute of the IMA MD300 filling machine during machinability testing. [Figure 2]

[0014] This figure illustrates the appearance of DUR sodium salt powder after mechanical filling. [Figure 3]

[0015] This figure shows the appearance of the bulk powder obtained by co-freeze-drying durlovactam and sulbactam. [Modes for carrying out the invention]

[0013]

[0016] In one embodiment, a fixed-dose combination comprising durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof is provided, wherein the durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof are present as a co-freeze-dried mixture.

[0014]

[0017] Durulobactam and ETX2514 are synonymous and refer to β-lactamase inhibitors having the following structure.

[0015] [ka]

[0016] Durulobactam is disclosed in PCT / GB2013 / 050869 and PCT / US2015 / 061076, the entire contents of each of these documents being incorporated herein by reference. Durulobactam-Na, durulobactam-Na salt, DUR-Na, DUR-Na salt, etc., are synonymous and refer to the sodium salt of durulobactam.

[0017]

[0018] Sulbactam refers to a β-lactamase inhibitor having the following structure:

[0018] [ka]

[0019] Unless otherwise specified, sulbactam includes the stereoisomers described above, as well as all other possible stereoisomers and mixtures of stereoisomers. However, in one embodiment, sulbactam as described herein refers to the stereoisomers described having at least 60%, at least 65%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99% stereochemical enrichment or molar excess. Sulbactam-Na, sulbactam-Na salt, SUL-Na, SUL-Na salt, etc., are synonymous and refer to the sodium salt of sulbactam.

[0020]

[0019] When used in the claims and / or as part of the disclosure, the terms “consisting of” or “consists of” mean that any elements, steps, or materials (except impurities that are typically associated with them) not specified in the claims or specification that follow the term are excluded. For example, “consisting of” a fixed-dose combination of dullobactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof means that the elements present are only dullobactam, sulbactam, or their salts, and any impurities that are typically associated with them. The term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is comprehensive or open-ended and does not exclude additional unspecified elements or method steps.

[0021]

[0020] The terms "fixed dose," "fixed dose combination," and "fixed dose composition" are used synonymously and refer to two or more active pharmaceutical ingredients (such as DUR and SUL) contained in a single dosage form, such as the same capsule, tablet, vial, or suppository.

[0022]

[0021] SUL and DUR can form pharmaceutically acceptable acid salts or base salts, and in such cases, administration as salts of the compounds may be appropriate. Examples of acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexylsulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Examples of base salts include ammonium salts; alkali metal salts such as sodium salts, lithium salts, and potassium salts; alkaline earth metal salts such as aluminum salts, calcium salts, and magnesium salts; salts with organic bases such as dicyclohexylamine salts and N-methyl-d-glucamine; and salts with amino acids such as arginine, lysine, and ornithine. In one embodiment, the pharmaceutically acceptable salt of DUR or SUL, or both, contained in the disclosed fixed dosage form is a potassium salt, a lithium salt, a calcium salt, or a sodium salt. In one embodiment, the pharmaceutically acceptable salt of DUR or SUL, or both, contained in the disclosed fixed dosage form is a sodium salt.

[0023]

[0022] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, corresponding to a reasonable benefit / risk ratio, without excessive toxicity, irritation, allergic response, or other problems or complications.

[0024]

[0023] The fixed-dose combination described herein contains SUL and DUR in co-lyophilized form. Lyophilization, also called freeze-drying, is a low-temperature dehydration process known in the art that freezes the product, reduces the pressure, and then removes the ice by sublimation. Co-lyophilized or co-lyophilization means that SUL and DUR, or one or both of their pharmaceutically acceptable salts, are lyophilized (e.g., in the same vessel or container).

[0025]

[0024] Also provided herein is a split-fill fixed-dose combination of lyophilized durulactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof, wherein the sulbactam or its salt and the lyophilized durulactam or its salt are sequentially filled.

[0026]

[0025] Various amounts of SUL and DUR, or salts thereof, can be used in the fixed-dose composition. As one option, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt of DUR (e.g., Na salt) present in the disclosed fixed-dose composition ranges from 0.1:2.0 w / w to 2.0:0.1 w / w. As another option, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt of DUR (e.g., Na salt) present in the disclosed fixed-dose composition ranges from 0.2:1.9 w / w to 1.9:0.2 w / w, 0.2:1.8 w / w to 1.8:0.2 w / w, and 0.3:1.7 w / w to 1. The ratios range from 7:0.3w / w, 0.4:1.6w / w to 1.6:0.4w / w, 0.5:1.5w / w to 1.5:0.5w / w, 0.6:1.4w / w to 1.4:0.6w / w, 0.7:1.3w / w to 1.3:0.7w / w, 0.8:1.2w / w to 1.2:0.8w / w, or 0.9:1.1w / w to 1.1:0.9w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt (e.g., Na salt) present in the disclosed fixed-dose composition ranges from 0.5:1.5 w / w to 1.5:0.5 w / w, 0.7:1.3 w / w to 1.3:0.7 w / w, 0.8:1.2 w / w to 1.2:0.8 w / w, or 0.8:1.1 w / w to 1.1:0.8 w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt (e.g., Na salt) present in the disclosed fixed-dose composition ranges from 0.9:1.1 w / w to 1.1:0.9 w / w.Alternatively, the weight ratios of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt of SUL (e.g., Na salt) present in the disclosed fixed-dose composition are 0.1:2.0 w / w, 0.1:1.9 w / w, 0.2:1.8 w / w, 0.3:1.7 w / w, 0.4:1.6 w / w, 0.5:1.5 w / w, and 0.6:1. The ratios are 0.4 w / w, 0.7:1.3 w / w, 0.8:1.2 w / w, 0.9:1.1 w / w, 1:1 w / w, 1.1:0.9 w / w, 1.2:0.8 w / w, 1.3:0.7 w / w, 1.4:0.6 w / w, 1.5:0.5 w / w, 1.6:0.4 w / w, 1.7:0.3 w / w, 1.8:0.2 w / w, 1.9:0.1 w / w, or 2.0:0.1 w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt of SUL (e.g., Na salt) present in the disclosed fixed-dose composition is 1:1 w / w.

[0027]

[0026] Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt (e.g., Na salt) present in the disclosed fixed-dose composition is equal to the weight ratio of DUR to SUL ranging from 0.1:2.0 w / w to 2.0:0.1 w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt (e.g., Na salt) present in the disclosed fixed-dose composition is 0.2:1.9 w / w to 1.9:0.2 w / w, 0.2:1.8 w / w to 1.8:0.2 w / w, 0.3:1.7 w / w to 1.7:0.3 w / w. This is equivalent to the weight ratio of DUR to SUL ranging from w, 0.4:1.6w / w to 1.6:0.4w / w, 0.5:1.5w / w to 1.5:0.5w / w, 0.6:1.4w / w to 1.4:0.6w / w, 0.7:1.3w / w to 1.3:0.7w / w, 0.8:1.2w / w to 1.2:0.8w / w, or 0.9:1.1w / w to 1.1:0.9w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt (e.g., Na salt) present in the disclosed fixed-dose composition is equal to the weight ratio of DUR to SUL ranging from 0.5:1.5 w / w to 1.5:0.5 w / w, 0.7:1.3 w / w to 1.3:0.7 w / w, 0.8:1.2 w / w to 1.2:0.8 w / w, or 0.8:1.1 w / w to 1.1:0.8 w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt (e.g., Na salt) present in the disclosed fixed-dose composition is equal to the weight ratio of DUR to SUL ranging from 0.9:1.1 w / w to 1.1:0.9 w / w.Alternatively, the weight ratios of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt of SUL (e.g., Na salt) present in the disclosed fixed-dose composition are 0.1:2.0 w / w, 0.1:1.9 w / w, 0.2:1.8 w / w, 0.3:1.7 w / w, 0.4:1.6 w / w, 0.5:1.5 w / w, 0.6:1.4 w / w, The weight ratio of DUR to SUL is equal to 0.7:1.3w / w, 0.8:1.2w / w, 0.9:1.1w / w, 1:1w / w, 1.1:0.9w / w, 1.2:0.8w / w, 1.3:0.7w / w, 1.4:0.6w / w, 1.5:0.5w / w, 1.6:0.4w / w, 1.7:0.3w / w, 1.8:0.2w / w, 1.9:0.1w / w, or 2.0:0.1w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt of SUL (e.g., Na salt) present in the disclosed fixed-dose composition is equal to a weight ratio of DUR to SUL of 1:1w / w.

[0028]

[0027] Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt (e.g., Na salt) present in the disclosed fixed-dose composition is equal to the weight ratio of DUR-Na salt to SUL-Na salt ranging from 0.1:2.0 w / w to 2.0:0.1 w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt (e.g., Na salt) present in the disclosed fixed-dose composition is 0.2:1.9 w / w to 1.9:0.2 w / w, 0.2:1.8 w / w to 1.8:0.2 w / w, 0.3:1.7 w / w to 1.7:0.3 w / w, 0. This is equivalent to weight ratios of DUR-Na salt to SUL-Na salt ranging from 4:1.6w / w to 1.6:0.4w / w, 0.5:1.5w / w to 1.5:0.5w / w, 0.6:1.4w / w to 1.4:0.6w / w, 0.7:1.3w / w to 1.3:0.7w / w, 0.8:1.2w / w to 1.2:0.8w / w, or 0.9:1.1w / w to 1.1:0.9w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt (e.g., Na salt) present in the disclosed fixed-dose composition is equal to the weight ratio of DUR-Na salt to SUL-Na salt ranging from 0.5:1.5 w / w to 1.5:0.5 w / w, 0.7:1.3 w / w to 1.3:0.7 w / w, 0.8:1.2 w / w to 1.2:0.8 w / w, or 0.8:1.1 w / w to 1.1:0.8 w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt (e.g., Na salt) present in the disclosed fixed-dose composition is equal to the weight ratio of DUR-Na salt to SUL-Na salt ranging from 0.9:1.1 w / w to 1.1:0.9 w / w.Alternatively, the weight ratios of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt of SUL (e.g., Na salt) present in the disclosed fixed-dose composition are 0.1:2.0 w / w, 0.1:1.9 w / w, 0.2:1.8 w / w, 0.3:1.7 w / w, 0.4:1.6 w / w, 0.5:1.5 w / w, 0.6:1.4 w / w, 0.7: The weight ratio of DUR-Na salt to SUL-Na salt is equal to 1.3 w / w, 0.8:1.2 w / w, 0.9:1.1 w / w, 1:1 w / w, 1.1:0.9 w / w, 1.2:0.8 w / w, 1.3:0.7 w / w, 1.4:0.6 w / w, 1.5:0.5 w / w, 1.6:0.4 w / w, 1.7:0.3 w / w, 1.8:0.2 w / w, 1.9:0.1 w / w, or 2.0:0.1 w / w. Alternatively, the weight ratio of DUR or a pharmaceutically acceptable salt of DUR (e.g., Na salt) to SUL or a pharmaceutically acceptable salt of SUL (e.g., Na salt) present in the disclosed fixed-dose composition is equal to the weight ratio of DUR-Na salt to SUL-Na salt at 1:1 w / w.

[0029]

[0028] Alternatively, the fixed-dose composition comprises DUR-Na salt and SUL-Na salt, and the weight ratio of DUR-Na salt to SUL-Na salt present in the disclosed fixed-dose composition is equal to the weight ratio of DUR to SUL ranging from 0.1:2.0 w / w to 2.0:0.1 w / w. Alternatively, the fixed-dose composition comprises DUR-Na salt and SUL-Na salt, and the weight ratio of DUR-Na salt to SUL-Na salt present in the disclosed fixed-dose composition is 0.2:1.9 w / w to 1.9:0.2 w / w, 0.2:1.8 w / w to 1.8:0.2 w / w, 0.3:1.7 w / w to 1.7:0.3 w / w, 0.4:1 This is equivalent to the weight ratio of DUR to SUL ranging from 0.6w / w to 1.6:0.4w / w, 0.5:1.5w / w to 1.5:0.5w / w, 0.6:1.4w / w to 1.4:0.6w / w, 0.7:1.3w / w to 1.3:0.7w / w, 0.8:1.2w / w to 1.2:0.8w / w, or 0.9:1.1w / w to 1.1:0.9w / w. Alternatively, the fixed-dose composition comprises a DUR-Na salt and a SUL-Na salt, and the weight ratio of DUR-Na salt to SUL-Na salt present in the disclosed fixed-dose composition is equal to the weight ratio of DUR to SUL ranging from 0.5:1.5 w / w to 1.5:0.5 w / w, 0.7:1.3 w / w to 1.3:0.7 w / w, 0.8:1.2 w / w to 1.2:0.8 w / w, or 0.8:1.1 w / w to 1.1:0.8 w / w. Alternatively, the fixed-dose composition comprises a DUR-Na salt and a SUL-Na salt, and the weight ratio of DUR-Na salt to SUL-Na salt present in the disclosed fixed-dose composition is equal to the weight ratio of DUR to SUL ranging from 0.9:1.1 w / w to 1.1:0.9 w / w.Alternatively, the fixed-dose composition comprises DUR-Na salt and SUL-Na salt, and the weight ratios of DUR-Na salt and SUL-Na salt present in the disclosed fixed-dose composition are 0.1:2.0 w / w, 0.1:1.9 w / w, 0.2:1.8 w / w, 0.3:1.7 w / w, 0.4:1.6 w / w, 0.5:1.5 w / w, 0.6:1.4 w / w, and 0.7:1.3 The weight ratios of DUR to SUL are equal to w / w, 0.8:1.2w / w, 0.9:1.1w / w, 1:1w / w, 1.1:0.9w / w, 1.2:0.8w / w, 1.3:0.7w / w, 1.4:0.6w / w, 1.5:0.5w / w, 1.6:0.4w / w, 1.7:0.3w / w, 1.8:0.2w / w, 1.9:0.1w / w, or 2.0:0.1w / w. Alternatively, a fixed-dose composition comprises a DUR-Na salt and a SUL-Na salt, where the weight ratio of DUR-Na salt to SUL-Na salt present in the disclosed fixed-dose composition is equal to a DUR-SUL weight ratio of 1:1w / w.

[0030]

[0029] As an alternative, the fixed-dose composition comprises DUR-Na salt and SUL-Na salt, and the weight ratio of DUR-Na salt to SUL-Na salt present in the disclosed fixed-dose composition ranges from 0.1:2.0 w / w to 2.0:0.1 w / w. Alternatively, the fixed-dose composition comprises a DUR-Na salt and a SUL-Na salt, and the weight ratio of DUR-Na salt to SUL-Na salt present in the disclosed fixed-dose composition ranges from 0.2:1.9w / w to 1.9:0.2w / w, 0.2:1.8w / w to 1.8:0.2w / w, 0.3:1.7w / w to 1.7:0.3w / w, 0.4:1.6w / w to 1.6:0.4w / w, 0.5:1.5w / w to 1.5:0.5w / w, 0.6:1.4w / w to 1.4:0.6w / w, 0.7:1.3w / w to 1.3:0.7w / w, 0.8:1.2w / w to 1.2:0.8w / w, or 0.9:1.1w / w to 1.1:0.9w / w. Alternatively, the fixed-dose composition comprises DUR-Na salt and SUL-Na salt, and the weight ratio of DUR-Na salt to SUL-Na salt present in the disclosed fixed-dose composition ranges from 0.5:1.5w / w to 1.5:0.5w / w, 0.7:1.3w / w to 1.3:0.7w / w, 0.8:1.2w / w to 1.2:0.8w / w, or 0.8:1.1w / w to 1.1:0.8w / w. Alternatively, the fixed-dose composition comprises DUR-Na salt and SUL-Na salt, and the weight ratio of DUR-Na salt to SUL-Na salt present in the disclosed fixed-dose composition ranges from 0.9:1.1w / w to 1.1:0.9w / w. Alternatively, the fixed-dose composition comprises DUR-Na salt and SUL-Na salt, and the weight ratios of DUR-Na salt and SUL-Na salt present in the disclosed fixed-dose composition are 0.1:2.0 w / w, 0.1:1.9 w / w, 0.2:1.8 w / w, 0.3:1.7 w / w, 0.4:1.6 w / w, 0.5:1.5 w / w, 0.6:1.4 w / w, 0 The ratios are 0.7:1.3w / w, 0.8:1.2w / w, 0.9:1.1w / w, 1:1w / w, 1.1:0.9w / w, 1.2:0.8w / w, 1.3:0.7w / w, 1.4:0.6w / w, 1.5:0.5w / w, 1.6:0.4w / w, 1.7:0.3w / w, 1.8:0.2w / w, 1.9:0.1w / w, or 2.0:0.1w / w.Alternatively, the fixed-dose composition comprises a DUR-Na salt and a SUL-Na salt, wherein the weight ratio of the DUR-Na salt to the SUL-Na salt present in the disclosed fixed-dose composition is 1:1 w / w.

[0031]

[0030] Disclosed fixed-dose compositions or split-fill fixed-dose combinations comprising co-freezed DUR and SUL, or pharmaceutically acceptable salts thereof, can be reconstituted with a pharmaceutically acceptable liquid (e.g., physiological saline, sterile water for injection, sodium chloride solution, dextrose, glucose, Ringer's lactate, invert sugar injection, etc.) before administration.

[0032]

[0031] Unless otherwise specified (for example, in the case of a fixed-dose composition "consisting of" DUR and SUL), the disclosed fixed-dose compositions may include one or more pharmaceutically acceptable excipients, stabilizers, pH adjusters, etc.

[0033]

[0032] Non-freefreezed SUL-DUR is currently in clinical development for the treatment of A. baumannii complex (ABC) infections and urinary tract infections (pyelonephritis). See, for example, US clinical trial identification numbers NCT03894046 and NCT03445195. Efficacy has also been demonstrated in preclinical models of Burkholderia infection, Enterobacteriaceae isolates, and Pseudomonas aeruginosa infection. See, for example, PCT / US2015 / 061076.

[0034]

[0033] In one embodiment, the disclosed fixed-dose composition is useful for treating bacterial infections, such as those caused by Gram-negative bacteria, also known as Gram-negative infections. In one embodiment of this embodiment, a Gram-negative infection is an infection that is resistant to one or more antibiotics. In one embodiment of this embodiment, a Gram-negative infection is a multidrug-resistant infection. In some embodiments, the Gram-negative bacteria are species of the genus Acinetobacter. In some embodiments, the Gram-negative bacteria are species of the genus Acinetobacter, such as Acinetobacter baumannii. In some embodiments, the Gram-negative bacteria are species of the genus Burkholderia. In some embodiments, the Gram-negative bacteria are Burkholderia pseudomallei. In some embodiments, the Gram-negative bacteria are Pseudomonas aeruginosa. In some embodiments, the Gram-negative bacteria are Enterobacteriaceae. In any of these embodiments, the Gram-negative infection arises from a pathogen or a pathogen that expresses one or more β-lactamases. In any of these embodiments, Gram-negative infection arises from a pathogen or a pathogen expressing one or more class A, class C, and / or class D β-lactamases. In any of these embodiments, Gram-negative infection arises from a pathogen or a pathogen expressing one or more class A β-lactamases. In any of these embodiments, Gram-negative infection arises from a pathogen or a pathogen expressing one or more class C β-lactamases. In any of these embodiments, Gram-negative infection arises from a pathogen or a pathogen expressing one or more class D β-lactamases.

[0035]

[0034] Infections caused by the family Enterobacteriaceae include, but are not limited to, species of bacteria such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella, Sigella, Proteus, Enterobacter, Serratia, and Citrobacter, and refer to any Gram-negative bacteria in this family of bacteria. Therefore, treatment of a bacterial infection caused by the family Enterobacteriaceae includes any infection caused by one or more bacteria that are part of this family. In one embodiment, a bacterial infection caused by the family Enterobacteriaceae includes a bacterial infection presenting at least one Salmonella pathogen. In one embodiment, a bacterial infection caused by the family Enterobacteriaceae includes a bacterial infection presenting at least one Escherichia coli pathogen. In one embodiment, a bacterial infection caused by the family Enterobacteriaceae includes a bacterial infection presenting at least one Yersinia pestis pathogen. In one embodiment, a bacterial infection caused by Enterobacteriaceae includes a bacterial infection containing at least one Klebsiella species pathogen. In one embodiment, a bacterial infection caused by Enterobacteriaceae includes a bacterial infection containing at least one Sigella species pathogen. In one embodiment, a bacterial infection caused by Enterobacteriaceae includes a bacterial infection containing at least one Proteus species pathogen. In one embodiment, a bacterial infection caused by Enterobacteriaceae includes a bacterial infection containing at least one Enterobacter species pathogen. In one embodiment, a bacterial infection caused by Enterobacteriaceae includes a bacterial infection containing at least one Serratia species pathogen. In one embodiment, a bacterial infection caused by Enterobacteriaceae includes a bacterial infection containing at least one Citrobacter species pathogen.

[0036]

[0035] In some embodiments, bacterial infection refers to an infection caused by Gram-negative bacteria of the Enterobacteriaceae family that express one or more β-lactamases of class A, class B, class C and / or class D. In one embodiment of this embodiment, the Gram-negative bacteria are Enterobacteriaceae that express at least one β-lactamase of class B.

[0037]

[0036] In some embodiments, the Gram-negative bacteria are Acinetobacter species expressing one or more β-lactamases. In one embodiment, the Gram-negative bacteria are Acinetobacter baumannii expressing one or more class A, class C and / or class D β-lactamases. In one embodiment, the Gram-negative bacteria are Acinetobacter baumannii expressing one or more class A β-lactamases. In one embodiment, the Gram-negative bacteria are Acinetobacter baumannii expressing one or more class C β-lactamases. In one embodiment, the Gram-negative bacteria are Acinetobacter baumannii expressing one or more class D β-lactamases. In one embodiment, the Gram-negative bacteria are Acinetobacter baumannii expressing TEM-1 or KPC-2.

[0038]

[0037] In one embodiment, bacterial infection can refer to a gynecological infection. In another embodiment, bacterial infection can refer to a respiratory tract infection (RTI). In yet another embodiment, bacterial infection can refer to a sexually transmitted infection. In yet another embodiment, bacterial infection can refer to a urinary tract infection (UTI). In yet another embodiment, bacterial infection can refer to a complicated urinary tract infection (cUTI). In yet another embodiment, bacterial infection can refer to an acute exacerbation of chronic bronchitis (ACEB). In yet another embodiment, bacterial infection can refer to acute otitis media. In yet another embodiment, bacterial infection can refer to acute sinusitis. In yet another embodiment, bacterial infection can refer to an infection caused by drug-resistant bacteria. In yet another embodiment, bacterial infection can refer to catheter-associated sepsis. In yet another embodiment, bacterial infection can refer to chancroid. In yet another embodiment, bacterial infection can refer to chlamydia. In yet another embodiment, bacterial infection can refer to community-acquired pneumonia (CAP). In yet another embodiment, bacterial infection can refer to complicated cutaneous or structural infection (cSSSI). In yet another embodiment, bacterial infection can refer to acute bacterial cutaneous or structural infection (ABSSSI). In yet another embodiment, bacterial infection can refer to uncomplicated cutaneous or structural infection (SSSI). In yet another embodiment, bacterial infection can refer to endocarditis. In yet another embodiment, bacterial infection can refer to febrile neutropenia. In yet another embodiment, bacterial infection can refer to gonococcal cervicitis. In yet another embodiment, bacterial infection can refer to gonococcal urethritis. In yet another embodiment, bacterial infection can refer to hospital-acquired pneumonia (HAP). In yet another embodiment, bacterial infection can refer to ventilator-associated pneumonia (VAP). In yet another embodiment, bacterial infection can refer to infections in immunocompromised hosts, such as liver abscess, biliary tract infection, and / or bacteremia. In yet another embodiment, bacterial infection can refer to bacteremia. In yet another embodiment, bacterial infection can refer to osteomyelitis. In yet another aspect, bacterial infection can refer to sepsis.In yet another embodiment, bacterial infection can refer to syphilis. In yet another embodiment, bacterial infection can refer to intraperitoneal infection (IAI). In yet another embodiment, bacterial infection can refer to pulmonary, septic, and / or bubonic plague. In yet another embodiment, bacterial infection can refer to anthrax. In yet another embodiment, bacterial infection can refer to glanders. In yet another embodiment, bacterial infection can refer to meidomygia. In yet another embodiment, bacterial infection can refer to tularemia.

[0039]

[0038] The Specified also provides a method for treating a bacterial infection in a subject requiring treatment of a bacterial infection as described herein, the method comprising the step of administering a therapeutically effective amount of a fixed-dose composition to the subject.

[0040]

[0039] The prepared fixed-dose compositions are also provided for use in treating bacterial infections in subjects requiring the treatment of bacterial infections described herein.

[0040] Further, the use of the prepared fixed-dose compositions in the manufacture of pharmaceuticals for treating bacterial infections in subjects requiring treatment of bacterial infections as described herein is provided.

[0041]

[0041] The terms “subject” and “patient” may be used synonymously and refer to mammals requiring treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human being requiring treatment.

[0042]

[0042] In this specification, the term “to treat” or “treatment” means to obtain a desired pharmacological and / or physiological effect. The effect may be a therapeutic effect and includes partially or substantially achieving one or more of the following results: partially or completely reducing the degree of a disease, disorder or syndrome; alleviating or improving the clinical symptoms or signs associated with the disorder; or delaying, inhibiting or reducing the likelihood of progression of a disease, disorder or syndrome. In one embodiment, the treatment may also be continued after the symptoms have disappeared, for example, to delay their recurrence. “To treat” or “treatment” also means inhibiting or delaying the rebound of an infection or the symptoms of an infection.

[0043]

[0043] Doses and treatment regimens specific to any particular patient depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, sex, diet, timing of administration, excretion rate, drug combinations, the judgment of the treating physician, and the severity of the specific disease being treated. However, in one embodiment, the fixed-dose compositions described herein are administered in an "effective dose" or "therapeutic effective dose." This refers to a fixed dose amount that elicits a biological or medical response in the subject, for example, a dose of 0.01 to 100 mg / kg of body weight / day.

[0044]

[0044] In some embodiments, the fixed-dose compositions described herein may be administered orally, parenterally, or topically. The term “parenterally” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intrafocal, and intracranial injection or infusion techniques. In some embodiments, the disclosed fixed-dose compositions are administered by intravenous injection (e.g., after reconstitution with sterile water for injection).

[0045]

[0045] The disclosed fixed-dose combinations may be packaged together with instructions for use in the form of a pharmaceutical kit, which may be optional. Example

[0046] Durlobactam and its sodium salts can be synthesized according to the procedure for Compound 1 in Example 10 of PCT / GB2013 / 050869, which is incorporated herein by reference. Sulbactam and its pharmaceutically acceptable salts are commercially available in the form of combinations Unasyn®, Cefina-SB®, Sulperazone®, Sultamicillin®, or Bacperazone®. The synthesis of sulbactam is also well known in the art. See, for example, Volkmann et al., Efficient Preparation of 6,6-dihalopenicillanic acids. Synthesis of Penicillanic Acid S,S-dioxide (Sulbactam), J. Org. Chem., 47(17):3344-3345 (1982).

[0046]

[0047] Attempts to develop a commercially viable fixed-dose combination of durlovactam and sulbactam by dry-filling glass vials with both DUR sodium salt and SUL sodium salt (as a 1:1 w / w mixture in salt form) were unsuccessful due to the high hygroscopicity and poor flow properties of DUR sodium salt. This resulted in significant powder adhesion to parts of the filling apparatus, clogging of the dosing chamber and piston. See, for example, Figure 1 showing DUR sodium salt powder residue observed on the feeding chute from concentrated suction during machinability trials. See also Figure 2 showing the appearance of the DUR sodium salt powder-filled product. Compare this to Figure 3, which shows the appearance of bulk powder obtained by co-freeze-drying durlovactam and sulbactam.

[0047]

[0048] Bulk and tap density analyses of DUR sodium salt were performed according to USP, and the compressibility index (CI) and Hausner ratio were calculated. Typically, materials are considered to have insufficient fluidity when the Hausner ratio is greater than 1.25 and / or the CI is greater than 25. See, for example, Leroy A. Sherrington, Amal Sherrington, Analytical Profiles of Drug Substances and Excipients, 1998. Here, the powder was found to have a compressibility index and Hausner ratio of 38% and >1.6, respectively, indicating an extremely insufficient fluidity material. These experimental values ​​are consistent with the observed powder adhesion.

[0048]

[0049] The fluidity issues associated with DUR sodium salt led to the decision to proceed with clinical use using three separate vials. This requires powder filling into three separate vials: two containing DUR sodium salt and one containing SUL sodium salt. Each drug is then reconstituted separately with sterile water for injection. Fixed amounts are then transferred from each of the three vials to an intravenous infusion bag, and the resulting combination is administered to the subject as needed. While promising clinical results were obtained, the need for multi-vial use and multi-processing procedures increases the risk of user error, increases bulk processing and packaging costs, expands waste, and is generally cumbersome.

[0049]

[0050] However, this study found that co-freeze-drying of dullobactam sodium salt and sulbactam sodium salt improved flow properties compared to freeze-drying dullobactam sodium salt alone. Initial experiments involved dissolving a 1:1 w / w mixture of dullobactam sodium salt and sulbactam sodium salt in water for injection and optimizing bulk freeze-drying conditions (for each scale). Table 1 shows the bulk density, tap density, and calculated compression index and Hausner ratio of this 1:1 w / w co-freeze-dried mixture of dullobactam sodium salt and sulbactam sodium salt.

[0050] [Table 1]

[0051]

[0051] As described above, co-freeze-dried compositions showed slight improvements in the Hausner ratio and compression index. Based on these values ​​and the latest literature in the art, it was expected that the fluidity of co-freeze-dried fixed-dose compositions would hinder the formation of feasible fixed-dose combinations. However, this was not the case.

[0052]

[0052] Furthermore, the co-freezed combinations showed good stability. For this purpose, the co-freezed mixtures were filled into vials and kept stable at 2-8°C, 25°C / 60% RH, and 40°C / 75% RH. The fixed-dose compositions of SUL-Na / DUR-Na consist of combining both co-freezed active ingredients in a single vial. Formulation tests were performed to evaluate the effects of combining two co-freezed fixed-dose active ingredients on physical attributes (hygroscopicity, particle size distribution, flowability) and chemical stability (assay and impurities). Tables 2-4 show the results of the stability (3-6 months) of the fixed-dose compositions when stored at 5°C, 25°C / 60% RH, and 40°C / 75% RH, respectively. 40°C / 75% RH represents stress conditions, where values ​​decrease while impurity levels increase. The 5°C condition represents long-term storage conditions, and the results show little change in assay values ​​and little increase in overall impurity levels. The 25°C / 60% RH conditions represent the accelerated storage conditions for this product, and the total impurity levels are slightly higher than those under 5°C storage conditions.

[0053] [Table 2]

[0054] [Table 3]

[0055] [Table 4]

[0056] Alternative split-fill method

[0053] Split-fill formulations of durlovactam sodium salt and sulbactam sodium salt were prepared and their stability was evaluated. Durlovactam sodium salt was dissolved in water and freeze-dried. Sulbactam sodium salt powder and freeze-dried durlovactam sodium salt were sequentially filled into glass vials (with the freeze-dried durlovactam sodium salt powder on top of the sulbactam sodium salt powder) in the presence of an inert nitrogen atmosphere, then the vials were stoppered and crimped. Durlovactam sodium salt and sulbactam sodium salt were present in a 1:1 ratio.

[0057] [Table 5]

[0058] [Table 6]

[0059] [Table 7]

[0060]

[0054] Although several embodiments have been described, the scope of this disclosure should be defined by the appended claims and not by the specific embodiments expressed as examples. The contents of all reference materials cited throughout this application (including references, published patents, published patent applications, and concurrently pending patent applications) are referred to by reference as a whole. It is explicitly incorporated into the specification. Unless otherwise defined, all scientific and technical terms used herein have the same meaning as those well known to those skilled in the art. Description of claims at the time of international filing [Section 1] A fixed-dose combination comprising durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof, wherein the durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof are present as a co-freely dried mixture. [Section 2] The fixed-dose combination according to claim 1, wherein the fixed-dose combination comprises durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof. [Section 3] A fixed-dose combination according to claim 1 or 2, wherein durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof are present in weight ratios in the range of 0.5:1.5 w / w to 1.5:0.5 w / w, 0.7:1.3 w / w to 1.3:0.7 w / w, 0.8:1.2 w / w to 1.2:0.8 w / w, or 0.9:1.1 w / w to 1.1:0.9 w / w. [Section 4] A fixed-dose combination according to any one of claims 1 to 3, wherein durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof are present in a weight ratio in the range of 0.9:1.1 w / w to 1.1:0.9 w / w. [Section 5] A fixed-dose combination according to any one of claims 1 to 4, wherein durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof are present in a weight ratio of 1:1 w / w. [Section 6] A fixed-dose combination according to any one of claims 1 to 5, wherein durlovactam is in the form of a sodium salt. [Section 7] A fixed-dose combination according to any one of claims 1 to 6, wherein sulbactam is in the form of a sodium salt. [Section 8] A fixed-dose combination according to claim 1 or 2, wherein durlovactam is in the form of a sodium salt and sulbactam is in the form of a sodium salt, each present in an amount equal to a DUR to SUL weight ratio in the range of 0.5:1.5 w / w to 1.5:0.5 w / w, 0.7:1.3 w / w to 1.3:0.7 w / w, 0.8:1.2 w / w to 1.2:0.8 w / w, or 0.9:1.1 w / w to 1.1:0.9 w / w. [Section 9] A fixed-dose combination according to any one of claims 1, 2, and 8, wherein durlovactam is in the form of a sodium salt and sulbactam is in the form of a sodium salt, each present in an amount equal to a DUR to SUL weight ratio in the range of 0.9:1.1 w / w to 1.1:0.9 w / w. [Section 10] A fixed-dose combination according to any one of claims 1, 2, 8, and 9, wherein durlovactam is in the form of a sodium salt and sulbactam is in the form of a sodium salt, each present in an amount equal to a DUR to SUL weight ratio of 1:1 w / w. [Section 11] A method for treating a bacterial infection in a subject requiring treatment for a bacterial infection, comprising the step of administering a therapeutically effective amount of a fixed-dose combination or pharmaceutically acceptable solution according to any one of claims 1 to 10 to the subject. [Section 12] Bacterial infections include pathogens of the Enterobacteriaceae family, Acinetobacter species, and Pseudomonas aeruginosa (P. aer). The method according to claim 11, caused by a pathogen of the genus *uginosa* or a fungal species of *Burkholderia*. [Section 13] A method for preparing a fixed-dose solution of durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof, comprising the step of co-freefreezing durlovactam or a pharmaceutically acceptable salt thereof together with sulbactam or a pharmaceutically acceptable salt thereof to form a co-freefreezed mixture. [Section 14] The method according to claim 13, further comprising the step of reconstituting the co-freeze-dried mixture in a pharmaceutically acceptable solvent. [Section 15] The method according to claim 13 or 14, wherein the pharmaceutically acceptable solvent is water. [Section 16] The method according to any one of claims 13 to 15, wherein the pharmaceutically acceptable solvent is water. [Section 17] A method for preparing a fixed-dose solution of durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof, comprising the step of mixing lyophilized durlovactam or a pharmaceutically acceptable salt thereof with sulbactam or a pharmaceutically acceptable salt thereof. [Section 18] A packaged pharmaceutical kit comprising a fixed-dose combination or pharmaceutically acceptable solution according to any one of claims 1 to 10.

Claims

1. A fixed-dose combination comprising durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof, wherein the durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof are present as a co-freely dried mixture.

2. The fixed-dose combination according to claim 1, wherein the fixed-dose combination comprises durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof.

3. A fixed-dose combination according to claim 1 or 2, wherein durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof are present in weight ratios ranging from 0.5:1.5 w / w to 1.5:0.5 w / w, 0.7:1.3 w / w to 1.3:0.7 w / w, 0.8:1.2 w / w to 1.2:0.8 w / w, or 0.9:1.1 w / w to 1.1:0.9 w / w.

4. A fixed-dose combination according to any one of claims 1 to 3, wherein durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof are present in a weight ratio in the range of 0.9:1.1 w / w to 1.1:0.9 w / w.

5. A fixed-dose combination according to any one of claims 1 to 4, wherein durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof are present in a weight ratio of 1:1 w / w.

6. A fixed-dose combination according to any one of claims 1 to 5, wherein durlovactam is in the form of a sodium salt.

7. A fixed-dose combination according to any one of claims 1 to 6, wherein sulbactam is in the form of a sodium salt.

8. A fixed-dose combination according to claim 1 or 2, wherein durlovactam is in the form of a sodium salt and sulbactam is in the form of a sodium salt, each present in an amount equal to a DUR to SUL weight ratio in the range of 0.5:1.5 w / w to 1.5:0.5 w / w, 0.7:1.3 w / w to 1.3:0.7 w / w, 0.8:1.2 w / w to 1.2:0.8 w / w, or 0.9:1.1 w / w to 1.1:0.9 w / w.

9. A fixed-dose combination according to any one of claims 1, 2, and 8, wherein durlovactam is in the form of a sodium salt and sulbactam is in the form of a sodium salt, each present in an amount equal to a DUR to SUL weight ratio in the range of 0.9:1.1 w / w to 1.1:0.9 w / w.

10. A fixed-dose combination according to any one of claims 1, 2, 8, and 9, wherein durlovactam is in the form of a sodium salt and sulbactam is in the form of a sodium salt, each present in an amount equal to a DUR to SUL weight ratio of 1:1 w / w.

11. A fixed-dose combination according to any one of claims 1 to 10, for use in a method of treating a bacterial infection in a subject requiring treatment for a bacterial infection.

12. Bacterial infections include pathogens of the Enterobacteriaceae family, Acinetobacter species, and Pseudomonas aeruginosa (P. aeruginosa). A fixed-dose combination according to claim 11, caused by a pathogen of the genus *uginosa* or a pathogen of the genus *Burkholderia*.

13. A method for preparing a fixed-dose solution of durlovactam or a pharmaceutically acceptable salt thereof and sulbactam or a pharmaceutically acceptable salt thereof, comprising the step of co-freefreezing durlovactam or a pharmaceutically acceptable salt thereof together with sulbactam or a pharmaceutically acceptable salt thereof to form a co-freefreezed mixture.

14. The method according to claim 13, further comprising the step of reconstituting the co-freeze-dried mixture in a pharmaceutically acceptable solvent.

15. The method according to claim 13 or 14, wherein the pharmaceutically acceptable solvent includes water.

16. The method according to any one of claims 13 to 15, wherein the pharmaceutically acceptable solvent is water.

17. A packaged pharmaceutical kit comprising a fixed-dose combination or a pharmaceutically acceptable solution according to any one of claims 1 to 10.

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