JP-7856662-B2 - fixed dose antibiotic composition

Inventors

• ジェイン，ラジーブ・エイ
• ロンスハイム，マシュー
• フォグリアート，ジョヴァンニ
• レゼミニ，ダリオ

Assignees

• エンタシス・セラピューティックス・リミテッド

Dates

Publication Date

20260511

Application Date

20220120

Priority Date

20210120

Claims (17)

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-freeze-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 and sulbactam or a pharmaceutically acceptable salt 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 exists in the form of a sodium salt, and sulbactam exists 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 exists in the form of a sodium salt, and sulbactam exists 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 exists in the form of a sodium salt, and sulbactam exists 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-freezing durlovactam or a pharmaceutically acceptable salt thereof together with sulbactam or a pharmaceutically acceptable salt thereof to form a co-freezing 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.

Description

Related applications [0001] This application claims priority under U.S. Provisional Patent Application No. 63/139,363, filed January 20, 2021, which is incorporated herein by reference in its entirety. [0002] Acinetobacter baumannii is a Gram-negative opportunistic pathogen and one of the leading causes of hospital-acquired infections. A. baumannii is generally multidrug resistant (MDR) in 50% to 60% of cases 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, and mortality rates can reach up to 50% or higher. [0003] In contrast to β-lactamase-mediated resistance, sulbactam (SUL) was one of the few antibiotics selected for the treatment of A. baumannii infection. Currently, the minimal treatment options still effective for A. baumannii infection have insufficient efficacy and tolerability, and the mortality rate for A. baumannii pneumonia and bloodstream infections is approaching 50%. [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/nmcrobiol.2017.104). In vitro, dullobactam exhibits intrinsic antibacterial activity against several Enterobacteria 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. A combination of sulbactam and dullobactam (SUL-DUR) is under development for the treatment of Baumannii infections and other bacterial-associated infections. [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. Treatment 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. Fixed doses are 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. [0006] We have now found that co-freezing durlovactam sodium and sulbactam sodium together improves the flow properties of durlovactam sodium, making fixed dose combinations of durlovactam-sulbactam possible. Initial attempts to formulate fixed doses involved dry powder filling of DUR sodium salt and SUL sodium salt together into glass vials. Due to the hygroscopic nature and insufficient flow properties of DUR sodium salt, significant powder adhesion occurred to the parts of the filling equipment (see Figure 1). This drawback leads to unreliable and inconsistent product administration. However, when DUR sodium salt and SUL sodium salt were co-freezed, powder adhesion was essentially eliminated. This result is not only achievable for a fixed-dose durlovactam-sulbactam combination, but is also remarkable when considering the relative differences between calculated fluidity parameters such as the Hausner ratio and the compression index (also known as the Carr index) compared to durlovactam sodium salt alone. See, for example, the examples section below. [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 was found to have good stability and showed 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/RH 60%. See, for example, Table 4. [0008] Also disclosed are pharmaceutically acceptable solutions comprising a co-lyophilized 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-lyophilized fixed-dose combination reconstituted with a solvent for administration (e.g., water for injection). [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] 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. [0