A composition containing vancomycin

Abstract

An aqueous storage-stable composition comprising vancomycin at a concentration of 25 to 75 mg / mL or a pharmaceutically acceptable salt thereof; D-lactic acid or a pharmaceutically acceptable salt thereof; a co-solvent selected from propylene glycol and a mixture of propylene glycol and glycerol; and an inorganic salt containing a metal cation.

Description

Technical Field

[0001] The present invention relates to an aqueous solution composition of vancomycin, particularly a composition ready for dilution that is storage-stable, non-toxic, and has higher dosing flexibility and improved handling properties.

Background Art

[0002] (Background) Vancomycin is a glycopeptide antibiotic consisting of a heptapeptide chain that forms a tricyclic ring system with sugars attached. The leucine of the N-terminal amino acid is extremely important for antibacterial activity. Vancomycin is derived from the fungus Amycolatopsis orientalis (formally Nocardia orientalis). It is used to treat various infectious diseases caused by Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin is typically used in the form of its hydrochloride salt with a molecular weight of 1485.71 Da.

[0003] Vancomycin blocks the transpeptidase step of bacterial cell wall synthesis by preventing the synthesis of important polymers within the peptidoglycan layer. Vancomycin forms a hydrogen bond with the D-alanyl-D-alanine site of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) peptides. This bond prevents the synthesis of NAM and NAG peptides that form the backbone chain of the bacterial cell wall.

[0004] Vancomycin can be administered either orally or intravenously depending on the specific situation. The invention disclosed herein is mainly related to vancomycin administered intravenously.

[0005] There are several lyophilized vancomycin products for intravenous use. These products require reconstitution and subsequent dilution into intravenous (IV) solution bags, and thus are quite inconvenient to use.

[0006] There are three commercially available liquid products that contain a formulation of premixed vancomycin formulated within an IV solution bag and can be administered as is. Namely, Vancomycin Injection, USP IV Frozen Premix (sold by Baxter), and VancoREADY™ (sold by Xellia). For the purposes of the present invention, such premixed products filled in an IV solution container such as a bag or bottle are referred to as "ready-to-administer" products.

[0007] Baxter's USP IV premix formulated within a GALAXY plastic container is a frozen and premixed 100 mL, 150 mL, or 200 mL solution that contains 500 mg, 750 mg, or 1 g of vancomycin as vancomycin hydrochloride, respectively. The solution contains approximately 5 g of glucose or 0.9 g of sodium chloride per 100 mL. The pH of the solution is adjusted with hydrochloric acid and / or sodium hydroxide. This product must be stored in a freezer that can maintain the temperature at -20°C or below. The thawed solution has a pH in the range of 3.0 to 5.0. After thawing at room temperature (25°C) or under refrigerated conditions (5°C), this solution is intended for intravenous use only. The need to store in frozen form and the need to thaw before use are a significant limitation and inconvenience for healthcare providers.

[0008] VancoREADY™ exists as a liquid product and is supplied as a clear, colorless to pale yellow, preservative-free solution in single-dose pre-mixed IV solution bags. It is available in seven different doses from 500 mg to 2 g. The solution contains 500 mg of vancomycin hydrochloride, 1.8 mL of PEG400, 1.36 g of N-acetyl-D-alanine, and 1.26 g of L-lysine hydrochloride per 100 mL at pH 5.0. Long-term storage is 16 months at room temperature (25°C) in an aluminum overwrap, and it remains stable for an additional 28 days at 25°C even after removal from the overwrap. VancoReady™ carries a “black box” warning due to the additives N-acetyl-D-alanine and PEG400, which are known to cause fetal abnormalities in animal reproductive studies, and thus this product is advised not to be used in pregnant women.

[0009] Typically, separate from the above-described ready-to-administer products containing 5 mg / ml of vancomycin hydrochloride, a liquid concentrate composition of vancomycin that requires dilution into an IV bag or bottle prior to use is needed. The benefit of such a concentrate product form compared to the pre-mixed ready-to-administer products is the high dosing flexibility to address various dosing regimens. For the purposes of the present invention, such a concentrated vancomycin composition is referred to as a “ready-to-dilute” product or a “composition concentrate”. Preferably, the ready-to-dilute product contains 50 mg / ml of vancomycin hydrochloride.

[0010] The present invention addresses the need for a stable and non-toxic vancomycin composition provided in a ready-to-dilute form, thereby providing higher dosing flexibility and improved handleability.

[0011] WO2014 / 194296A1 (SCIDOSE) discloses a composition comprising vancomycin or a pharmaceutically acceptable salt thereof; a polar solvent such as propylene glycol, polyethylene glycol, and mixtures thereof; lactic acid, lactate, or mixtures thereof; and optionally, a pH adjuster in an amount sufficient to maintain the pH of the composition from about 3 to about 8.

[0012] WO2017 / 123912A1 (SCIDOSE) discloses a composition comprising vancomycin or a pharmaceutically acceptable salt thereof, a polyol such as glycerol, and lactic acid or a lactate.

[0013] US2020 / 0188478A1 (FTF PHARMA) discloses a premixed vancomycin composition that is said to be suitable for injection.

[0014] JP2008 / 201778A (Motoyama Pharmaceutical Co., Ltd.) discloses a vancomycin composition that is said to be suitable for long-term storage and oral administration.

[0015] WO2017 / 194385A1 (XELLIA PHARMACEUTICALS) discloses a liquid formulation of a glycopeptide antibiotic such as vancomycin that is said to be suitable as an infusion solution.

[0016] US2018 / 0133286A1 (XELLIA PHARMACEUTICALS) discloses a composition containing vancomycin and an amino acid or an amino acid derivative such as N-acetyl-glycine or N-acetyl-D-alanine. [Summary of the Invention]

[0017] (Summary of the Invention) The present invention particularly provides: Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof; A co-solvent selected from propylene glycol and a mixture of propylene glycol and glycerol; and An inorganic salt containing a metal cation to provide a storage-stable aqueous solution composition. [Modes for Carrying Out the Invention]

[0018] (Detailed Description of the Invention) In the composition of the present invention, vancomycin may be present in the form of a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include hydrochloride, citrate, formate, acetate, tartrate, sulfate, tosylate, nitrate, mesylate, napsylate, besylate, oxalate, maleate, phosphate, pamoate, fumarate, hippurate, succinate, and carbonate. In one embodiment, the form of the vancomycin is vancomycin hydrochloride. To avoid ambiguity, any reference to "vancomycin" in this specification is intended to include, unless otherwise stated, pharmaceutically acceptable salts of vancomycin, particularly hydrochloride.

[0019] The composition of the present invention is a "pre-diluted" composition containing vancomycin at a higher concentration than required for administration (usually intravenous administration) (and may also be described as a "composition concentrate"). Therefore, the composition of the present invention is usually diluted to the concentration required immediately before administration. Before use, the composition is usually stored in a suitable container such as a sealed vial. In one embodiment, the concentration of vancomycin or its pharmaceutically acceptable salt is 30 - 70 mg / mL, 35 - 65 mg / mL, 40 - 60 mg / mL, or about 50 mg / mL.

[0020] As described in the background of the invention, VancoReady™, a currently marketed liquid vancomycin composition, contains N-acetyl-D-alanine (NADA) and PEG400 as additives, both of which are reported to be associated with fetal malformations in animal reproductive studies and should therefore be avoided in such situations. As described in Example 3 of the present disclosure, N-acetyl-D-alanine (NADA) in the VancoReady™ composition appears to have a stabilizing effect. As described in Example 4, the inventors have found that a stable composition can be prepared using D-lactate in place of NADA. When L-lactate was used in place of NADA, no stabilizing effect was observed. As shown in Examples 6 and 7, the racemic form of lactate (DL-lactate) also has a stabilizing effect, but the concentration is typically twice that of D-lactate to achieve a comparable stabilizing effect.

[0021] In one embodiment, the composition comprises a pharmaceutically acceptable salt of D-lactic acid (also referred to herein as "D-lactate"). Suitable pharmaceutically acceptable salts of D-lactic acid include sodium D-lactate, calcium D-lactate, and potassium D-lactate. In one embodiment, the pharmaceutically acceptable salt of D-lactic acid is sodium D-lactate. In one embodiment, the concentration of D-lactic acid or its pharmaceutically acceptable salt is 100 to 1000 mM, such as 200 to 1000 mM, 100 to 500 mM or 200 to 500 mM, particularly about 400 to 450 mM or about 400 mM or about 200 mM.

[0022] In one embodiment, the composition substantially does not contain or does not contain L-lactic acid and its salts. That is, the only form of lactic acid or lactate in the composition is D-lactic acid or a pharmaceutically acceptable salt thereof. In this embodiment, "substantially does not contain" means that less than 1% of the total molar concentration of lactic acid (i.e., the total molar concentration of D-lactic acid or its salt and L-lactic acid or its salt) is in the form of L-lactic acid or its salt. For example, in the case of a composition containing D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 500 mM, the composition is assumed to contain less than 5 mM of L-lactic acid or its salt.

[0023] In one embodiment, the source of D-lactic acid or a pharmaceutically acceptable salt thereof is DL-lactic acid or a pharmaceutically acceptable salt thereof (also referred to herein as "DL-lactate"). Suitable pharmaceutically acceptable salts of DL-lactic acid include sodium DL-lactate, calcium DL-lactate, and potassium DL-lactate. In one embodiment, the pharmaceutically acceptable salt of DL-lactic acid is sodium DL-lactate. In one embodiment, the concentration of DL-lactic acid or a pharmaceutically acceptable salt thereof is 200 - 1000 mM, for example, 400 - 1000 mM, for example, 500 - 1000 mM, and in particular, about 800 mM or about 400 - 450 mM, or about 400 mM.

[0024] It should be noted that the pharmaceutically acceptable salts of D-lactate or DL-lactate can be generated in situ by adding D-lactic acid or DL-lactic acid to the composition and then adjusting the pH (for example, by adding a base such as NaOH) to form D-lactate or DL-lactate. It is expected that D-lactate added to the composition in the form of sodium D-lactate will have the same effect as the addition of the same (molar) amount of lactic acid and the subsequent pH adjustment step using sodium hydroxide.

[0025] As described above, it has been found that the currently marketed VancoReady™ composition can be modified to replace NADA, a stabilizer, with D-lactate while maintaining a composition with good stability. As shown in Examples 4-7, the inventors have also found that further modification of the D-lactate composition by replacing PEG400 with propylene glycol or a mixture of propylene glycol and glycerol results in a surprising relative increase in stability.

[0026] Accordingly, in one embodiment, the composition of the present invention comprises a co-solvent selected from propylene glycol and a mixture of propylene glycol and glycerol, the co-solvent being present at a concentration of 5-50% (v / v), such as 10-50% (v / v), 15-50% (v / v), 20-50% (v / v), 25-50% (v / v), 30-50% (v / v), 35-50% (v / v), 5-40% (v / v), 10-40% (v / v), 15-40% (v / v), 20-40% (v / v), 25-40% (v / v), 30-40% (v / v), 35-40% (v / v), 5-30% (v / v), 10-30% (v / v), 15-30% (v / v), 20-30% (v / v), 25-30% (v / v), 5-25% (v / v), 10-25% (v / v), 15-25% (v / v), 20-25% (v / v), 5-20% (v / v), 10-20% (v / v), 15-20% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v). In one embodiment, the composition of the present invention comprises a co-solvent selected from propylene glycol and a mixture of propylene glycol and glycerol, the co-solvent being present at a concentration of 5-50% (v / v), 10-50% (v / v), 10-40% (v / v), 10-30% (v / v), or 15-30% (v / v). The term “v / v” means “volume per volume” and is used to express the concentration of a liquid substance in a composition on a volume per volume basis. For example, 20% (v / v) propylene glycol means that there is about 20 mL of propylene glycol in 100 mL of the composition.

[0027] In one embodiment, the composition of the present invention contains propylene glycol as a co-solvent, preferably at a concentration of 5 to 50% (v / v), such as 10 to 50% (v / v), 15 to 50% (v / v), 20 to 50% (v / v), 25 to 50% (v / v), 30 to 50% (v / v), 35 to 50% (v / v), 5 to 40% (v / v), 10 to 40% (v / v), 15 to 40% (v / v), 20 to 40% (v / v), 25 to 40% (v / v), 30 to 40% (v / v), 35 to 40% (v / v), 5 to 30% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), 20 to 30% (v / v), 25 to 30% (v / v), 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), about 50% (v / v), about 45% (v / v), about 40% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v). In one embodiment, the composition of the present invention contains propylene glycol as a co-solvent at a concentration of 5 to 50% (v / v), such as 10 to 50% (v / v), 10 to 40% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), about 20% (v / v), or about 25% (v / v). In one embodiment, the composition of the present invention contains propylene glycol as a co-solvent at a concentration of 5 to 25% (v / v), such as 5 to 20% (v / v), 10 to 20% (v / v), about 20% (v / v), or about 15% (v / v). In this embodiment, the composition does not contain glycerol.

[0028] In one embodiment, the composition of the present invention comprises a mixture of propylene glycol and glycerol as a co-solvent, preferably at a combined total concentration of 5 to 50% (v / v), such as 10 to 50% (v / v), 15 to 50% (v / v), 20 to 50% (v / v), 25 to 50% (v / v), 30 to 50% (v / v), 35 to 50% (v / v), 5 to 40% (v / v), 10 to 40% (v / v), 15 to 40% (v / v), 20 to 40% (v / v), 25 to 40% (v / v), 30 to 40% (v / v), 35 to 40% (v / v), 5 to 30% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), 20 to 30% (v / v), 25 to 30% (v / v), 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), about 50% (v / v), about 45% (v / v), about 40% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v). In one embodiment, the composition of the present invention comprises a mixture of propylene glycol and glycerol as a co-solvent at a combined total concentration of 5 to 50% (v / v), such as 10 to 50% (v / v), 10 to 40% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), about 25% (v / v), or about 50% (v / v).

[0029] In one embodiment, the composition of the present invention is a mixture of propylene glycol and glycerol, wherein the propylene glycol is present at a concentration of 2 to 25% (v / v), for example, 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 2 to 20% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), 2 to 15% (v / v), 5 to 15% (v / v), 10 to 15% (v / v), 2 to 10% (v / v), 5 to 10% (v / v), about 10% (v / v), or about 15% (v / v) (in particular, present at a concentration of 2 to 25% (v / v), 5 to 25% (v / v), 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v); and the glycerol is present at a concentration of 2 to 45% (v / v), for example, 5 to 45% (v / v), 10 to 45% (v / v), 15 to 45% (v / v), 20 to 45% (v / v), 25 to 45% (v / v), 30 to 45% (v / v), 35 to 45% (v / v), 40 to 45% (v / v), 2 to 40% (v / v), 5 to 40% (v / v), 10 to 40% (v / v), 15 to 40% (v / v), 20 to 40% (v / v), 25 to 40% (v / v), 30 to 40% (v / v), 35 to 40% (v / v), 2 to 35% (v / v), 5 to 35% (v / v), 10 to 35% (v / v), 15 to 35% (v / v), 20 to 35% (v / v), 25 to 35% (v / v), 30 to 35% (v / v), 2 to 30% (v / v), 5 to 30% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), 20 to 30% (v / v), 25 to 30% (v / v), 2 to 25% (v / v), 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 2 to 20% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), 2 to 15% (v / v), 5 to 15% (v / v), 10 to 15% (v / v), 2 to 10% (v / v), 5 to 10% (v / v), 2 to 5% (v / v), about 10% (v / v), about 15% (v / v), about 20% (v / v), or about 35% (v / v) (in particular, present at a concentration of 2 to 45% (v / v), 5 to 40% (v / v), 5 to 35% (v / v), about 10% (v / v), or about 35% (v / v)), and contains a cosolvent which is the said mixture.In this embodiment, preferably, the total concentration of the composite of propylene glycol and glycerol as a co-solvent is 5 to 50% (v / v), 10 to 50% (v / v), 15 to 50% (v / v), 20 to 50% (v / v), 25 to 50% (v / v), 30 to 50% (v / v), 35 to 50% (v / v), 5 to 40% (v / v), 10 to 40% (v / v), 15 to 40% (v / v), 20 to 40% (v / v), 25 to 40% (v / v), 30 to 40% (v / v), 35 to 40% (v / v), 5 to 30% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), 20 to 30% (v / v), 25 to 30% (v / v), 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), about 50% (v / v), about 45% (v / v), about 40% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v) (in particular, 5 to 50% (v / v), 10 to 50% (v / v), 10 to 40% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), about 25% (v / v), or about 50% (v / v)).

[0030] In one embodiment, the composition includes a mixture of propylene glycol and glycerol as a co-solvent, and the concentration of propylene glycol is 2-25% (v / v), for example, 5-25% (v / v), 10-25% (v / v), 15-25% (v / v), 20-25% (v / v), 2-20% (v / v), 5-20% (v / v), 10-20% (v / v), 15-20% (v / v), 2-15% (v / v), 5-15% (v / v), 10-15% (v / v), 2-10% (v / v), 5-10% (v / v), about 10% (v / v), or about 15% (v / v) (in particular, 2-25% (v / v), 5-25% (v / v), 5-20% (v / v), 5-15% (v / v), 10-20% (v / v), about 10% (v / v), or about 15% (v / v); and the concentration of glycerol is 35-45% (v / v), for example, 40-45% (v / v), 35-40% (v / v), about 35% (v / v), or about 40% (v / v). In this embodiment, preferably, the combined total concentration of propylene glycol and glycerol as the co-solvent is 40-50% (v / v), for example, 45-50% (v / v), about 45% (v / v), or about 50% (v / v). In one embodiment, the ratio of propylene glycol to glycerol (v / v) is between 1:3 and 1:1.5.

[0031] In one embodiment, the composition includes a mixture of propylene glycol and glycerol as a co-solvent, the concentration of propylene glycol is about 10% (v / v), and the concentration of glycerol is about 35% (v / v), or the concentration of propylene glycol is about 15% (v / v), and the concentration of glycerol is about 35% (v / v).

[0032] In one embodiment, the composition comprises a mixture of propylene glycol and glycerol as a co-solvent, and the concentration of propylene glycol is 2 to 25% (v / v), for example, 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 35% (v / v), 2 to 20% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), 2 to 15% (v / v), 5 to 15% (v / v), 10 to 15% (v / v), 2 to 10% (v / v), 5 to 10% (v / v), about 10% (v / v), or about 15% (v / v) (in particular, 2 to 25% (v / v), 5 to 25% (v / v), 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v); and the concentration of glycerol is 2 to 10% (v / v), for example, 5 to 10% (v / v), about 5% (v / v), or about 10% (v / v). In this embodiment, preferably, the combined total concentration of propylene glycol and glycerol as a co-solvent is 5 to 40% (v / v), for example, 10 to 40% (v / v), 15 to 40% (v / v), 20 to 40% (v / v), 25 to 40% (v / v), 30 to 40% (v / v), 35 to 40% (v / v), 5 to 30% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), 20 to 30% (v / v), 25 to 30% (v / v), 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), about 40% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v) (in particular, 5 to 40% (v / v), 10 to 30% (v / v), or about 25% (v / v). In one embodiment, the ratio of propylene glycol to glycerol (v / v) is between 2:1 and 1.2:1.

[0033] In one embodiment, the composition comprises a mixture of propylene glycol and glycerol as a co-solvent, the concentration of propylene glycol is about 15% (v / v), and the concentration of glycerol is about 10% (v / v).

[0034] In one embodiment, the molar ratio of vancomycin or a pharmaceutically acceptable salt thereof to a co-solvent (i.e., propylene glycol, or a mixture of propylene glycol and glycerol) is between 1:10 and 1:100, for example, between 1:20 and 1:60.

[0035] In one embodiment, the molar osmolar concentration of the composition is 1500 - 8000 mOsm / L, for example, 2000 - 6000 mOsm / L, for example, 3000 - 6000 mOsm / L.

[0036] To avoid ambiguity, any reference herein to "molar osmolar concentration" means the calculated molar osmolar concentration. Molar osmolar concentration is calculated as the sum of the molar concentrations of all individual species dissolved in the solution and is expressed as osmoles per liter (Osm / L) or milliosmoles per liter (mOsm / L). For species that do not dissociate in solution, the molar osmolar concentration (Osm / L or mOsm / L) is equal to the molar concentration (in mol / L or mmol / L). For example, 500 mM glycerol in a solution at pH 5.0 does not dissociate, so the solution has a molar osmolar concentration of 500 mOsm / L. For species that dissociate in solution, the molar osmolar concentration is the sum of the molar concentrations of all dissociated species. For example, 500 mM sodium chloride at pH 5.0 dissociates into 500 mM sodium cations and 500 mM chloride anions, so the solution has a molar osmolar concentration of 1000 mOsm / L.

[0037] The composition of the present invention is an aqueous composition and contains at least 95% (v / v) water, for example, at least 90% (v / v), at least 85% (v / v), at least 80% (v / v), at least 75% (v / v), at least 70% (v / v), at least 65% (v / v), at least 60% (v / v), at least 55% (v / v), or at least 50% (v / v) water, for example, water for injection, sterilized or bacteriostatic.

[0038] The composition of the present invention contains an inorganic salt containing a metal cation. As shown in Examples 5 to 8, this salt provides a stabilizing effect. In one embodiment, the composition further comprises an inorganic salt containing a Group 1 or Group 2 metal cation. In one embodiment, the inorganic salt containing a metal cation is selected from the group consisting of sodium chloride, calcium chloride, sodium oxamate, and sodium sulfate. In one embodiment, the inorganic salt containing a metal cation is sodium oxamate. In one embodiment, the inorganic salt containing a metal cation is sodium chloride or calcium chloride, particularly sodium chloride. The concentration of the inorganic salt containing a metal cation is typically 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM or about 200 mM. The concentration of the above-mentioned inorganic salt shall generally represent the concentration of an inorganic salt such as sodium chloride added to the composition.

[0039] The effect of pH on the stability of the vancomycin composition is shown in Example 2. In Example 2, a pH value range of 3.5 to 9.5 was tested, and the optimal pH was found to be between 4.5 and 5.5. Thus, in one embodiment, the pH of the composition of the present invention is in the range of 4.0 to 6.0, for example, about 5.0.

[0040] It should be noted that whenever "pH" is mentioned in this specification, it means the pH of the composition evaluated at 21°C. "pK a " Whenever mentioned, it means the pK a of the ionizable group evaluated at 25°C (see "CRC Handbook of Chemistry and Physics", 79th edition, 1998, D. R. Lide).

[0041] In one embodiment, the composition further comprises an antioxidant, which is preferably selected from the group consisting of monothioglycerol, butylhydroxyanisole, glutathione (reduced form), ascorbate, cysteine, and methionine, and is preferably methionine. When included, the antioxidant is typically present in the composition at a concentration of 1 to 100 mM, for example, 10 to 50 mM or 25 to 50 mM.

[0042] In one embodiment, the composition of the present invention is substantially free or free of amino acids. In one embodiment, the composition of the present invention is substantially free or free of polyethylene glycol (PEG), particularly PEG400. In one embodiment, the composition of the present invention is substantially free or free of glycerol. In one embodiment, the composition of the present invention is substantially free or free of N-acetyl-D-alanine. In one embodiment, the composition of the present invention is substantially free or free of ethanol. In one embodiment, the composition of the present invention is substantially free or free of EDTA. In one embodiment, the composition of the present invention is substantially free or free of cyclodextrins, such as sulfobutyl ether-β-cyclodextrin. In all of these embodiments, "substantially free" means that the composition contains less than 0.1 mM of the stated component.

[0043] The composition may contain a nonionic surfactant, which is preferably selected from the group consisting of alkyl glycosides, polysorbates, alkyl ethers of polyethylene glycol, block copolymers of polyethylene glycol and polypropylene glycol, and alkyl phenyl ethers of polyethylene glycol.

[0044] When the nonionic surfactant is an alkyl glucoside, it is preferably selected from the group consisting of dodecyl maltoside, dodecyl glucoside, octyl glucoside, octyl maltoside, decyl glucoside, decyl maltoside, decyl glucopyranoside, tridecyl glucoside, tridecyl maltoside, tetradecyl glucoside, tetradecyl maltoside, hexadecyl glucoside, hexadecyl maltoside, sucrose monooctanoate, sucrose monodecanoate, sucrose monolaurate, sucrose monotridecanoate, sucrose monomyristate, and sucrose monopalmitate. In one embodiment, the alkyl glucoside is dodecyl maltoside or decyl glucopyranoside, and particularly dodecyl maltoside.

[0045] When the nonionic surfactant is a polysorbate, it is preferably selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. In one embodiment, the nonionic surfactant is polysorbate 20 or polysorbate 80. Polysorbates are known under various brand names, including in particular Tween "XX" and Alkest TW "XX" (where "XX" is 20, 40, 60, or 80).

[0046] When the nonionic surfactant is an alkyl ether of polyethylene glycol, it is preferably selected from the group consisting of polyethylene glycol (2) hexadecyl ether (Brij 52), polyethylene glycol (2) oleyl ether (Brij 93), polyethylene glycol (2) dodecyl ether (Brij L4), polyethylene glycol (4) lauryl ether (Brij 30), polyethylene glycol (10) lauryl ether (Brij 35), polyethylene glycol (20) hexadecyl ether (Brij 58), and polyethylene glycol (10) stearyl ether (Brij 78).

[0047] When the nonionic surfactant is a block copolymer of polyethylene glycol and polypropylene glycol, it is preferably selected from the group consisting of poloxamer 188, poloxamer 407, poloxamer 171, or poloxamer 185. Also, poloxamers are also known by the brand names Pluronics or Koliphors. For example, poloxamer 188 is sold as Pluronic F-68.

[0048] When the nonionic surfactant is an alkylphenyl ether of polyethylene glycol, it is preferably 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol, also known by the brand name Triton X-100.

[0049] When included, the concentration of the nonionic surfactant is typically in the range of 1 - 5000 μg / mL, 1 - 1000 μg / mL, for example, 5 - 500 μg / mL, 10 - 400 μg / mL, 20 - 400 μg / mL, 50 - 400 μg / mL, 10 - 300 μg / mL, 20 - 300 μg / mL, 50 - 300 μg / mL, 10 - 200 μg / mL, 20 - 200 μg / mL, 50 - 200 μg / mL, 10 - 100 μg / mL, 20 - 100 μg / mL, 50 - 100 μg / mL, or about 50 μg / mL.

[0050] The composition of the present invention may further contain a preservative such as a phenolic or benzyl preservative. The preservative is preferably selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, propyl paraben, and methyl paraben, particularly phenol, m-cresol, and benzyl alcohol, and mixtures thereof. When included, the concentration of the preservative (total concentration when two or more preservatives are present) is typically 10 - 100 mM, for example, 20 - 80 mM, for example, 25 - 50 mM. The optimal concentration of the preservative in the composition is selected such that the composition will surely pass the Pharmacopeial Antimicrobial Effectiveness Test (USP <51>, Vol. 32).

[0051] In one embodiment, vancomycin at a concentration of 25 to 75 mg / mL, such as 35 to 65 mg / mL or about 50 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 1000 mM, such as 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM, or a pharmaceutically acceptable salt thereof, or DL-lactic acid at a concentration of 200 to 1000 mM, such as 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; propylene glycol as a co-solvent at a concentration of 5 to 25% (v / v), such as 5 to 20% (v / v), 10 to 20% (v / v), about 20% (v / v), or about 15% (v / v); and an inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, such as 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, in particular sodium oxamate, sodium chloride, or calcium chloride; comprising a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, such as about 5.0, is provided.

[0052] In one embodiment, vancomycin at a concentration of 25 to 75 mg / mL, such as 35 to 65 mg / mL or about 50 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 1000 mM, such as 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM, or a pharmaceutically acceptable salt thereof, or DL-lactic acid at a concentration of 200 to 1000 mM, such as 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5-25% (v / v), for example, 5-20% (v / v), 5-15% (v / v), 10-20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 35-45% (v / v), for example, 40-45% (v / v), 35-40% (v / v), about 35% (v / v), or about 40% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 40-50% (v / v), for example, 45-50% (v / v), about 45% (v / v), or about 50% (v / v); and An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5-300 mM, for example, 50-200 mM, 50-150 mM, 50-100 mM, 100-200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, in particular, sodium oxamate, sodium chloride, or calcium chloride; comprising There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0-6.0, for example, about 5.0.

[0053] In one embodiment, Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25-75 mg / mL, for example, 35-65 mg / mL or about 50 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100-1000 mM, for example, 200-1000 mM, 100-500 mM, 200-500 mM, about 400-450 mM or about 400 mM or about 200 mM, or DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200-1000 mM, for example, 400-1000 mM, 500-1000 mM, about 800 mM or about 400-450 mM, or about 400 mM; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 to 10% (v / v), for example, 5 to 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 5 to 40% (v / v), 10 to 30% (v / v), or about 25% (v / v); and An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, in particular, sodium oxamate, sodium chloride, or calcium chloride; comprising A storage-stable aqueous solution composition is provided, wherein the pH is in the range of 4.0 to 6.0, for example, about 5.0.

[0054] In one embodiment, Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 1000 mM, for example, 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM; Propylene glycol as a co-solvent at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 10 to 20% (v / v), about 20% (v / v), or about 15% (v / v); and An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, in particular, sodium oxamate, sodium chloride, or calcium chloride; comprising There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0.

[0055] In one embodiment, vancomycin at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL, or a pharmaceutically acceptable salt thereof; DL-lactic acid at a concentration of 200 to 1000 mM, for example, 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; propylene glycol as a co-solvent at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 10 to 20% (v / v), about 20% (v / v), or about 15% (v / v); and an inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, in particular, sodium oxamate, sodium chloride, or calcium chloride; comprising There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0.

[0056] In one embodiment, vancomycin at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 1000 mM, for example, 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM, or a pharmaceutically acceptable salt thereof; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 35 to 45% (v / v), for example, 40 to 45% (v / v), 35 to 40% (v / v), about 35% (v / v), or about 40% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 40 to 50% (v / v), for example, 45 to 50% (v / v), about 45% (v / v), or about 50% (v / v); and An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, in particular, sodium oxamate, sodium chloride, or calcium chloride; comprising There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0.

[0057] In one embodiment, Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, for example, 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 35 to 45% (v / v), for example, 40 to 45% (v / v), 35 to 40% (v / v), about 35% (v / v), or about 40% (v / v), and the combined total concentration of propylene glycol and glycerol as the co-solvent is preferably 40 to 50% (v / v), for example, 45 to 50% (v / v), about 45% (v / v), or about 50% (v / v); and An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxamate, sodium chloride, or calcium chloride; comprising A storage-stable aqueous solution composition is provided, wherein the pH is in the range of 4.0 to 6.0, for example, about 5.0.

[0058] In one embodiment, Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 1000 mM, for example, 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5-25% (v / v), for example, 5-20% (v / v), 5-15% (v / v), 10-20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2-10% (v / v), for example, 5-10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 5-40% (v / v), 10-30% (v / v), or about 25% (v / v); and An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5-300 mM, for example, 50-200 mM, 50-150 mM, 50-100 mM, 100-200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxamate, sodium chloride, or calcium chloride; comprising A storage-stable aqueous solution composition is provided, wherein the pH is in the range of 4.0-6.0, for example, about 5.0.

[0059] In one embodiment, Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25-75 mg / mL, for example, 35-65 mg / mL or about 50 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100-1000 mM, for example, 200-1000 mM, 100-500 mM, 200-500 mM, about 400-450 mM or about 400 mM or about 200 mM; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), such as 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 to 10% (v / v), such as 5 to 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as the co-solvent is preferably 5 to 40% (v / v), 10 to 30% (v / v), or about 25% (v / v); and Sodium chloride at a concentration of 5 to 300 mM, such as 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM; comprising A storage-stable aqueous solution composition is provided, wherein the pH is in the range of 4.0 to 6.0, such as about 5.0.

[0060] In one embodiment, Vancomycin or a pharmaceutically acceptable salt thereof, such as vancomycin hydrochloride, at a concentration of 25 to 75 mg / mL, such as 35 to 65 mg / mL or about 50 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof, such as sodium D-lactate, at a concentration of 100 to 1000 mM, such as 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), such as 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 to 10% (v / v), such as 5 to 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as the co-solvent is preferably 5 to 40% (v / v), 10 to 30% (v / v), or about 25% (v / v); and Sodium chloride at a concentration of 5 to 300 mM, such as 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM; comprising having a pH in the range of 4.0 to 6.0, such as about 5.0; and There is provided a storage-stable aqueous solution composition having an osmolality of 1500 to 8000 mOsm / L, such as 2000 to 6000 mOsm / L, or 3000 to 6000 mOsm / L.

[0061] In one embodiment, vancomycin at a concentration of about 50 mg / mL or a pharmaceutically acceptable salt thereof, such as vancomycin hydrochloride; D-lactic acid at a concentration of 200 to 500 mM, such as about 400 to 450 mM or about 400 mM or about 200 mM, or a pharmaceutically acceptable salt thereof, such as sodium D-lactate; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of about 15% (v / v), and the glycerol is present at a concentration of about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably about 25% (v / v), said mixture; and sodium chloride at a concentration of 100 to 200 mM, such as about 150 mM; comprising having a pH in the range of 4.0 to 6.0; and There is provided a storage-stable aqueous solution composition having an osmolality of 3000 to 6000 mOsm / L.

[0062] In one embodiment, vancomycin at a concentration of about 50 mg / mL or a pharmaceutically acceptable salt thereof, such as vancomycin hydrochloride; D-lactic acid at a concentration of about 400 to 450 mM or a pharmaceutically acceptable salt thereof, such as sodium D-lactate; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of about 15% (v / v), and the glycerol is present at a concentration of about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably about 25% (v / v), said mixture; and Sodium chloride at a concentration of 100 - 200 mM, for example, about 150 mM; comprising having a pH in the range of 4.0 - 6.0; and there is provided a storage-stable aqueous solution composition having an osmolality of 3000 - 6000 mOsm / L.

[0063] In one embodiment, Vancomycin at a concentration of about 50 mg / mL or a pharmaceutically acceptable salt thereof, for example, vancomycin hydrochloride; D-lactic acid at a concentration of about 200 mM or a pharmaceutically acceptable salt thereof, for example, sodium D-lactate; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of about 15% (v / v), and the glycerol is present at a concentration of about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably about 25% (v / v), said mixture; and Sodium chloride at a concentration of 100 - 200 mM, for example, about 150 mM; comprising having a pH in the range of 4.0 - 6.0; and there is provided a storage-stable aqueous solution composition having an osmolality of 3000 - 6000 mOsm / L.

[0064] In one embodiment, Vancomycin at a concentration of 25 - 75 mg / mL, for example, 35 - 65 mg / mL or about 50 mg / mL or a pharmaceutically acceptable salt thereof; DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, for example, 400 - 1000 mM, 500 - 1000 mM, about 800 mM or about 400 - 450 mM, or about 400 mM; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 - 25% (v / v), for example, 5 - 20% (v / v), 5 - 15% (v / v), 10 - 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 - 10% (v / v), for example, 5 - 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 5 - 40% (v / v), 10 - 30% (v / v), or about 25% (v / v), said mixture; and An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 - 300 mM, for example, 50 - 200 mM, 50 - 150 mM, 50 - 100 mM, 100 - 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, in particular, sodium oxamate, sodium chloride, or calcium chloride; comprising There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 - 6.0, for example, about 5.0.

[0065] In one embodiment, Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 - 75 mg / mL, for example, 35 - 65 mg / mL or about 50 mg / mL; DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, for example, 400 - 1000 mM, 500 - 1000 mM, about 800 mM or about 400 - 450 mM, or about 400 mM; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 to 10% (v / v), for example, 5 to 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 5 to 40% (v / v), 10 to 30% (v / v), or about 25% (v / v); and Sodium chloride at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, or about 75 mM; comprising There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0.

[0066] In one embodiment, Vancomycin or a pharmaceutically acceptable salt thereof, such as vancomycin hydrochloride, at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; DL-lactic acid or a pharmaceutically acceptable salt thereof, such as sodium DL-lactate, at a concentration of 200 to 1000 mM, for example, 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 to 10% (v / v), for example, 5 to 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 5 to 40% (v / v), 10 to 30% (v / v), or about 25% (v / v); and Sodium chloride at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, or about 75 mM; comprising the pH is in the range of 4.0 to 6.0, for example, about 5.0; and a storage-stable aqueous solution composition is provided, wherein the osmolality is 1500 to 8000 mOsm / L, for example, 2000 to 6000 mOsm / L, or 3000 to 6000 mOsm / L.

[0067] In one embodiment, vancomycin at a concentration of about 50 mg / mL or a pharmaceutically acceptable salt thereof, for example, vancomycin hydrochloride; DL-lactic acid at a concentration of about 400 to 450 mM or a pharmaceutically acceptable salt thereof, for example, sodium DL-lactate; a mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of about 15% (v / v), and the glycerol is present at a concentration of about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably about 25% (v / v), said mixture; and sodium chloride at a concentration of 50 to 100 mM, for example, about 75 mM; comprising the pH is in the range of 4.0 to 6.0; and a storage-stable aqueous solution composition is provided, wherein the osmolality is 3000 to 6000 mOsm / L.

[0068] In one embodiment, (i) vancomycin at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL, or a pharmaceutically acceptable salt thereof; (ii) D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 - 1000 mM, such as 200 - 1000 mM, 100 - 500 mM, 200 - 500 mM, about 400 - 450 mM or about 400 mM or about 200 mM, or DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, such as 400 - 1000 mM, 500 - 1000 mM, about 800 mM or about 400 - 450 mM, or about 400 mM; (iii) Propylene glycol as a co-solvent at a concentration of 5 - 25% (v / v), 5 - 20% (v / v), 10 - 20% (v / v), about 20% (v / v), or about 15% (v / v); (iv) An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 - 300 mM, such as 50 - 200 mM, 50 - 150 mM, 50 - 100 mM, 100 - 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, especially sodium oxamate, sodium chloride, or calcium chloride; (v) Water, such as water for injection; (vi) Optionally, an antioxidant; (vii) Optionally, a non-ionic surfactant; and (viii) Optionally, a preservative; consisting of, or consisting essentially of: A storage-stable aqueous solution composition is provided, wherein the pH is in the range of 4.0 - 6.0, such as about 5.0.

[0069] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 - 75 mg / mL, such as 35 - 65 mg / mL or about 50 mg / mL; (ii) D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 - 1000 mM, such as 200 - 1000 mM, 100 - 500 mM, 200 - 500 mM, about 400 - 450 mM or about 400 mM or about 200 mM, or DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, such as 400 - 1000 mM, 500 - 1000 mM, about 800 mM or about 400 - 450 mM, or about 400 mM; (iii) A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 35 to 45% (v / v), for example, 40 to 45% (v / v), 35 to 40% (v / v), about 35% (v / v), or about 40% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 40 to 50% (v / v), for example, 45 to 50% (v / v), about 45% (v / v), or about 50% (v / v), said mixture; (iv) An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxamate, sodium chloride, or calcium chloride; (v) Water, for example, water for injection; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or consisting essentially of: A storage-stable aqueous solution composition is provided, wherein the pH is in the range of 4.0 to 6.0, for example, about 5.0.

[0070] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; (ii) D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 - 1000 mM, for example, 200 - 1000 mM, 100 - 500 mM, 200 - 500 mM, about 400 - 450 mM, or about 400 mM, or about 200 mM, or DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, for example, 400 - 1000 mM, 500 - 1000 mM, about 800 mM, or about 400 - 450 mM, or about 400 mM; (iii) A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 - 25% (v / v), for example, 5 - 20% (v / v), 5 - 15% (v / v), 10 - 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 - 10% (v / v), for example, 5 - 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 5 - 40% (v / v), 10 - 30% (v / v), or about 25% (v / v); (iv) An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 - 300 mM, for example, 50 - 200 mM, 50 - 150 mM, 50 - 100 mM, 100 - 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxamate, sodium chloride, or calcium chloride; (v) Water, for example, water for injection; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; Comprising, or consisting essentially of: A storage-stable aqueous solution composition is provided, having a pH in the range of 4.0 - 6.0, for example, about 5.0.

[0071] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 - 75 mg / mL, for example, 35 - 65 mg / mL, or about 50 mg / mL; (ii) D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 - 1000 mM, for example, 200 - 1000 mM, 100 - 500 mM, 200 - 500 mM, about 400 - 450 mM, or about 400 mM, or about 200 mM; (iii) Propylene glycol as a co-solvent at a concentration of 5 - 25% (v / v), for example, 5 - 20% (v / v), 10 - 20% (v / v), about 20% (v / v), or about 15% (v / v); (iv) An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 - 300 mM, for example, 50 - 200 mM, 50 - 150 mM, 50 - 100 mM, 100 - 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxamate, sodium chloride, or calcium chloride; (v) Water, for example, water for injection; (vi) Optionally, an antioxidant; (vii) Optionally, a non-ionic surfactant; and (viii) Optionally, a preservative; consisting of or essentially consisting of: There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 - 6.0, for example, about 5.0.

[0072] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 - 75 mg / mL, for example, 35 - 65 mg / mL or about 50 mg / mL; (ii) DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, for example, 400 - 1000 mM, 500 - 1000 mM, about 800 mM, or about 400 - 450 mM, or about 400 mM; (iii) Propylene glycol as a co-solvent at a concentration of 5 - 25% (v / v), for example, 5 - 20% (v / v), 10 - 20% (v / v), about 20% (v / v), or about 15% (v / v); (iv) An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxalate, sodium chloride, or calcium chloride; (v) Water, for example, water for injection; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of, or consisting essentially of: There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0.

[0073] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; (ii) D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 1000 mM, for example, 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM; (iii) A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 35 to 45% (v / v), 40 to 45% (v / v), 35 to 40% (v / v), about 35% (v / v), or about 40% (v / v), and the combined total concentration of propylene glycol and glycerol is preferably 40 to 50% (v / v), for example, 45 to 50% (v / v), about 45% (v / v), or about 50% (v / v); and (iv) An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxalate, sodium chloride, or calcium chloride; (v) Water, for example, water for injection; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or essentially consisting of: There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0.

[0074] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; (ii) DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, for example, 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM; (iii) A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 35 to 45% (v / v), for example, 40 to 45% (v / v), 35 to 40% (v / v), about 35% (v / v), or about 40% (v / v), and the combined total concentration of propylene glycol and glycerol is preferably 40 to 50% (v / v), for example, 45 to 50% (v / v), about 45% (v / v), or about 50% (v / v); (iv) An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, such as 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxalate, sodium chloride, or calcium chloride; (v) Water, such as water for injection; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or essentially consisting of: There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, such as about 5.0.

[0075] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, such as 35 to 65 mg / mL or about 50 mg / mL; (ii) D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 1000 mM, such as 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM; (iii) A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), such as 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 to 10% (v / v), such as 5 to 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol is preferably 5 to 40% (v / v), 10 to 30% (v / v), or about 25% (v / v); and (iv) An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxalate, sodium chloride, or calcium chloride; (v) Water, for example, water for injection; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of, or essentially consisting of: There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0.

[0076] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; (ii) DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, for example, 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM; (iii) A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 to 10% (v / v), for example, 5 to 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol is preferably 5 to 40% (v / v), 10 to 30% (v / v), or about 25% (v / v); (iv) An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, such as 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxalate, sodium chloride, or calcium chloride; (v) Water, such as water for injection; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of, or consisting essentially of: There is provided a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, such as about 5.0.

[0077] As used herein when referring to the compositions of the present invention, the term "consisting of" means that no further components other than those listed are included in the composition. As used herein when referring to the compositions of the present invention, the term "consisting essentially of" means that certain further components may be present, provided that such components do not substantially affect the essential characteristics of the composition and are usually present in minimal amounts.

[0078] Preferably, the composition of the present invention remains a clear solution after storage at 2 to 8°C for a long period, such as at least 6 months, at least 12 months, at least 18 months, or at least 24 months (e.g., measured by a visual evaluation method in a general method).

[0079] Preferably, the composition of the present invention remains a clear solution after storage at 25°C for at least 1 week, such as at least 2 weeks, at least 4 weeks, or at least 8 weeks (e.g., measured by a visual evaluation method in a general method).

[0080] Preferably, after storage at 2 - 8°C for a long period, for example, at least 6 months, at least 12 months, at least 18 months, or at least 24 months, the composition of the present invention contains total impurities not exceeding 12% and each individual impurity is not >4% (based on the total weight of vancomycin or a pharmaceutically acceptable salt thereof in the composition), as described in the United States Pharmacopeia monograph (vancomycin hydrochloride for injection, United States Pharmacopeia 29).

[0081] Preferably, after storage at 2 - 8°C for a long period, for example, at least 6 months, at least 12 months, at least 18 months, or at least 24 months, the composition of the present invention contains total impurities not exceeding 7% and each individual impurity is not >4% (based on the total weight of vancomycin or a pharmaceutically acceptable salt thereof in the composition), as described in the European Pharmacopeia monograph (vancomycin hydrochloride, EP 6.0).

[0082] Preferably, after storage at 25°C for at least 1 week, for example, at least 2 weeks, at least 4 weeks, or at least 8 weeks, the composition of the present invention contains total impurities not exceeding 12% and each individual impurity is not >4% (based on the total weight of vancomycin or a pharmaceutically acceptable salt thereof in the composition), as described in (vancomycin hydrochloride for injection, United States Pharmacopeia 29).

[0083] Preferably, after storage at 25°C for at least 1 week, for example, at least 2 weeks, at least 4 weeks, or at least 8 weeks, the composition of the present invention contains total impurities not exceeding 7% and each individual impurity is not >4% (based on the total weight of vancomycin or a pharmaceutically acceptable salt thereof in the composition), as described in the European Pharmacopeia monograph (vancomycin hydrochloride, EP 6.0).

[0084] In one embodiment, the composition of the present invention is a composition for use in therapy. In one embodiment, the composition of the present invention is a pharmaceutical composition.

[0085] Vancomycin (especially vancomycin hydrochloride) is indicated particularly for the treatment of bacterial infections, especially severe or serious bacterial infections caused by susceptible strains of methicillin-resistant (β-lactam-resistant) staphylococci. This is for patients with penicillin allergy, patients who cannot be administered or who do not respond to other drugs including penicillin or cephalosporin, and bacterial infections caused by vancomycin-susceptible organisms resistant to other antimicrobial drugs. Vancomycin (especially vancomycin hydrochloride) is indicated for initial therapy when methicillin-resistant staphylococci are suspected, but the therapy should be adjusted according to the susceptibility data after it becomes available.

[0086] Also, vancomycin (especially vancomycin hydrochloride) is effective in the treatment of staphylococcal endocarditis. Its effectiveness has also been documented in other bacterial infections caused by staphylococci, including sepsis, bone infections, lower respiratory tract infections, and skin and skin structure infections. When the staphylococcal infection is localized and purulent, the antibiotic is used as an adjunct to appropriate surgical treatment. Vancomycin (especially vancomycin hydrochloride) has been reported to be effective alone or in combination with an aminoglycoside in endocarditis caused by Streptococcus viridans or Streptococcus bovis. For endocarditis caused by Enterococcus spp. (e.g., Enterococcus faecalis), vancomycin (especially vancomycin hydrochloride) has been reported to be effective only in combination with an aminoglycoside. Vancomycin has been reported to be effective in the treatment of diphtheroid endocarditis. Vancomycin has been successfully used in combination with either rifampin or an aminoglycoside or both in early-onset prosthetic valve endocarditis caused by Staphylococcus epidermidis or diphtheroids.

[0087] Accordingly, in one embodiment, there is provided a composition as described hereinabove for use in the treatment of bacterial infections. In one embodiment, there is provided a composition as described hereinabove for use in the production of a medicament for treating bacterial infections. In one embodiment, there is provided a method of treating a bacterial infection comprising administering to a patient in need thereof, particularly a human patient, a therapeutically effective amount of a composition as described hereinabove. Since the compositions of the present invention are composition concentrates, they are usually diluted before use.

[0088] In one embodiment, the bacterial infection is caused by a Gram-positive bacterium and is preferably selected from the group consisting of Clostridium difficile, Listeria monocytogenes, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus viridans, Streptococcus bovis, Staphylococcus epidermidis, methicillin-resistant Staphylococcus epidermidis, Staphylococcos aureus, methicillin-resistant Staphylococcos aureus, Actinomyces species, Lactobacillus species, Enterococcus faecalis, and diphtheroids.

[0089] The vancomycin compositions of the present invention can be used as monotherapy or in combination with one or more other therapeutic agents. In one embodiment, the additional therapeutic agent is an antibiotic selected from the group consisting of, for example, rifampicin, aminoglycosides (such as gentamicin), and β-lactam antibiotics (such as amoxicillin).

[0090] In one embodiment, for example, there is provided a composition as described above herein for use in the treatment of bacterial infections with an antibiotic selected from the group consisting of rifampicin, aminoglycosides (such as gentamicin), and β-lactam antibiotics (such as amoxicillin). In one embodiment, there is provided an antibiotic selected from the group consisting of rifampicin, aminoglycosides (such as gentamicin), and β-lactam antibiotics (such as amoxicillin) for use in the treatment of bacterial infections with a composition as described above herein.

[0091] All of the embodiments described above with respect to the aqueous composition apply equally to the methods and uses of the present invention.

[0092] Also provided is a container containing a single dose or multiple doses of a composition as described above herein. The container is preferably a vial, for example, a plastic or glass vial. Preferably, the glass vial is a type 1 glass vial containing, for example, 80% silica and 10% boron oxide together with small amounts of sodium oxide and aluminum oxide. In one embodiment, there is provided a multiple-dose vial, particularly a glass vial, containing a composition as described above herein. In one embodiment, the filling volume of the vial is 10 mL, 20 mL, 25 mL, 40 mL, 50 mL, 75 mL, or 100 mL. Typically, vials with larger filling volumes are preferred as they allow for the use of a smaller number of vials for the preparation of single doses.

[0093] The composition of the present invention is preferably diluted before administration. Once diluted, the resulting solution (ready-to-administer solution) is typically administered by intravenous infusion. A typical method for the administration of the diluted composition of the present invention involves transferring a certain volume of the composition concentrate into a container, preferably an intravenous (IV) solution bag or bottle, where the volume of the ready-to-dilute composition is calculated according to the required dose and the volume of the container. After complete mixing of the dilution solution, the contents of the container can be administered to the patient.

[0094] When the container is an IV solution bag, it is preferably composed of a plastic such as PVC, polyolefin, polypropylene, a blend of PO and PP (polyolefin blend), polyurethane, or a material substantially free of PVC, plasticizer, adhesive, and latex, such as DEHP (di(2-ethylhexyl) phthalate). When the container is a bottle, it can be made of plastic (such as those described above for IV solution bags) or can be made of glass, for example, it is a type 1 glass bottle. In one embodiment, the volume of the IV solution bag or bottle is 50 ml to 1 L, for example, 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 400 mL, 500 mL, 750 mL, or 1 L.

[0095] The composition of the present invention can be diluted in a pharmaceutically acceptable diluent such as 0.9% saline, 5% glucose in water, or water (e.g., sterile water for injection or bacteriostatic water for injection).

[0096] Preferably, the composition of the present invention is diluted in a suitable diluent by mixing 1 volume part of the composition with 4 to 14 volume parts (e.g., 9 volume parts) of a suitable diluent, and the described concentration of vancomycin is achieved. Thus, the concentration of vancomycin or a pharmaceutically acceptable salt thereof in the resulting ready-to-administer composition is 5 to 15 times (e.g., 10 times) lower than in the original ready-to-dilute composition. In one embodiment, the concentration of vancomycin or a pharmaceutically acceptable salt thereof in the diluted composition (ready-to-administer) is 5 to 15% (e.g., 10%) of the concentration in the ready-to-dilute composition. In one embodiment, the diluted composition contains 1 to 10 mg / mL (e.g., 2.5 to 7.5 mg / mL, or about 5 mg / mL) of vancomycin (optionally in the form of a pharmaceutically acceptable salt, such as hydrochloride).

[0097] Preferably, the diluted form of the composition of the present invention is a colorless to slightly yellow solution that does not contain visually observable particles. In one embodiment, the diluted form of the composition is isotonic. In another embodiment, the diluted form of the composition is slightly hypertonic. Typically, the diluted form of the composition is slightly hypertonic. Preferably, when prepared, the diluted form of the composition is stable at 2-8°C for at least 24 hours and at 25°C and room light for at least 3 hours.

[0098] Accordingly, in one embodiment, there is provided a method for preparing a solution for intravenous administration by diluting a composition concentrate as described above herein in a diluent selected from 0.9% saline, 5% glucose in water, and water (e.g., sterile water for injection or bacteriostatic water for injection). In one embodiment, the method provides a diluted composition containing 1-10 mg / mL, such as 2.5-7.5 mg / mL, or about 5 mg / mL of vancomycin (e.g., vancomycin hydrochloride).

[0099] The present invention is further defined by the following items: (Item 1) Vancomycin at a concentration of 25-75 mg / mL or a pharmaceutically acceptable salt thereof; D-lactic acid or a pharmaceutically acceptable salt thereof; A co-solvent selected from propylene glycol and a mixture of propylene glycol and glycerol; and An inorganic salt containing a metal cation A storage-stable aqueous solution composition comprising: (Item 2) The storage-stable aqueous solution composition according to Item 1, wherein the form of the vancomycin is vancomycin hydrochloride. (Item 3) The storage-stable aqueous solution composition according to Item 1 or 2, wherein the concentration of vancomycin or a pharmaceutically acceptable salt thereof is 35-65 mg / mL or about 50 mg / mL. (Item 4) The storage-stable aqueous solution composition according to any one of Items 1-3, which substantially does not contain or does not contain L-lactic acid and its salts. (Item 5) The storage-stable aqueous solution composition according to any one of items 1 to 4, comprising sodium D-lactate, calcium D-lactate, or potassium D-lactate, particularly sodium D-lactate. (Item 6) The storage-stable aqueous solution composition according to any one of items 1 to 3 or 5, wherein the source of the D-lactic acid or a pharmaceutically acceptable salt thereof is DL-lactic acid or a pharmaceutically acceptable salt thereof. (Item 7) The storage-stable aqueous solution composition according to item 6, comprising sodium DL-lactate, calcium DL-lactate, or potassium DL-lactate, particularly sodium DL-lactate. (Item 8) The storage-stable aqueous solution composition according to any one of items 1 to 7, wherein the concentration of the D-lactic acid or a pharmaceutically acceptable salt thereof is 100 to 1000 mM, for example, 100 to 500 mM, particularly about 200 mM or about 400 to 450 mM, or about 400 mM. (Item 9) The storage-stable aqueous solution composition according to item 6 or 7, wherein the concentration of the DL-lactic acid or a pharmaceutically acceptable salt thereof is 200 to 1000 mM, for example, particularly about 400 to 450 mM or about 400 mM, or about 800 mM. (Item 10) The concentration of the cosolvent selected from propylene glycol and a mixture of propylene glycol and glycerol is 5 to 50% (v / v), for example, 10 to 50% (v / v), 15 to 50% (v / v), 20 to 50% (v / v), 25 to 50% (v / v), 30 to 50% (v / v), 35 to 50% (v / v), 5 to 40% (v / v), 10 to 40% (v / v), 15 to 40% (v / v), 20 to 40% (v / v), 25 to 40% (v / v), 30 to 40% (v / v), 35 to 40% (v / v), 5 to 30% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), 20 to 30% (v / v), 25 to 30% (v / v), 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), about 50% (v / v), about 45% (v / v), about 40% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v). The storage-stable aqueous solution composition according to any one of items 1 to 9. (Item 11) The storage-stable aqueous solution composition according to any one of items 1 to 10, wherein the cosolvent is propylene glycol. (Item 12) The storage-stable aqueous solution composition according to item 11, containing propylene glycol at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 10 to 20% (v / v), about 20% (v / v), or about 15% (v / v). (Item 13) The storage-stable aqueous solution composition according to any one of items 1 to 10, wherein the cosolvent is a mixture of propylene glycol and glycerol. (Item 14) The storage-stable aqueous solution composition according to item 13, wherein the combined total concentration of propylene glycol and glycerol is 5 to 50% (v / v), for example, 10 to 50% (v / v), 15 to 50% (v / v), 20 to 50% (v / v), 25 to 50% (v / v), 30 to 50% (v / v), 35 to 50% (v / v), 5 to 40% (v / v), 10 to 40% (v / v), 15 to 40% (v / v), 20 to 40% (v / v), 25 to 40% (v / v), 30 to 40% (v / v), 35 to 40% (v / v), 5 to 30% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), 20 to 30% (v / v), 25 to 30% (v / v), 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), about 50% (v / v), about 45% (v / v), about 40% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v). (Item 15) The storage-stable aqueous solution composition according to item 13 or 14, wherein the concentration of propylene glycol is 2 to 25% (v / v), for example, 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 2 to 20% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), 2 to 15% (v / v), 5 to 15% (v / v), 10 to 15% (v / v), 2 to 10% (v / v), 5 to 10% (v / v), about 10% (v / v), or about 15% (v / v); and the concentration of glycerol is 35 to 45% (v / v), for example, 40 to 45% (v / v), 35 to 40% (v / v), about 35% (v / v), or about 40% (v / v). (Item 16) The storage-stable aqueous solution composition according to item 15, wherein the combined total concentration of propylene glycol and glycerol is 40 to 50% (v / v), for example, 45 to 50% (v / v), about 45% (v / v), or about 50% (v / v). (Item 17) The storage-stable aqueous solution composition according to item 15 or 16, wherein the ratio of propylene glycol to glycerol (v / v) is between 1:3 and 1:1.5. (Item 18) The storage-stable aqueous solution composition according to Item 17, wherein the concentration of propylene glycol is about 10% (v / v) and the concentration of glycerol is about 35% (v / v), or the concentration of propylene glycol is about 15% (v / v) and the concentration of glycerol is about 35% (v / v). (Item 19) The storage-stable aqueous solution composition according to Item 13 or 14, wherein the concentration of propylene glycol is 2-25% (v / v), 5-25% (v / v), 10-25% (v / v), 15-25% (v / v), 20-35% (v / v), 2-20% (v / v), 5-20% (v / v), 10-20% (v / v), 15-20% (v / v), 2-15% (v / v), 5-15% (v / v), 10-15% (v / v), 2-10% (v / v), 5-10% (v / v), about 10% (v / v), or about 15% (v / v); and the concentration of glycerol is 2-10% (v / v), for example, 5-10% (v / v), about 5% (v / v), or about 10% (v / v). (Item 20) The storage-stable aqueous solution composition according to Item 19, wherein the combined total concentration of propylene glycol and glycerol is 5-40% (v / v), for example, 10-40% (v / v), 15-40% (v / v), 20-40% (v / v), 25-40% (v / v), 30-40% (v / v), 35-40% (v / v), 5-30% (v / v), 10-30% (v / v), 15-30% (v / v), 20-30% (v / v), 25-30% (v / v), 5-25% (v / v), 10-25% (v / v), 15-25% (v / v), 20-25% (v / v), 5-20% (v / v), 10-20% (v / v), 15-20% (v / v), about 40% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v). (Item 21) The storage-stable aqueous solution composition according to Item 19 or 20, wherein the ratio (v / v) of propylene glycol to glycerol is between 2:1 and 1.2:1. (Item 22) The storage-stable aqueous solution composition according to item 21, wherein the concentration of propylene glycol is about 15% (v / v) and the concentration of glycerol is about 10% (v / v). (Item 23) The storage-stable aqueous solution composition according to any one of items 1 to 22, wherein the molar ratio of vancomycin or a pharmaceutically acceptable salt thereof to the co-solvent is between 1:10 and 1:100, for example, between 1:20 and 1:60. (Item 24) The storage-stable aqueous solution composition according to any one of items 1 to 23, wherein for the inorganic salt containing the metal cation, the metal cation is a Group 1 or Group 2 metal cation. (Item 25) The storage-stable aqueous solution composition according to item 24, wherein the inorganic salt containing the metal cation is selected from the group consisting of sodium chloride, calcium chloride, sodium oxamate, and sodium sulfate. (Item 26) The storage-stable aqueous solution composition according to item 25, wherein the inorganic salt containing the metal cation is sodium oxamate. (Item 27) The storage-stable aqueous solution composition according to item 25, wherein the inorganic salt containing the metal cation is sodium chloride or calcium chloride, particularly sodium chloride. (Item 28) The storage-stable aqueous solution composition according to any one of items 1 to 27, wherein the concentration of the inorganic salt containing the metal cation is 5 to 300 mM, for example, 50 to 200 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM. (Item 29) The storage-stable aqueous solution composition according to any one of items 1 to 28, wherein the pH is in the range of 4.0 to 6.0, for example, about 5.0. (Item 30) The storage-stable aqueous solution composition according to any one of items 1 to 29, further comprising an antioxidant selected from the group consisting of monothioglycerol, butylhydroxyanisole, glutathione (reduced form), ascorbate, cysteine, and methionine, preferably methionine. (Item 31) The storage-stable aqueous solution composition according to item 30, wherein the antioxidant is present at a concentration of 1 to 100 mM, for example, 10 to 50 mM or 25 to 50 mM. (Item 32) The storage-stable aqueous solution composition according to any one of items 1 to 31, which substantially does not contain or does not contain an amino acid. (Item 33) The storage-stable aqueous solution composition according to any one of items 1 to 32, wherein the composition substantially does not contain or does not contain polyethylene glycol. (Item 34) The storage-stable aqueous solution composition according to any one of items 1 to 33, further comprising a nonionic surfactant. (Item 35) The storage-stable aqueous solution composition according to item 34, wherein the nonionic surfactant is selected from the group consisting of alkyl glucoside, polysorbate, alkyl ether of polyethylene glycol, block copolymer of polyethylene glycol and polypropylene glycol, and alkyl phenyl ether of polyethylene glycol. (Item 36) The storage-stable aqueous solution composition according to item 35, wherein the nonionic surfactant is preferably an alkyl glucoside selected from the group consisting of dodecyl maltoside, dodecyl glucoside, octyl glucoside, octyl maltoside, decyl glucoside, decyl maltoside, decyl glucopyranoside, tridecyl glucoside, tridecyl maltoside, tetradecyl glucoside, tetradecyl maltoside, hexadecyl glucoside, hexadecyl maltoside, sucrose monooctanoate, sucrose monodecanoate, sucrose monolaurate, sucrose monotridecanoate, sucrose monomyristate, and sucrose monopalmitate; and particularly, dodecyl maltoside or decyl glucopyranoside, especially dodecyl maltoside. (Item 37) The storage-stable aqueous solution composition according to item 35, wherein the nonionic surfactant is preferably a polysorbate which is polysorbate 20 or polysorbate 80. (Item 38) The storage-stable aqueous solution composition according to item 35, wherein the nonionic surfactant is preferably an alkyl ether of polyethylene glycol selected from the group consisting of polyethylene glycol (2) hexadecyl ether (Brij 52), polyethylene glycol (2) oleyl ether (Brij 93), polyethylene glycol (2) dodecyl ether (Brij L4), polyethylene glycol (4) lauryl ether (Brij 30), polyethylene glycol (10) lauryl ether (Brij 35), polyethylene glycol (20) hexadecyl ether (Brij 58), and polyethylene glycol (10) stearyl ether (Brij 78). (Item 39) The storage-stable aqueous solution composition according to item 35, wherein the nonionic surfactant is preferably a block copolymer of polyethylene glycol and polypropylene glycol selected from the group consisting of poloxamer 188, poloxamer 407, poloxamer 171, or poloxamer 185. (Item 40) The storage-stable aqueous solution composition according to item 35, wherein the nonionic surfactant is preferably an alkyl phenyl ether of polyethylene glycol which is 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol. (Item 41) The storage-stable aqueous solution composition according to any one of items 34 to 40, wherein the nonionic surfactant is present at a concentration of 1 to 5000 μg / mL, 1 to 1000 μg / mL, for example, 5 to 500 μg / mL, 10 to 400 μg / mL, 20 to 400 μg / mL, 50 to 400 μg / mL, 10 to 300 μg / mL, 20 to 300 μg / mL, 50 to 300 μg / mL, 10 to 200 μg / mL, 20 to 200 μg / mL, 50 to 200 μg / mL, 10 to 100 μg / mL, 20 to 100 μg / mL, 50 to 100 μg / mL, or about 50 μg / mL. (Item 42) The storage-stable aqueous solution composition according to any one of items 1 to 41, further comprising a preservative such as a phenolic or benzyl-based preservative. (Item 43) The phenolic or benzyl preservative is selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, propyl paraben, and methyl paraben, and the storage-stable aqueous solution composition according to Item 42. (Item 44) The storage-stable aqueous solution composition according to any one of Items 1 to 43, containing at least 95% (v / v) of water, for example, at least 90% (v / v), at least 85% (v / v), at least 80% (v / v), at least 75% (v / v), at least 70% (v / v), at least 65% (v / v), at least 60% (v / v), at least 55% (v / v), or at least 50% (v / v) of water, for example, water for injection, sterilized or bacteriostatic. (Item 45) The storage-stable aqueous solution composition according to any one of Items 1 to 44, having an osmolality of 1500 to 8000 mOsm / L, for example, 2000 to 6000 mOsm / L, for example, 3000 to 6000 mOsm / L. (Item 46) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 1000 mM, for example, 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM, or DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, for example, 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM; Propylene glycol as a co-solvent at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 10 to 20% (v / v), about 20% (v / v), or about 15% (v / v); and An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, such as 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxamate, sodium chloride, or calcium chloride; comprising, The storage-stable aqueous solution composition according to item 1, wherein the pH is in the range of 4.0 to 6.0, for example, about 5.0. (Item 47) Vancomycin at a concentration of 25 to 75 mg / mL, such as 35 to 65 mg / mL or about 50 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 1000 mM, such as 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM, or a pharmaceutically acceptable salt thereof, or DL-lactic acid at a concentration of 200 to 1000 mM, such as 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), such as 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 35 to 45% (v / v), such as 40 to 45% (v / v), 35 to 40% (v / v), about 35% (v / v), or about 40% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 40 to 50% (v / v), such as 45 to 50% (v / v), about 45% (v / v), or about 50% (v / v); and An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, such as 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxamate, sodium chloride, or calcium chloride; comprising, The storage-stable aqueous solution composition according to item 1, wherein the pH is in the range of 4.0 to 6.0, for example, about 5.0. (Item 48) Vancomycin at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 1000 mM, for example, 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM, or a pharmaceutically acceptable salt thereof, or DL-lactic acid at a concentration of 200 to 1000 mM, for example, 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; A mixture of propylene glycol and glycerol as a co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 to 10% (v / v), for example, 5 to 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as a co-solvent is preferably 5 to 40% (v / v), 10 to 30% (v / v), or about 25% (v / v); and An inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, in particular, sodium oxamate, sodium chloride, or calcium chloride; comprising The storage-stable aqueous solution composition according to item 1, wherein the pH is in the range of 4.0 to 6.0, for example, about 5.0. (Item 49) The storage-stable aqueous solution composition according to any one of items 1 to 48, which is a pharmaceutical composition. (Item 50) The storage-stable aqueous solution composition according to any one of items 1 to 48 or the pharmaceutical composition according to item 49 for use in therapy. (Item 51) The storage-stable aqueous solution composition or pharmaceutical composition according to item 50 for use in the treatment of bacterial infections. (Item 52) A method for treating a bacterial infection, comprising administering to a patient in need thereof a therapeutically effective amount of the storage-stable aqueous solution composition according to any one of items 1 to 48 or the pharmaceutical composition according to item 49. (Item 53) The storage-stable aqueous solution composition for use according to item 51 or the method according to item 52, wherein the bacterial infection is caused by a Gram-positive bacterium, preferably selected from the group consisting of Clostridium difficile, Listeria monocytogenes, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus viridans, Streptococcus bovis, Staphylococcus epidermidis, methicillin-resistant Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus aureus, Actinomyces spp., Lactobacillus spp., Enterococcus faecalis, and diphtheroids. (Item 54) The storage-stable aqueous solution composition or method for use according to any one of items 50 to 53 for use in combination with one or more additional therapeutic agents. (Item 55) The storage-stable aqueous solution composition or method for use according to item 54, wherein the one or more additional therapeutic agents are selected from the group consisting of rifampicin, aminoglycosides (such as gentamicin), and β-lactam antibiotics (such as amoxicillin). (Item 56) The storage-stable aqueous solution composition or method for use according to any one of items 50 to 55, which is in a pre-diluted form and is diluted before administration. (Item 57) The storage-stable aqueous solution composition or method for use according to item 56, wherein the pre-dilution prepared composition is diluted with a diluent selected from, for example, 0.9% physiological saline, 5% glucose in water, and water (for example, sterilized water for injection or bacteriostatic water for injection). (Item 58) The storage-stable aqueous solution composition or method for use according to item 56 or 57, wherein the concentration of vancomycin or a pharmaceutically acceptable salt thereof in the diluted composition (ready-for-administration form) is 5 to 15%, for example, 10% of the concentration in the pre-dilution prepared form. (Item 59) The storage-stable aqueous solution composition or method for use according to any one of items 56 to 58, wherein the concentration of vancomycin or a pharmaceutically acceptable salt thereof in the diluted composition (ready-for-administration form) is 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL. (Item 60) The storage-stable aqueous solution composition or method for use according to any one of items 56 to 59, wherein after dilution of the pre-dilution prepared composition, the diluted composition (ready-for-administration form) is administered by intravenous injection. (Item 61) A method for preparing a solution for intravenous administration (ready-for-administration form) by diluting the pre-dilution prepared composition according to any one of items 1 to 49 with a diluent selected from, for example, 0.9% physiological saline, 5% glucose in water, and water (for example, sterilized water for injection or bacteriostatic water for injection). (Item 62) The method according to item 61, wherein the concentration of vancomycin or a pharmaceutically acceptable salt thereof in the diluted composition (ready-for-administration) is 5 to 15%, for example, 10% of the concentration in the pre-dilution prepared composition. (Item 63) The method according to item 61 or 62, wherein the concentration of vancomycin or a pharmaceutically acceptable salt thereof in the diluted composition (ready-for-administration form) is 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL. (Item 64) A composition ready for administration for intravenous administration of vancomycin or a pharmaceutically acceptable salt thereof, prepared by the method according to any one of items 61 to 63. (Item 65) A vial, preferably a glass vial, containing the storage-stable aqueous solution composition according to any one of items 1 to 49. (Item 66) The vial according to item 65, which is a multi-dose vial.

Examples

[0100] (Example) (General method) (Reverse-phase chromatography method (RP-HPLC)) Perform high-speed reverse-phase chromatography using a Thermo-Scientific Ultimate 3000 HPLC equipped with a diode array detector (DAD3000) and Zorbax Stable Bond C18 250 mm × 4.6 mm, 5 μm particle size and 80 Å pore size. Mobile phase A is a mixture of triethylamine buffer (mix 4 mL of triethylamine and 2000 mL of water, adjust to pH 3.2 with phosphoric acid), acetonitrile, and tetrahydrofuran in a volume ratio of 92:7:1. Mobile phase B is a mixture of triethylamine buffer, acetonitrile, and tetrahydrofuran in a volume ratio of 70:29:1. A sample containing vancomycin (or a pharmaceutically acceptable salt thereof) is bound in mobile phase A and eluted using a gradient of mobile phase A and mobile phase B. The volume of the sample is 20 microliters, the flow rate is 1.0 mL / min, and 284 nm UV detection is used. All analyses are performed at 25 °C.

[0101] (Visual evaluation method) Visible particles are preferably detected using the 2.9.20. European Pharmacopoeia monograph (Microscopic particles: visible particles). The required equipment is · A matte black panel of appropriate size held vertically · A non-reflective white panel of appropriate size held vertically next to the black panel ·An adjustable lamp holder equipped with a suitable white light source with shade and a suitable diffuser (an observation illuminator containing two 13W fluorescent tubes each with a length of 525mm is preferred). It consists of an observation table equipped with . The intensity of irradiation at the observation point is maintained between 2000 lux and 3750 lux.

[0102] All attached labels are removed from the container, and the outside is washed and dried. The container is gently rotated or reversed to ensure that no air bubbles are introduced, and it is observed in front of the white panel for about 5 seconds. This procedure is repeated in front of the black panel. The presence of particles is recorded. The visual score is ranked as follows: Visual score 1: A clear solution substantially free of particles Visual score 2: Approximately 5 very small particles Visual score 3: Approximately 10 - 20 very small particles Visual score 4: 20 - 50 particles containing larger particles Visual score 5: >50 particles containing larger particles.

[0103] Particles with visual scores of 4 and 5 in the sample are clearly detectable by a simplified visual evaluation under normal light, while samples with visual scores of 1 - 3 generally appear as clear solutions in the same evaluation. Samples with visual scores of 1 - 3 are considered "qualified"; samples with visual scores of 4 - 5 are considered "unqualified".

[0104] (Example 1: Composition Example) The following exemplary aqueous compositions can be prepared. Example A: Vancomycin hydrochloride 50 mg / mL D - lactic acid 200 mM Propylene glycol 20% (v / v) Sodium chloride 100 mM pH 5.0 Example B: Vancomycin hydrochloride 50 mg / mL D - lactic acid 400 mM Propylene glycol 20% (v / v) Sodium chloride 100 mM pH 5.0 Example C: Vancomycin hydrochloride 50 mg / mL Sodium D-lactate 200 mM Propylene glycol 20% (v / v) Sodium chloride 100 mM pH 5.0 Example D: Vancomycin hydrochloride 50 mg / mL Sodium D-lactate 400 mM Propylene glycol 20% (v / v) Sodium chloride 100 mM pH 5.0 Example E: Vancomycin hydrochloride 50 mg / mL D-lactic acid 200 mM Propylene glycol 15% (v / v) Glycerol 10% (v / v) Sodium chloride 100 mM pH 5.0 Example F: Vancomycin hydrochloride 50 mg / mL D-lactic acid 400 mM Propylene glycol 15% (v / v) Glycerol 10% (v / v) Sodium chloride 100 mM pH 5.0 Example G: Vancomycin hydrochloride 50 mg / mL D-lactic acid 200 mM Propylene glycol 15% (v / v) Glycerol 10% (v / v) Sodium oxamate 100 mM pH 5.0 Example H: Vancomycin hydrochloride 50 mg / mL D-lactic acid 400 mM Propylene glycol 15% (v / v) Glycerol 10% (v / v) Sodium oxamate 100 mM pH 5.0 Example I: Vancomycin hydrochloride 50 mg / mL D-Lactic acid 200 mM Propylene glycol 15% (v / v) Glycerol 10% (v / v) Sodium chloride 200 mM pH 5.0 Example J: Vancomycin hydrochloride 50 mg / mL D-Lactic acid 400 mM Propylene glycol 15% (v / v) Glycerol 10% (v / v) Sodium chloride 200 mM pH 5.0 Example K: Vancomycin hydrochloride 50 mg / mL D-Lactic acid 200 mM Propylene glycol 15% (v / v) Glycerol 35% (v / v) Sodium chloride 100 mM pH 5.0 Example L: Vancomycin hydrochloride 50 mg / mL D-Lactic acid 400 mM Propylene glycol 15% (v / v) Glycerol 35% (v / v) Sodium chloride 100 mM pH 5.0 Example M: Vancomycin hydrochloride 50 mg / mL D / L-Lactic acid 400 mM Propylene glycol 15% (v / v) Glycerol 10% (v / v) Sodium chloride 100 mM pH 5.0 Example N: Vancomycin hydrochloride 50 mg / mL D / L-Lactic acid 800 mM Propylene glycol 15% (v / v) Glycerol 10% (v / v) Sodium chloride 100 mM pH 5.0 Example O: Vancomycin hydrochloride 50 mg / mL Sodium D-lactate 800 mM Propylene glycol 15% (v / v) Glycerol 10% (v / v) Sodium chloride 100 mM pH 5.0

[0105] In all of the above compositions, the pH of the composition is adjusted to the required pH by the addition of a base such as sodium hydroxide. It should be noted that when "sodium chloride" is described as a component of the composition, the stated amount of sodium chloride is added to the composition.

[0106] (Example 2: Effect of pH on the stability of vancomycin compositions) The effect of pH on the stability of vancomycin compositions after storage at 60 °C for 3 days was investigated using RP-HPLC as described in the general method. All compositions contained 5 mg / mL of vancomycin hydrochloride in water for injection (WFI). The results are shown in Table 1, which shows the % impurities observed in the compositions at time zero (T0) and after storage at 60 °C for 3 days. (Table 1: Stability of vancomycin hydrochloride (5 mg / mL) compositions evaluated using RP-HPLC)

Table 1

[0107] From Table 1, it can be seen that the pH range of 4.5 - 6.5 is the most stable, and the decomposition rate becomes faster on either side of these ranges and very fast at higher, more alkaline pH values. All of the compositions in the subsequent examples were prepared at pH 5.0.

[0108] (Example 3: Effect of Composition Additives on the Stability of Vancomycin) The effects of the individual composition additives N-acetyl-D-alanine (NADA), PEG400, and lysine hydrochloride on the stability of vancomycin were investigated using the RP-HPLC method described in the general method. All of the compositions contained 5 mg / mL of vancomycin hydrochloride in water for injection (WFI) and additional additives as listed in Table 2 below and were adjusted to pH 5.0. Table 2 shows the % impurities observed in the compositions at time zero (T0) and after storage at 25°C for 15 and 30 days. Composition 7 corresponds to the commercial composition of VancoReady™. (Table 2: Stability of Vancomycin Hydrochloride (5 mg / mL) Compositions Represented as % Impurities at Time Zero (T0))

Table 2

[0109] From Table 2, it can be seen that the removal of NADA from the VancoReady™ product resulted in a significant deterioration of stability (compare Compositions 7 and 8). The removal of PEG400 or lysine HCl did not appear to have a significant effect on the stability of the vancomycin composition. Thus, NADA appears to be an important stabilizing additive in VancoReady™.

[0110] (Example 4: Stability of Vancomycin Compositions in the Presence of Various Organic Acids and Propylene Glycol) The effects of various additives (N-acetyl-D-alanine (NADA), N-acetyl-L-alanine (NALA), PEG400, lysine hydrochloride, sodium D-lactate, sodium L-lactate, and propylene glycol (PG)) on the stability of vancomycin compositions were investigated using the RP-HPLC method described in the general method. All compositions contained 5 mg / mL of vancomycin hydrochloride in water for injection (WFI) and additional additives as listed in Table 3 below, and were adjusted to pH 5.0. Table 4 shows the % impurities observed in the compositions at time zero (T0) and after storage at 25 °C for 6, 12, 40, and 69 days. Composition 7 corresponds to the commercially available composition of VancoReady™. (Table 3: Vancomycin hydrochloride (5 mg / mL) compositions)

Table 3

Table 4

[0111] Comparing Compositions 7 and 8, it can also be seen here that the removal of NADA from the VancoReady™ composition results in a significant deterioration in stability. Replacing NADA with N-acetyl-L-alanine (NALA) also resulted in a significant deterioration in stability (compare Compositions 7 and 13). However, when NADA was replaced with sodium D-lactate, the decrease in composition stability was quite small (compare Compositions 7 and 14). A similar effect was not observed in the case of sodium L-lactate, in which case the stability decreased significantly (compare Compositions 7 and 16). Modifying the composition containing sodium D-lactate and sodium L-lactate to replace PEG400 with propylene glycol resulted in a surprisingly relative increase in stability (compare Compositions 14 and 15 and Compositions 16 and 17).

[0112] (Example 5: Stability of Vancomycin Compositions in the Presence of Higher Concentrations of D-Lactate and Propylene Glycol and in the Presence of Inorganic Salts) The effects of various concentrations of sodium D-lactate and propylene glycol (PG) and the effect of adding inorganic salts to the vancomycin composition were investigated using the RP-HPLC method described in the general method. All compositions contained 5 mg / mL of vancomycin hydrochloride in water for injection (WFI) and additional amounts of additives as listed in Table 5 (below) and were adjusted to pH 5.0. Table 6 shows the increase in % total impurities (compared to time zero) after storage at 25 °C for 2, 4, and 8 weeks. (Table 5: Vancomycin Hydrochloride (5 mg / mL) Compositions)

Table 5

Table 6

[0113] From Table 6, it can be seen that increasing the concentration of sodium D-lactate (comparing Compositions 18 and 19) leads to an improvement in composition stability, similar to increasing the concentration of propylene glycol (comparing Compositions 20 and 21). The addition of sodium chloride, an inorganic salt, brings about a further stabilizing effect (comparing Compositions 18 and 21).

[0114] (Example 6: Stability of vancomycin compositions (5 mg / mL) in the presence of various concentrations of D-lactate, DL-lactate, and propylene glycol, and additional additives) The effects of various concentrations of sodium D-lactate, sodium DL-lactate, and propylene glycol (PG) on the stability of vancomycin compositions were investigated using the RP-HPLC method described in the general method. The effects of adding sodium oxamate, polysorbate 80, and methionine were also investigated. All compositions contained 5 mg / mL of vancomycin hydrochloride in water for injection (WFI) and additional amounts of additives as listed in Table 7 (below) and were adjusted to pH 5.0. Table 8 shows the increase in % total impurities after storage at 2 - 8 °C for 8 weeks and at 25 °C for 8 weeks (compared to time zero). (Table 7: Vancomycin hydrochloride (5 mg / mL) compositions)

Table 7

Table 8

[0115] From Table 8, it can be seen that increasing the concentration of sodium D-lactate results in an improvement in the stability of the composition (compare Compositions 23 and 26, 24 and 27, and 25 and 28). Increasing the concentration of PG also results in improved composition stability (compare Compositions 23 - 24 and Compositions 26 - 28). Interestingly, the racemic form of lactate (sodium DL-lactate) also has a stabilizing effect, but the concentration has to be twice as high as when D-lactate is used for the same degree of stabilizing effect (compare Compositions 28 - 30).

[0116] The addition of sodium oxamate leads to an improvement in stability (compare Compositions 24 and 31). The addition of methionine results in a slight improvement in stability, similar to the addition of polysorbate 80 (compare Compositions 24 and 33 and 25 and 34) (compare Compositions 25 and 32).

[0117] (Example 7: Stability of vancomycin compositions (50 mg / mL) in the presence of various concentrations of D-lactate, DL-lactate, and propylene glycol, and sodium chloride) The effects of various concentrations of sodium D-lactate, sodium DL-lactate, and propylene glycol (PG) on the stability of vancomycin compositions were investigated using the RP-HPLC method described in the general method. The effects of adding sodium chloride and glycerol were also investigated. All compositions contained 50 mg / mL of vancomycin hydrochloride in water for injection (WFI) and additional amounts of additives as listed in Table 9 below, and were adjusted to pH 5.0. Table 10 shows the increase in % total impurities after storage at 2 - 8 °C for 8 weeks and at 25 °C for 8 weeks (compared to time zero). (Table 9: Vancomycin hydrochloride (50 mg / mL) compositions)

Table 9

Table 10

[0118] From Table 10, it can be seen that increasing the concentration of sodium D-lactate results in an improvement in the stability of the composition (compare Compositions 23 and 26). Increasing the concentration of PG also results in improved composition stability (compare Compositions 23 and 24). Interestingly, the racemic form of lactate (DL-sodium lactate) also provides a stabilizing effect, but the concentration has to be twice as high as when used for a comparable stabilizing effect (compare Compositions 24 and 28).

[0119] The addition of sodium chloride leads to an improvement in stability (compare Compositions 23 and 29). The use of glycerol instead of propylene glycol results in a decrease in stability (compare Compositions 26 and 27), but the combination of propylene glycol and glycerol provides a stabilizing effect similar to that of using propylene glycol alone (compare Compositions 24 and 25).

[0120] (Example 8: Stability of vancomycin composition (50 mg / mL) in the presence of inorganic salts containing metal cations) The effect of adding sodium chloride and calcium chloride on the stability of the vancomycin composition was investigated using the visual evaluation method described in the general method. All compositions contained 50 mg / mL of vancomycin hydrochloride in water for injection (WFI), the amounts of sodium D-lactate shown in Table 11 (below), as well as propylene glycol and glycerol, and were adjusted to pH 5.0. Table 12 shows the visual appearance of the compositions after storage at 25°C for 19 weeks. (Table 11: Vancomycin hydrochloride (50 mg / mL) composition)

Table 11

Table 12

[0121] From Table 12, it can be seen that the addition of both sodium chloride and calcium chloride brought about a significant improvement in the stability of the composition when stored at 2 - 8°C.

[0122] (Example 9: Long - term stability of the prepared - diluted vancomycin composition (50 mg / mL)) Long - term stability tests were set up for two compositions at 2 - 8°C and 25°C. Both compositions contained 50 mg / mL of vancomycin hydrochloride and the additional additives shown in Table 13, and were adjusted to pH 5.0. The compositions were filled into type 1 glass vials under aseptic conditions. The stability of the compositions at 2 - 8°C and 25°C was investigated using the RP - HPLC method and visual evaluation method described in the general method. All the compositions remained clear and colorless (visual score 1) throughout the long - term stability test. As a result of RP - HPLC, the increase in the percentage of total impurities and specific individual impurities is shown in Tables 14 - 15 (2 - 8°C) and Tables 16 - 17 (25°C). (Table 13: Vancomycin hydrochloride (50 mg / mL) composition)

Table 13

Table 14

Table 15

Table 16

Table 17

[0123] Importantly, the United States Pharmacopeia monograph (Vancomycin Hydrochloride for Injection, USP 29) requires that vancomycin pharmaceuticals have the following purity: · A vancomycin purity of 88% or more (i.e., total impurities not exceeding 12%) · All individual impurities of 4% or less to be present.

[0124] The results in Tables 14 - 17 demonstrate that the compositions tested (Compositions Nos. 35 and 36) exhibit long-term storage stability and, in particular, meet the conditions listed in the United States Pharmacopeia monograph (USP 29) after 6 months of storage at both 2 - 8°C and 25°C.

[0125] These results indicate that the compositions tested (Compositions Nos. 35 and 36) are expected to have a shelf life of at least 24 months at 2 - 8°C and that the compositions remain stable and furthermore are expected to remain in compliance with the conditions listed in the United States Pharmacopeia monograph (USP 29) after 6 months of deviation at 25°C prior to use.

Claims

1. Vancomycin at a concentration of 25 to 75 mg / mL or a pharmaceutically acceptable salt thereof; D-lactic acid or a pharmaceutically acceptable salt thereof; A co-solvent selected from propylene glycol and a mixture of propylene glycol and glycerol; and An inorganic salt containing a metal cation A storage-stable aqueous solution composition comprising the same.

2. The form of the vancomycin is vancomycin hydrochloride; and / or The storage-stable aqueous solution composition according to Claim 1, wherein the concentration of vancomycin or a pharmaceutically acceptable salt thereof is 35 to 65 mg / mL or about 50 mg / mL.

3. The storage-stable aqueous solution composition according to Claim 1 or 2, wherein the concentration of the D-lactic acid or a pharmaceutically acceptable salt thereof is 100 to 1000 mM, for example, 100 to 500 mM, particularly about 200 mM or about 400 to 450 mM, or about 400 mM.

4. The source of the D-lactic acid or a pharmaceutically acceptable salt thereof is DL-lactic acid or a pharmaceutically acceptable salt thereof, The storage-stable aqueous solution composition according to Claim 1 or 2, wherein the concentration of the DL-lactic acid or a pharmaceutically acceptable salt thereof is preferably 200 to 1000 mM, for example, particularly about 400 to 450 mM or about 400 mM, or about 800 mM.

5. The storage-stable aqueous solution composition according to any one of Claims 1 to 4, wherein the concentration of the co-solvent selected from propylene glycol and a mixture of propylene glycol and glycerol is 5 to 50% (v / v), for example, 10 to 50% (v / v), 15 to 50% (v / v), 20 to 50% (v / v), 25 to 50% (v / v), 30 to 50% (v / v), 35 to 50% (v / v), 5 to 40% (v / v), 10 to 40% (v / v), 15 to 40% (v / v), 20 to 40% (v / v), 25 to 40% (v / v), 30 to 40% (v / v), 35 to 40% (v / v), 5 to 30% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), 20 to 30% (v / v), 25 to 30% (v / v), 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), about 50% (v / v), about 45% (v / v), about 40% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v). Claim 6 The storage-stable aqueous solution composition according to any one of claims 1 to 5, wherein the co-solvent is propylene glycol present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 10 to 20% (v / v), about 20% (v / v), or about 15% (v / v). Claim 7 The storage-stable aqueous solution composition according to any one of claims 1 to 5, wherein the co-solvent is a mixture of propylene glycol and glycerol present at a combined total concentration of 5 to 50% (v / v), for example, 10 to 50% (v / v), 15 to 50% (v / v), 20 to 50% (v / v), 25 to 50% (v / v), 30 to 50% (v / v), 35 to 50% (v / v), 5 to 40% (v / v), 10 to 40% (v / v), 15 to 40% (v / v), 20 to 40% (v / v), 25 to 40% (v / v), 30 to 40% (v / v), 35 to 40% (v / v), 5 to 30% (v / v), 10 to 30% (v / v), 15 to 30% (v / v), 20 to 30% (v / v), 25 to 30% (v / v), 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), about 50% (v / v), about 45% (v / v), about 40% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v). Claim 8 The concentration of propylene glycol is 2 to 25% (v / v), for example, 5 to 25% (v / v), 10 to 25% (v / v), 15 to 25% (v / v), 20 to 25% (v / v), 2 to 20% (v / v), 5 to 20% (v / v), 10 to 20% (v / v), 15 to 20% (v / v), 2 to 15% (v / v), 5 to 15% (v / v), 10 to 15% (v / v), 2 to 10% (v / v), 5 to 10% (v / v), about 10% (v / v), or about 15% (v / v); and the concentration of glycerol is 35 to 45% (v / v), for example, 40 to 45% (v / v), 35 to 40% (v / v), about 35% (v / v), or about 40% (v / v), The storage-stable aqueous solution composition according to claim 7, wherein the combined total concentration of propylene glycol and glycerol is 40 to 50% (v / v), for example, 45 to 50% (v / v), about 45% (v / v), or about 50% (v / v). Claim 9 The ratio (v / v) of propylene glycol to glycerol is between 1:3 and 1:1.

5. For example, the concentration of propylene glycol is about 10% (v / v) and the concentration of glycerol is about 35% (v / v), or the concentration of propylene glycol is about 15% (v / v) and the concentration of glycerol is about 35% (v / v). The storage-stable aqueous solution composition according to claim 8.

10. The concentration of propylene glycol is 2-25% (v / v), 5-25% (v / v), 10-25% (v / v), 15-25% (v / v), 20-35% (v / v), 2-20% (v / v), 5-20% (v / v), 10-20% (v / v), 15-20% (v / v), 2-15% (v / v), 5-15% (v / v), 10-15% (v / v), 2-10% (v / v), 5-10% (v / v), about 10% (v / v), or about 15% (v / v); and the concentration of glycerol is 2-10% (v / v), for example, 5-10% (v / v), about 5% (v / v), or about 10% (v / v); The combined total concentration of propylene glycol and glycerol is 5-40% (v / v), for example, 10-40% (v / v), 15-40% (v / v), 20-40% (v / v), 25-40% (v / v), 30-40% (v / v), 35-40% (v / v), 5-30% (v / v), 10-30% (v / v), 15-30% (v / v), 20-30% (v / v), 25-30% (v / v), 5-25% (v / v), 10-25% (v / v), 15-25% (v / v), 20-25% (v / v), 5-20% (v / v), 10-20% (v / v), 15-20% (v / v), about 40% (v / v), about 35% (v / v), about 30% (v / v), about 25% (v / v), about 20% (v / v), or about 15% (v / v). The storage-stable aqueous solution composition according to claim 9.

11. The ratio (v / v) of propylene glycol to glycerol is between 2:1 and 1.2:

1. For example, the concentration of propylene glycol is about 15% (v / v) and the concentration of glycerol is about 10% (v / v). The storage-stable aqueous solution composition according to claim 10.

12. The molar ratio of the vancomycin or a pharmaceutically acceptable salt thereof to propylene glycol or the molar ratio of the vancomycin or a pharmaceutically acceptable salt thereof to a mixture of propylene glycol and glycerol is between 1:10 and 1:100, for example, between 1:20 and 1:

60. The storage-stable aqueous solution composition according to any one of claims 1 to 11.

13. Regarding the inorganic salt containing the metal cation, the metal cation is a Group 1 or Group 2 metal cation, and in particular, is selected from the group consisting of sodium chloride, calcium chloride, sodium oxamate, and sodium sulfate. The storage-stable aqueous solution composition according to any one of claims 1 to 12.

14. The inorganic salt containing the metal cation is sodium chloride or calcium chloride, in particular, sodium chloride. The storage-stable aqueous solution composition according to claim 13.

15. The concentration of the inorganic salt containing the metal cation is 5 to 300 mM, for example, 50 to 200 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM. The storage-stable aqueous solution composition according to any one of claims 1 to 14.

16. The pH is in the range of 4.0 to 6.0, for example, about 5.0; and / or At least 95% (v / v) water, for example, at least 90% (v / v), at least 85% (v / v), at least 80% (v / v), at least 75% (v / v), at least 70% (v / v), at least 65% (v / v), at least 60% (v / v), at least 55% (v / v), or at least 50% (v / v) water, for example, water for injection, sterilized or bacteriostatic. The storage-stable aqueous solution composition according to any one of claims 1 to 15.

17. Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; The D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 1000 mM, for example, 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM, or the DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, for example, 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM; A mixture of propylene glycol and glycerol as the co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 35 to 45% (v / v), for example, 40 to 45% (v / v), 35 to 40% (v / v), about 35% (v / v), or about 40% (v / v), and the combined total concentration of propylene glycol and glycerol as the co-solvent is preferably 40 to 50% (v / v), for example, 45 to 50% (v / v), about 45% (v / v), or about 50% (v / v), said mixture; and The inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, in particular, sodium oxamate, sodium chloride, or calcium chloride; comprising The storage-stable aqueous solution composition according to claim 1, wherein the pH is in the range of 4.0 to 6.0, for example, about 5.

0.

18. The vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 25 to 75 mg / mL, for example, 35 to 65 mg / mL or about 50 mg / mL; The D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 1000 mM, for example, 200 to 1000 mM, 100 to 500 mM, 200 to 500 mM, about 400 to 450 mM or about 400 mM or about 200 mM, or the DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, for example, 400 to 1000 mM, 500 to 1000 mM, about 800 mM or about 400 to 450 mM, or about 400 mM; A mixture of propylene glycol and glycerol as the co-solvent, wherein the propylene glycol is present at a concentration of 5 to 25% (v / v), for example, 5 to 20% (v / v), 5 to 15% (v / v), 10 to 20% (v / v), about 10% (v / v), or about 15% (v / v), and the glycerol is present at a concentration of 2 to 10% (v / v), for example, 5 to 10% (v / v), about 5% (v / v), or about 10% (v / v), and the combined total concentration of propylene glycol and glycerol as the co-solvent is preferably 5 to 40% (v / v), 10 to 30% (v / v), or about 25% (v / v), said mixture; and Said inorganic salt containing a Group 1 or Group 2 metal cation at a concentration of 5 to 300 mM, for example, 50 to 200 mM, 50 to 150 mM, 50 to 100 mM, 100 to 200 mM, about 75 mM, about 100 mM, about 150 mM, or about 200 mM, particularly sodium oxamate, sodium chloride, or calcium chloride; comprising The storage-stable aqueous solution composition according to claim 1, having a pH in the range of 4.0 to 6.0, for example, about 5.

0.

19. The storage-stable aqueous solution composition according to any one of claims 1 to 18 for use in therapy.

20. The storage-stable aqueous solution composition or pharmaceutical composition according to claim 19 for use in the treatment of bacterial infections, wherein the bacterial infection is preferably caused by Gram-positive bacteria and is preferably selected from the group consisting of Clostridium difficile, Listeria monocytogenes, Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus viridans, Streptococcus bovis, Staphylococcus epidermidis, multi-drug resistant Staphylococcus epidermidis, Staphylococcus aureus, Actinomyces spp., Lactobacillus spp., Enterococcus faecalis, and diphtheroids, said storage-stable aqueous solution composition or pharmaceutical composition.

21. The storage-stable aqueous solution composition for use according to claim 19 or 20, which is in a pre-diluted form and is diluted before administration.

22. Said pre-diluted composition is diluted with a diluent selected from, for example, 0.9% physiological saline, 5% glucose in water, and water (for example, sterile water for injection or bacteriostatic water for injection); and / or The concentration of vancomycin or a pharmaceutically acceptable salt thereof in the diluted composition (ready-for-administration form) is 5 to 15%, for example, 10% of the concentration in the diluted-ready form; and / or A storage-stable aqueous solution composition for use according to claim 21, wherein the concentration of vancomycin or a pharmaceutically acceptable salt thereof in the diluted composition (ready-for-administration form) is 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL.

23. A method for preparing a solution for intravenous administration (ready-for-administration form) by diluting the diluted-ready composition according to any one of claims 1 to 18 with a diluent selected from, for example, 0.9% physiological saline, 5% glucose in water, and water (for example, sterile water for injection or bacteriostatic water for injection).

24. The concentration of vancomycin or a pharmaceutically acceptable salt thereof in the diluted composition (ready-for-administration) is 5 to 15%, for example, 10% of the concentration in the diluted-ready composition; and / or The method according to claim 23, wherein the concentration of vancomycin or a pharmaceutically acceptable salt thereof in the diluted composition (ready-for-administration form) is 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL.

25. A vial, preferably a glass vial, containing the storage-stable aqueous solution composition according to any one of claims 1 to 18, preferably a multi-dose vial.

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