Novel composition

Abstract

In particular, provided is a storage-stable aqueous solution composition containing vancomycin at a concentration of 1 to 10 mg / mL or a pharmaceutically acceptable salt thereof; D-lactic acid or a pharmaceutically acceptable salt thereof; and a polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof, and having an osmolality of 400 to 1250 mOsm / L.

Description

Technical Field

[0001] The present invention relates to an aqueous solution composition of vancomycin, and in particular, to a composition ready for administration that is storage-stable and non-toxic.

Background Art

[0002] (Background) Vancomycin is a glycopeptide antibiotic consisting of a heptapeptide chain that forms a tricyclic ring system to which sugars are 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 an important polymer 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 an intravenous (IV) solution bag, and thus are quite inconvenient to use.

[0006] There are three commercially available liquid products that contain a formulated and premixed vancomycin formulation in 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 in 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 light brown, preservative-free solution in single-dose premixed 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 PEG 400, 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 after removal from the overwrap. VancoREADY™ has a “black box” warning due to the additives N-acetyl-D-alanine and PEG 400, 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] The present invention addresses the need for a stable and non-toxic vancomycin composition.

[0010] 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.

[0011] WO2017 / 123912A1 (SCIDOSE) discloses a composition comprising vancomycin or a pharmaceutically acceptable salt thereof, a polyol such as glycerol, and lactic acid or lactate.

[0012] US2020 / 0188478A1 (FTF PHARMA) discloses a premixed vancomycin composition that is said to be suitable for injection.

[0013] JP2008 / 201778A (Mochida Pharmaceutical Co., Ltd.) discloses a vancomycin composition that is said to be suitable for long-term storage and oral administration.

[0014] WO2017 / 194385A1 (Xellia Pharmaceuticals) discloses a liquid formulation of glycopeptide antibiotics such as vancomycin that is said to be suitable as an infusion solution.

[0015] 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

[0016] (Summary of the Invention) The present invention particularly relates to: Vancomycin at a concentration of 1 to 10 mg / mL or a pharmaceutically acceptable salt thereof; D-lactic acid or a pharmaceutically acceptable salt thereof; and A polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof; comprising having an osmolality of 400 to 1250 mOsm / L, and providing a storage-stable aqueous solution composition.

Modes for Carrying Out the Invention

[0017] (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 doubt, any reference to "vancomycin" in this specification is intended to include pharmaceutically acceptable salts of vancomycin, particularly hydrochloride, unless otherwise stated.

[0018] The composition of the present invention is "ready for administration" in the sense that it can be administered to a patient as it is, without dilution. The composition is typically administered intravenously and is stored in an IV solution container such as a bag or bottle. In one embodiment, the concentration of vancomycin or its pharmaceutically acceptable salt is 1-9 mg / mL, 2-8 mg / mL, 2.5-7.5 mg / mL, or about 5 mg / mL.

[0019] As described in the Background of the Invention, the currently marketed liquid vancomycin composition, VancoReady™, contains N-acetyl-D-alanine (NADA) and PEG400 as additives, both of which have been 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 instead of NADA. When L-lactate was used instead 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 as high as that of D-lactate to achieve a comparable stabilizing effect.

[0020] 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 100-500 mM, 200-500 mM, 100-400 mM, 200-400 mM, 100-300 mM, 200-300 mM, 100-200 mM, 100-150 mM, 150-250 mM, about 200 mM or about 100 mM.

[0021] 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 its pharmaceutically acceptable salt. 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 its pharmaceutically acceptable salt at a concentration of 500 mM, the composition is assumed to contain less than 5 mM of L-lactic acid or its salt.

[0022] In one embodiment, the source of D-lactic acid or its pharmaceutically acceptable salt is DL-lactic acid or its pharmaceutically acceptable salt (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 its pharmaceutically acceptable salt is 200-1000 mM, 400-1000 mM, 200-800 mM, 400-800 mM, 200-600 mM, 400-600 mM, 200-400 mM, 200-300 mM, 300-500 mM, about 400 mM or about 200 mM.

[0023] It should be noted that 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 (e.g., by adding a base such as NaOH) to produce the 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 subsequent pH adjustment step using sodium hydroxide.

[0024] As described above, it has been found that the currently marketed VancoReady™ composition can be modified to replace the stabilizer NADA with D - lactate while maintaining a composition with good stability. As shown in Examples 4 - 6, the inventors have also found that further modification of the D - lactate composition by replacing PEG400 with propylene glycol results in a surprising relative increase in stability. As shown in Example 9, this stabilizing effect was also shown for the polyols sucrose, trehalose, glycerol, and mannitol. As shown in Example 7, a combination of two polyols (propylene glycol and glycerol) also showed a stabilizing effect. Accordingly, the compositions of the present invention include a polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof.

[0025] In one embodiment, the concentration of the polyol in the composition (or, if more than two polyols are present, the combined total concentration of the polyols) is 200 - 1200 mM, for example, 300 - 800 mM.

[0026] In one embodiment, the composition of the present invention comprises a single polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol. In another embodiment, the composition comprises a mixture of two polyols selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol. In one embodiment, the or each polyol is selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol. In one embodiment, the or each polyol is selected from the group consisting of propylene glycol, sucrose, trehalose, lactose, glucose, sorbitol, and mannitol. In one embodiment, the or each polyol is selected from the group consisting of sucrose, trehalose, lactose, glucose, sorbitol, and mannitol.

[0027] In one embodiment, the single polyol is propylene glycol, which is preferably present in the composition at a concentration of 660 to 1200 mM, for example, 700 to 1200 mM, 750 to 1200 mM, 800 to 1200 mM or 850 to 1200 mM. In one embodiment, the single polyol is glycerol, which is preferably present in the composition at a concentration of 200 to 1200 mM, for example, 300 to 800 mM. In one embodiment, the single polyol is sucrose, which is preferably present in the composition at a concentration of 200 to 1200 mM, for example, 300 to 800 mM. In one embodiment, the single polyol is trehalose, which is preferably present in the composition at a concentration of 200 to 1200 mM, for example, 300 to 800 mM. In one embodiment, the single polyol is lactose, which is preferably present in the composition at a concentration of 200 to 1200 mM, for example, 300 to 800 mM. In one embodiment, the single polyol is glucose, which is preferably present in the composition at a concentration of 200 to 1200 mM, for example, 300 to 800 mM. In one embodiment, the single polyol is sorbitol, which is preferably present in the composition at a concentration of 200 to 1200 mM, for example, 300 to 800 mM. In one embodiment, the single polyol is mannitol, which is preferably present in the composition at a concentration of 200 to 1200 mM, for example, 300 to 800 mM.

[0028] In one embodiment, the composition comprises a mixture of propylene glycol and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol. In this embodiment, preferably, propylene glycol is present in the composition at a concentration of 10 to 160 mM, such as 10 to 150 mM or 10 to 125 mM, and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is present in the composition at a concentration of 40 to 1190 mM, such as 50 to 1190 mM or 75 to 1190 mM. In this embodiment, the combined total concentration of propylene glycol and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is preferably 200 to 1200 mM, such as 300 to 800 mM.

[0029] In one embodiment, the polyol is a mixture of propylene glycol and glycerol. In this embodiment, preferably, propylene glycol is present in the composition at a concentration of 10 to 160 mM, such as 10 to 150 mM or 10 to 125 mM, and glycerol is present in the composition at a concentration of 40 to 1190 mM, such as 50 to 1190 mM or 75 to 1190 mM. In this embodiment, the combined total concentration of propylene glycol and glycerol is preferably 200 to 1200 mM, such as 300 to 800 mM.

[0030] In one embodiment, the polyol is a mixture of propylene glycol and sucrose. In this embodiment, preferably, propylene glycol is present in the composition at a concentration of 10 to 160 mM, such as 10 to 150 mM or 10 to 125 mM, and sucrose is present in the composition at a concentration of 40 to 1190 mM, such as 50 to 1190 mM or 75 to 1190 mM. In this embodiment, the combined total concentration of propylene glycol and sucrose is preferably 200 to 1200 mM, such as 300 to 800 mM.

[0031] In one embodiment, the polyol is a mixture of propylene glycol and mannitol. In this embodiment, preferably, the propylene glycol is present in the composition at a concentration of 10-160 mM, for example, 10-150 mM or 10-125 mM, and the mannitol is present in the composition at a concentration of 40-1190 mM, for example, 50-1190 mM or 75-1190 mM. In this embodiment, the combined total concentration of propylene glycol and mannitol is preferably 200-1200 mM, for example, 300-800 mM.

[0032] In one embodiment, the molar ratio of vancomycin or a pharmaceutically acceptable salt thereof to the polyol (or the combined molar concentration if two or more polyols are present) is between 1:100 and 1:1000, for example, between 1:100 and 1:500, particularly between 1:100 and 1:250.

[0033] The composition ready for administration of the present invention can be administered to a patient as it is without dilution. To minimize the risk of hemolysis and patient discomfort during administration, hypotonic compositions (e.g., compositions with a molar osmotic concentration of less than 300 mOsm / L) and significantly hypertonic compositions should be avoided. It is generally accepted that compositions with a molar osmotic concentration up to about 700 mOsm / L can be used for intravenous delivery without significant risk of patient discomfort or hemolysis. For compositions where small uncharged species such as polyols are important components, the maximum limit of the molar osmotic concentration can be made higher. However, in any case, a molar osmotic concentration exceeding 1250 mOsm / L should be avoided in the composition ready for administration. As a result, although higher concentrations of polyol have been shown to provide improved stability of vancomycin, the concentration of polyol in the composition of the present invention is limited to ensure that the molar osmotic concentration does not exceed 1250 mOsm / L.

[0034] To avoid ambiguity, any reference in this specification to "osmolarity" means the calculated osmolarity. Osmolarity is calculated as the sum of the molar concentrations of all the 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 osmolarity (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 an osmolarity of 500 mOsm / L. For species that dissociate in solution, the osmolarity is the sum of the molar concentrations of all the 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 an osmolarity of 1000 mOsm / L.

[0035] The osmolality of the composition of the present invention is 400 to 1250 mOsm / L. In one embodiment, the osmolality of the composition is 410 to 1250 mOsm / L, 425 to 1250 mOsm / L, 450 to 1250 mOsm / L, 500 to 1250 mOsm / L, 550 to 1250 mOsm / L, 600 to 1250 mOsm / L, 700 to 1250 mOsm / L, 400 to 1100 mOsm / L, 410 to 1100 mOsm / L, 425 to 1100 mOsm / L, 450 to 1100 mOsm / L, 500 to 1100 mOsm / L, 550 to 1100 mOsm / L, 600 to 1100 mOsm / L, 700 to 1100 mOsm / L, 400 to 1000 mOsm / L, 410 to 1000 mOsm / L, 425 to 1000 mOsm / L, 450 to 1000 mOsm / L, 500 to 1000 mOsm / L, 550 to 1000 mOsm / L, 600 to 1000 mOsm / L, 700 to 1000 mOsm / L, 400 to 800 mOsm / L, 410 to 800 mOsm / L, 425 to 800 mOsm / L, 450 to 800 mOsm / L, 500 to 800 mOsm / L, 550 to 800 mOsm / L, 600 to 800 mOsm / L, 700 to 800 mOsm / L, 400 to 600 mOsm / L, 410 to 600 mOsm / L, 425 to 600 mOsm / L, 450 to 600 mOsm / L, 500 to 600 mOsm / L, or 500 to 600 mOsm / L.

[0036] Preferably, the composition is slightly hypertonic.

[0037] The composition of the present invention is an aqueous solution composition and contains at least 80% (v / v) water, for example, at least 70% (v / v), at least 60% (v / v), at least 55% (v / v), at least 50% (v / v), at least 45% (v / v), at least 40% (v / v), at least 35% (v / v), at least 30% (v / v), at least 25% (v / v), at least 20% (v / v), at least 15% (v / v), at least 10% (v / v), at least 5% (v / v), or at least 2.5% (v / v) water, for example, water for injection, sterilized or bacteriostatic.

[0038] In one embodiment, as shown in Examples 5 to 8, the addition of an inorganic salt containing a metal cation has a further stabilizing effect on the compositions described herein.

[0039] Accordingly, in one embodiment, the composition further comprises an inorganic salt containing a metal cation, particularly 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 oxalate, and sodium sulfate. In one embodiment, the composition comprises an inorganic salt containing a metal cation that is sodium chloride or calcium chloride, particularly sodium chloride. In one embodiment, the composition comprises an inorganic salt containing a metal cation that is sodium oxalate. The concentration of the inorganic salt containing a metal cation is typically 1 to 500 mM, for example, 50 to 250 mM or 75 to 150 mM. The concentration of the above-mentioned inorganic salt usually represents the concentration of an inorganic salt such as sodium chloride added to the composition.

[0040] 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. Accordingly, 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.

[0041] It should be noted that whenever "pH" is mentioned herein, 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).

[0042] 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 preferably is methionine. When included, the antioxidant is typically present in the composition at a concentration of 1 to 100 mM, such as 10 to 50 mM or 25 to 50 mM.

[0043] 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 propylene glycol. 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.

[0044] 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.

[0045] 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 in particular, dodecyl maltoside.

[0046] 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).

[0047] 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).

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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, propylparaben, and methylparaben, 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).

[0052] In one embodiment, vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; or DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; a polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof, at a total concentration of 200 to 1200 mM, such as 300 to 800 mM; and optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 to 1250 mOsm / L, such as 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and 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.

[0053] In one embodiment, vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; or DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; propylene glycol at a concentration of 660 to 1200 mM, such as 700 to 1200 mM, 750 to 1200 mM, 800 to 1200 mM, or 850 to 1200 mM; and Optionally, an inorganic salt containing a metal cation; comprising, the osmolality is 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and 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.

[0054] In one embodiment, vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 - 10 mg / mL, for example, 2.5 - 7.5 mg / mL, or about 5 mg / mL; D - lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 - 500 mM, 100 - 300 mM, 100 - 200 mM, 100 - 150 mM, about 100 mM, or about 200 mM; or DL - lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, 200 - 600 mM, 200 - 400 mM, 200 - 300 mM, about 200 mM, or about 400 mM; sucrose at a concentration of 200 - 1200 mM, for example, 300 - 800 mM; and Optionally, an inorganic salt containing a metal cation; comprising, the osmolality is 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and 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.

[0055] In one embodiment, vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 - 10 mg / mL, for example, 2.5 - 7.5 mg / mL, or about 5 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 - 500 mM, 100 - 300 mM, 100 - 200 mM, 100 - 150 mM, about 100 mM, or about 200 mM; or DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, 200 - 600 mM, 200 - 400 mM, 200 - 300 mM, about 200 mM, or about 400 mM; A mixture of two polyols selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a combined total concentration of 200 - 1200 mM, for example, 300 - 800 mM; and Optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and a storage-stable aqueous solution composition having a pH in the range of 4.0 - 6.0, for example, about 5.0, is provided.

[0056] In one embodiment, vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 - 10 mg / mL, for example, 2.5 - 7.5 mg / mL, or about 5 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 - 500 mM, 100 - 300 mM, 100 - 200 mM, 100 - 150 mM, about 100 mM, or about 200 mM; or DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, 200 - 600 mM, 200 - 400 mM, 200 - 300 mM, about 200 mM, or about 400 mM; A mixture of propylene glycol at a concentration of 10 - 160 mM, for example 10 - 150 mM or 10 - 125 mM, and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a concentration of 40 - 1190 mM, for example 50 - 1190 mM or 75 - 1190 mM; wherein the combined total concentration of propylene glycol and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is 200 - 1200 mM, for example 300 - 800 mM, said mixture; and Optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 - 1250 mOsm / L, for example 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and a storage - stable aqueous solution composition having a pH in the range of 4.0 - 6.0, for example about 5.0, is provided.

[0057] In one embodiment, vancomycin at a concentration of 1 - 10 mg / mL, for example 2.5 - 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; D - lactic acid at a concentration of 100 - 500 mM, 100 - 300 mM, 100 - 200 mM, 100 - 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; a polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof, at a total concentration of 200 - 1200 mM, for example 300 - 800 mM; and Optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 - 1250 mOsm / L, for example 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and a storage - stable aqueous solution composition having a pH in the range of 4.0 - 6.0, for example about 5.0, is provided.

[0058] In one embodiment, vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; propylene glycol at a concentration of 660 to 1200 mM, such as 700 to 1200 mM, 750 to 1200 mM, 800 to 1200 mM, or 850 to 1200 mM; and optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 to 1250 mOsm / L, such as 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and 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.

[0059] In one embodiment, vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; propylene glycol at a concentration of 660 to 1200 mM, such as 700 to 1200 mM, 750 to 1200 mM, 800 to 1200 mM, or 850 to 1200 mM; and an inorganic salt containing a metal cation at a concentration of 1 to 500 mM, such as 50 to 250 mM; comprising having an osmolality of 400 to 1250 mOsm / L, such as 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and 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.

[0060] In one embodiment, vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof, such as vancomycin hydrochloride; D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof, such as sodium D-lactate; propylene glycol at a concentration of 660 to 1200 mM, such as 700 to 1200 mM, 750 to 1200 mM, 800 to 1200 mM, or 850 to 1200 mM; and sodium chloride at a concentration of 1 to 500 mM, such as 50 to 250 mM; comprising having an osmolality of 400 to 1250 mOsm / L, such as 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and 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.

[0061] In one embodiment, vancomycin at a concentration of about 5 mg / mL, or a pharmaceutically acceptable salt thereof, such as vancomycin hydrochloride; D-lactic acid at a concentration of 100 to 200 mM, or a pharmaceutically acceptable salt thereof, such as sodium D-lactate; propylene glycol at a concentration of 660 to 1200 mM; and sodium chloride at a concentration of 50 to 250 mM; comprising having an osmolality of 550 to 1250 mOsm / L; and having a pH in the range of 4.0 to 6.0 a storage-stable aqueous solution composition is provided.

[0062] In one embodiment, Vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; Glycerol at a concentration of 200 to 1200 mM, such as 300 to 800 mM; and Optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 to 1250 mOsm / L, such as 400 to 1000 mOsm / L, or 500 to 800 mOsm / L; and 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.

[0063] In one embodiment, Vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof, such as vancomycin hydrochloride; D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof, such as sodium D-lactate; and Glycerol at a concentration of 200 to 1200 mM, such as 300 to 800 mM; comprising having an osmolality of 400 to 1250 mOsm / L, such as 400 to 1000 mOsm / L, or 500 to 800 mOsm / L; and 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.

[0064] In one embodiment, Vancomycin at a concentration of about 5 mg / mL, or a pharmaceutically acceptable salt thereof, such as vancomycin hydrochloride; D-lactic acid or a pharmaceutically acceptable salt thereof, such as sodium D-lactate, at a concentration of 100-200 mM, 100-150 mM, for example, about 100 mM or about 200 mM; and glycerol at a concentration of 300-800 mM; comprising having an osmolality of 500-800 mOsm / L; and having a pH in the range of 4.0-6.0, a storage-stable aqueous solution composition is provided.

[0065] In one embodiment, vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1-10 mg / mL, for example, 2.5-7.5 mg / mL, or about 5 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100-500 mM, 100-300 mM, 100-200 mM, 100-150 mM, about 100 mM, or about 200 mM; sucrose at a concentration of 200-1200 mM, for example, 300-800 mM; and optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400-1250 mOsm / L, for example, 450-1250 mOsm / L, or 550-1250 mOsm / L; and having a pH in the range of 4.0-6.0, for example, about 5.0, a storage-stable aqueous solution composition is provided.

[0066] In one embodiment, vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1-10 mg / mL, for example, 2.5-7.5 mg / mL, or about 5 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100-500 mM, 100-300 mM, 100-200 mM, 100-150 mM, about 100 mM, or about 200 mM; A mixture of two polyols selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a total concentration of 200 to 1200 mM, for example, 300 to 800 mM; and Optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0, is provided.

[0067] In one embodiment, vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL; D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM; a mixture of propylene glycol at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM; wherein the total concentration of propylene glycol and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is 200 to 1200 mM, for example, 300 to 800 mM, said mixture; and Optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0, is provided.

[0068] In one embodiment, vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; a polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof, at a total concentration of 200 to 1200 mM, such as 300 to 800 mM; and optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 to 1250 mOsm / L, such as 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and 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.

[0069] In one embodiment, vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; propylene glycol at a concentration of 660 to 1200 mM, such as 700 to 1200 mM, 750 to 1200 mM, 800 to 1200 mM, or 850 to 1200 mM; and optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 to 1250 mOsm / L, such as 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and There is provided a storage-stable aqueous solution composition in which the pH is in the range of 4.0 to 6.0, for example, about 5.0.

[0070] In one embodiment, vancomycin at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; glycerol at a concentration of 200 to 1200 mM, for example, 300 to 800 mM; and optionally, an inorganic salt containing a metal cation; comprising the osmolality is 400 to 1250 mOsm / L, for example, 400 to 1000 mOsm / L, or 500 to 800 mOsm / L; and There is provided a storage-stable aqueous solution composition in which the pH is in the range of 4.0 to 6.0, for example, about 5.0.

[0071] In one embodiment, vancomycin at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof, for example, vancomycin hydrochloride; DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof, for example, sodium DL-lactate; and glycerol at a total concentration of 200 to 1200 mM, for example, 300 to 800 mM; comprising the osmolality is 400 to 1250 mOsm / L, for example, 400 to 1000 mOsm / L, or 500 to 800 mOsm / L; and There is provided a storage-stable aqueous solution composition in which the pH is in the range of 4.0 to 6.0, for example, about 5.0.

[0072] In one embodiment, Vancomycin at a concentration of about 5 mg / mL or a pharmaceutically acceptable salt thereof, for example, vancomycin hydrochloride; DL-lactic acid at a concentration of 200 - 400 mM, 200 - 300 mM, for example, about 200 mM or about 400 mM, or a pharmaceutically acceptable salt thereof, for example, sodium DL-lactate; and Glycerol at a concentration of 300 - 800 mM; comprising having an osmolality of 500 - 800 mOsm / L; and a storage-stable aqueous solution composition having a pH in the range of 4.0 - 6.0 is provided.

[0073] In one embodiment, vancomycin at a concentration of 1 - 10 mg / mL, for example, 2.5 - 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; DL-lactic acid at a concentration of 200 - 1000 mM, 200 - 600 mM, 200 - 400 mM, 200 - 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; sucrose at a concentration of 200 - 1200 mM, for example, 300 - 800 mM; and optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and a storage-stable aqueous solution composition having a pH in the range of 4.0 - 6.0, for example, about 5.0, is provided.

[0074] In one embodiment, vancomycin at a concentration of 1 - 10 mg / mL, for example, 2.5 - 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; DL-lactic acid at a concentration of 200 - 1000 mM, 200 - 600 mM, 200 - 400 mM, 200 - 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; A mixture of two polyols selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a total concentration of 200 to 1200 mM, for example, 300 to 800 mM; and Optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0, is provided.

[0075] In one embodiment, vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL; DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM; a mixture of propylene glycol at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM, wherein the total concentration of propylene glycol and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is 200 to 1200 mM, for example, 300 to 800 mM; and Optionally, an inorganic salt containing a metal cation; comprising having an osmolality of 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0, is provided.

[0076] In one embodiment, (i) Vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; (ii) D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; or DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; (iii) A polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof, at a total concentration of 200 to 1200 mM, such as 300 to 800 mM; (iv) Water, such as water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or consisting essentially of: having an osmolality of 400 to 1250 mOsm / L, such as 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and 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.

[0077] In one embodiment, (i) Vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; (ii) D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM; or DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM; (iii) Propylene glycol at a concentration of 660 to 1200 mM, for example, 700 to 1200 mM, 750 to 1200 mM, 800 to 1200 mM, or 850 to 1200 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; Consisting of or essentially consisting of: The osmolality is 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and 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.

[0078] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL; (ii) D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM; or DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM; (iii) Sucrose at a concentration of 200 to 1200 mM, for example, 300 to 800 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or essentially consisting of: having an osmolality of 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and a storage - stable aqueous solution composition having a pH in the range of 4.0 - 6.0, for example, about 5.0, is provided.

[0079] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 - 10 mg / mL, for example, 2.5 - 7.5 mg / mL, or about 5 mg / mL; (ii) D - lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 - 500 mM, 100 - 300 mM, 100 - 200 mM, 100 - 150 mM, about 100 mM, or about 200 mM; or DL - lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, 200 - 600 mM, 200 - 400 mM, 200 - 300 mM, about 200 mM, or about 400 mM; (iii) A mixture of two polyols selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a combined total concentration of 200 - 1200 mM, for example, 300 - 800 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or essentially consisting of: having an osmolality of 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and 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.

[0080] In one embodiment, (i) vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL; (ii) D-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM; or DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM; (iii) a mixture of propylene glycol at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM, and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM; wherein the combined total concentration of propylene glycol and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is 200 to 1200 mM, for example, 300 to 800 mM; (iv) water, for example, water for injection; (v) optionally, an inorganic salt containing a metal cation; (vi) optionally, an antioxidant; (vii) optionally, a nonionic surfactant; and (viii) optionally, a preservative; comprising or consisting essentially of: having an osmolality of 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and 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.

[0081] In one embodiment, (i) vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; (ii) D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; (iii) a polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof, at a total concentration of 200 to 1200 mM, such as 300 to 800 mM; (iv) water, such as water for injection; (v) optionally, an inorganic salt containing a metal cation; (vi) optionally, an antioxidant; (vii) optionally, a nonionic surfactant; and (viii) optionally, a preservative; consisting of or consisting essentially of: having an osmolality of 400 to 1250 mOsm / L, such as 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and 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.

[0082] In one embodiment, (i) vancomycin at a concentration of 1 to 10 mg / mL, such as 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; (ii) D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; (iii) propylene glycol at a concentration of 660 to 1200 mM, such as 700 to 1200 mM, 750 to 1200 mM, 800 to 1200 mM, or 850 to 1200 mM; (iv) water, such as water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of, or consisting essentially of: having an osmolality of 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and a storage - stable aqueous solution composition having a pH in the range of 4.0 - 6.0, for example, about 5.0, is provided.

[0083] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 - 10 mg / mL, for example, 2.5 - 7.5 mg / mL, or about 5 mg / mL; (ii) D - lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 100 - 500 mM, 100 - 300 mM, 100 - 200 mM, 100 - 150 mM, about 100 mM, or about 200 mM; (iii) Sucrose at a concentration of 200 - 1200 mM, for example, 300 - 800 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of, or consisting essentially of: having an osmolality of 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and a storage - stable aqueous solution composition having a pH in the range of 4.0 - 6.0, for example, about 5.0, is provided.

[0084] In one embodiment, (i) Vancomycin at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; (ii) D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; (iii) A mixture of two polyols selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a combined total concentration of 200 to 1200 mM, for example, 300 to 800 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or consisting essentially of: having an osmolality of 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and a storage-stable aqueous solution composition having a pH in the range of 4.0 to 6.0, for example, about 5.0, is provided.

[0085] In one embodiment, (i) Vancomycin at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; (ii) D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; (iii) A mixture of propylene glycol at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM, and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM, wherein the combined total concentration of propylene glycol and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is 200 to 1200 mM, for example, 300 to 800 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or essentially consisting of: having an osmolality of 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and having a pH in the range of 4.0 to 6.0, for example, about 5.0, a storage-stable aqueous solution composition is provided.

[0086] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL; (ii) DL-lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM; (iii) A polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof, at a total concentration of 200 to 1200 mM, for example, 300 to 800 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or consisting essentially of: having an osmolality of 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and 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.

[0087] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 - 10 mg / mL, for example, 2.5 - 7.5 mg / mL, or about 5 mg / mL; (ii) DL - lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, 200 - 600 mM, 200 - 400 mM, 200 - 300 mM, about 200 mM, or about 400 mM; (iii) Propylene glycol at a concentration of 660 - 1200 mM, for example, 700 - 1200 mM, 750 - 1200 mM, 800 - 1200 mM, or 850 - 1200 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or consisting essentially of: having an osmolality of 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and 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.

[0088] In one embodiment, (i) Vancomycin at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; (ii) DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; (iii) Sucrose at a concentration of 200 to 1200 mM, for example, 300 to 800 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; Consisting of or consisting essentially of: The osmolality is 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and 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.

[0089] In one embodiment, (i) Vancomycin at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; (ii) DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; (iii) A mixture of two polyols selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a combined total concentration of 200 to 1200 mM, for example, 300 to 800 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or essentially consisting of: having a molar osmotic concentration of 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and a storage - stable aqueous solution composition is provided, having a pH in the range of 4.0 - 6.0, for example, about 5.0.

[0090] In one embodiment, (i) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 - 10 mg / mL, for example, 2.5 - 7.5 mg / mL, or about 5 mg / mL; (ii) DL - lactic acid or a pharmaceutically acceptable salt thereof at a concentration of 200 - 1000 mM, 200 - 600 mM, 200 - 400 mM, 200 - 300 mM, about 200 mM, or about 400 mM; (iii) A mixture of propylene glycol at a concentration of 10 - 160 mM, for example, 10 - 150 mM or 10 - 125 mM and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a concentration of 40 - 1190 mM, for example, 50 - 1190 mM or 75 - 1190 mM, wherein the combined total concentration of propylene glycol and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is 200 - 1200 mM, for example, 300 - 800 mM; (iv) Water, for example, water for injection; (v) Optionally, an inorganic salt containing a metal cation; (vi) Optionally, an antioxidant; (vii) Optionally, a nonionic surfactant; and (viii) Optionally, a preservative; consisting of or essentially consisting of: having a molar osmotic concentration of 400 - 1250 mOsm / L, for example, 450 - 1250 mOsm / L, or 550 - 1250 mOsm / L; and 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.

[0091] 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 "essentially consisting 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.

[0092] Preferably, the composition of the present invention remains a clear solution 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 (measured, for example, by the visual evaluation method in the general method).

[0093] Preferably, the composition of the present invention remains a clear solution 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 (measured, for example, by the visual evaluation method in the general method).

[0094] Preferably, the composition of the present invention contains total impurities not exceeding 12% and individual impurities are all not >4% (total weight standard of vancomycin or its pharmaceutically acceptable salts in the composition) as described in the United States Pharmacopeia monograph (vancomycin hydrochloride for injection, United States Pharmacopeia 29) 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.

[0095] 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 Pharmacopoeia monograph (Vancomycin Hydrochloride, EP 6.0).

[0096] 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 the United States Pharmacopoeia monograph (Vancomycin Hydrochloride for Injection, USP 29).

[0097] 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 Pharmacopoeia monograph (Vancomycin Hydrochloride, EP 6.0).

[0098] 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.

[0099] Vancomycin (especially vancomycin hydrochloride) is indicated, in particular, for the treatment of bacterial infections, especially for the treatment of 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 did 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.

[0100] In addition, vancomycin (especially vancomycin hydrochloride) is also 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, antibiotics are used as an adjunct to appropriate surgical procedures. Vancomycin (especially vancomycin hydrochloride) has been reported to be effective alone or in combination with an aminoglycoside in the treatment of 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 the treatment of early-onset prosthetic valve endocarditis caused by Staphylococcus epidermidis or diphtheroids, either alone or in combination with rifampin and / or an aminoglycoside.

[0101] 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.

[0102] In one embodiment, said bacterial infection is 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, Staphylococcus aureus methicillin-resistant, Actinomyces spp., Lactobacillus spp., Enterococcus faecalis, and diphtheroids.

[0103] The vancomycin composition 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).

[0104] In one embodiment, there is provided a composition as described hereinabove for use in the treatment of bacterial infections in combination with an antibiotic selected from the group consisting of, for example, 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, for example, rifampicin, aminoglycosides (such as gentamicin), and β-lactam antibiotics (such as amoxicillin) for use in the treatment of bacterial infections in combination with a composition as described hereinabove.

[0105] All of the embodiments described above with respect to the aqueous composition apply equally to the methods and uses of the present invention.

[0106] Also provided are containers containing a single dose or multiple doses of a composition as described hereinabove. The container is preferably an intravenous (IV) solution bag or bottle. When the container is an IV solution bag, it is preferably made of 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 an IV solution 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.

[0107] Preferably, the composition is a colorless to slightly yellow solution that does not contain visible particles. Preferably, when opened, 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.

[0108] The present invention is further defined by the following items: (Item 1) Vancomycin at a concentration of 1 - 10 mg / mL or a pharmaceutically acceptable salt thereof; D-lactic acid or a pharmaceutically acceptable salt thereof; and A polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof; comprising having an osmolality of 400 - 1250 mOsm / L A storage-stable aqueous solution composition. (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 the vancomycin or a pharmaceutically acceptable salt thereof is 2.5 to 7.5 mg / mL, or about 5 mg / mL. (Item 4) The storage-stable aqueous solution composition according to any one of Items 1 to 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, which contains 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, which contains 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 500 mM, for example, 100 to 300 mM, particularly 100 to 200 mM, for example, about 100 mM or about 200 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, 200 to 600 mM, particularly 200 to 400 mM, for example, about 200 mM or about 400 mM. (Item 10) The storage-stable aqueous solution composition according to any one of Items 1 to 9, wherein the total concentration of the polyol in the composition is 200 to 1200 mM, for example, 300 to 800 mM. (Item 11) The storage-stable aqueous solution composition according to any one of Items 1 to 10, comprising a single polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol. (Item 12) The storage-stable aqueous solution composition according to Item 11, wherein the single polyol is propylene glycol, and the propylene glycol is preferably present in the composition at a concentration of 660 to 1200 mM, for example, 700 to 1200 mM, 750 to 1200 mM, 800 to 1200 mM, or 850 to 1200 mM. (Item 13) The storage-stable aqueous solution composition according to Item 11, wherein the single polyol is glycerol, and the glycerol is preferably present in the composition at a concentration of 200 to 1200 mM, for example, 300 to 800 mM. (Item 14) The storage-stable aqueous solution composition according to Item 11, wherein the single polyol is sucrose, and the sucrose is preferably present in the composition at a concentration of 200 to 1200 mM, for example, 300 to 800 mM. (Item 15) The storage-stable aqueous solution composition according to Item 11, wherein the single polyol is mannitol, and the mannitol is preferably present in the composition at a concentration of 200 to 1200 mM, for example, 300 to 800 mM. (Item 16) The storage-stable aqueous solution composition according to any one of Items 1 to 10, comprising a mixture of two polyols selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol. (Item 17) The storage-stable aqueous solution composition according to any one of Items 1 to 11 or 16, wherein the or each polyol is selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol. (Item 18) The storage-stable aqueous solution composition according to any one of Items 1 to 11 or 16, wherein the polyol or each polyol is selected from the group consisting of propylene glycol, sucrose, trehalose, lactose, glucose, sorbitol, and mannitol. (Item 19) The storage-stable aqueous solution composition according to any one of Items 1 to 11 or 16, wherein the polyol or each polyol is selected from the group consisting of sucrose, trehalose, lactose, glucose, sorbitol, and mannitol. (Item 20) Comprising a mixture of propylene glycol and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol; The storage-stable aqueous solution composition according to Item 16, wherein the propylene glycol is preferably present at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM; and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is preferably present at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM. (Item 21) The storage-stable aqueous solution composition according to Item 20, wherein the combined total concentration of propylene glycol and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is 200 to 1200 mM, for example, 300 to 800 mM. (Item 22) The storage-stable aqueous solution composition according to Item 20, comprising a mixture of propylene glycol and glycerol, wherein the propylene glycol is preferably present in the composition at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM, and the glycerol is preferably present in the composition at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM. (Item 23) The storage-stable aqueous solution composition according to item 22, wherein the combined total concentration of propylene glycol and glycerol is 200 to 1200 mM, for example, 300 to 800 mM. (Item 24) The storage-stable aqueous solution composition according to item 16, which contains a mixture of propylene glycol and sucrose, wherein the propylene glycol is preferably present in the composition at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM, and the sucrose is preferably present in the composition at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM. (Item 25) The storage-stable aqueous solution composition according to item 20, wherein the combined total concentration of propylene glycol and sucrose is 200 to 1200 mM, for example, 300 to 800 mM. (Item 26) The storage-stable aqueous solution composition according to item 16, which contains a mixture of propylene glycol and mannitol, wherein the propylene glycol is preferably present in the composition at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM, and the mannitol is preferably present in the composition at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM. (Item 27) The storage-stable aqueous solution composition according to item 26, wherein the combined total concentration of propylene glycol and mannitol is 200 to 1200 mM, for example, 300 to 800 mM. (Item 28) The storage-stable aqueous solution composition according to any one of items 1 to 27, wherein the molar ratio of the vancomycin or a pharmaceutically acceptable salt thereof to the polyol is between 1:100 and 1:1000, for example, between 1:100 and 1:500, particularly between 1:100 and 1:250. (Item 29) The storage-stable aqueous solution composition according to any one of items 1 to 28, wherein the osmolality concentration is 410 to 1250 mOsm / L, 425 to 1250 mOsm / L, 450 to 1250 mOsm / L, 500 to 1250 mOsm / L, 550 to 1250 mOsm / L, 600 to 1250 mOsm / L, 700 to 1250 mOsm / L, 400 to 1100 mOsm / L, 410 to 1100 mOsm / L, 425 to 1100 mOsm / L, 450 to 1100 mOsm / L, 500 to 1100 mOsm / L, 550 to 1100 mOsm / L, 600 to 1100 mOsm / L, 700 to 1100 mOsm / L, 400 to 1000 mOsm / L, 410 to 1000 mOsm / L, 425 to 1000 mOsm / L, 450 to 1000 mOsm / L, 500 to 1000 mOsm / L, 550 to 1000 mOsm / L, 600 to 1000 mOsm / L, 700 to 1000 mOsm / L, 400 to 800 mOsm / L, 410 to 800 mOsm / L, 425 to 800 mOsm / L, 450 to 800 mOsm / L, 500 to 800 mOsm / L, 550 to 800 mOsm / L, 600 to 800 mOsm / L, 700 to 800 mOsm / L, 400 to 600 mOsm / L, 410 to 600 mOsm / L, 425 to 600 mOsm / L, 450 to 600 mOsm / L, 500 to 600 mOsm / L, or 500 to 600 mOsm / L. (Item 30) The storage-stable aqueous solution composition according to any one of items 1 to 29, comprising an inorganic salt containing a metal cation, particularly a Group 1 or Group 2 metal cation. (Item 31) The storage-stable aqueous solution composition according to item 30, wherein the inorganic salt containing the metal cation is selected from the group consisting of sodium chloride, calcium chloride, sodium oxalate, and sodium sulfate. (Item 32) The storage-stable aqueous solution composition according to item 30 or 31, wherein the concentration of the inorganic salt containing the metal cation is 1 to 500 mM, for example, 50 to 250 mM or 75 to 150 mM. (Item 33) The storage-stable aqueous solution composition according to any one of items 1 to 32, wherein the pH is in the range of 4.0 to 6.0, for example, about 5.0. (Item 34) The storage-stable aqueous solution composition according to any one of Items 1 to 33, further comprising an antioxidant. (Item 35) The storage-stable aqueous solution composition according to Item 34, wherein the antioxidant is selected from the group consisting of monothioglycerol, butylhydroxyanisole, glutathione (reduced form), ascorbate, cysteine, and methionine, and preferably methionine. (Item 36) The storage-stable aqueous solution composition according to Item 34 or 35, 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 37) The storage-stable aqueous solution composition according to any one of Items 1 to 36, substantially free of or free of amino acids. (Item 38) The storage-stable aqueous solution composition according to any one of Items 1 to 37, further comprising a nonionic surfactant. (Item 39) The storage-stable aqueous solution composition according to Item 38, wherein the nonionic surfactant is selected from the group consisting of alkyl glycoside, polysorbate, alkyl ether of polyethylene glycol, block copolymer of polyethylene glycol and polypropylene glycol, and alkyl phenyl ether of polyethylene glycol. (Item 40) 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; particularly, the storage-stable aqueous solution composition according to item 39, which is dodecyl maltoside or decyl glucopyranoside, especially dodecyl maltoside. (Item 41) The storage-stable aqueous solution composition according to item 39, wherein the nonionic surfactant is preferably a polysorbate, which is polysorbate 20 or polysorbate 80. (Item 42) The storage-stable aqueous solution composition according to item 39, 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 43) The storage-stable aqueous solution composition according to item 39, 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 44) The storage-stable aqueous solution composition according to item 39, wherein the nonionic surfactant is preferably an alkylphenyl ether of polyethylene glycol which is 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene glycol. (Item 45) The storage-stable aqueous solution composition according to any one of items 38 to 44, 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 46) The storage-stable aqueous solution composition according to any one of items 1 to 45, further comprising a preservative such as a phenolic or benzyl preservative. (Item 47) The storage-stable aqueous solution composition according to item 46, wherein the phenolic or benzyl preservative is selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, propyl paraben, and methyl paraben. (Item 48) The storage-stable aqueous solution composition according to any one of items 1 to 47, comprising at least 80% (v / v) of water, for example, at least 70% (v / v), at least 60% (v / v), at least 55% (v / v), at least 50% (v / v), at least 45% (v / v), at least 40% (v / v), at least 35% (v / v), at least 30% (v / v), at least 25% (v / v), at least 20% (v / v), at least 15% (v / v), at least 10% (v / v), at least 5% (v / v), or at least 2.5% (v / v) of water, for example, water for sterile injection or water for bacteriostatic injection. (Item 49) Vancomycin or a pharmaceutically acceptable salt thereof at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL; D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; or DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; A polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof, at a total concentration of 200 to 1200 mM, for example, 300 to 800 mM; and Optionally, an inorganic salt containing a metal cation; Comprising, consisting essentially of, or consisting of these, Having an osmolality of 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and The pH is in the range of 4.0 to 6.0, for example, about 5.0. The storage-stable aqueous solution composition according to item 1. (Item 50) Vancomycin at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; or DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; A mixture of two polyols selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a combined total concentration of 200 to 1200 mM, for example, 300 to 800 mM; and Optionally, an inorganic salt containing a metal cation; Comprising, consisting essentially of, or consisting of these: The osmolarity is 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and The pH is in the range of 4.0 to 6.0, for example, about 5.0, the storage-stable aqueous solution composition according to item 1. (Item 51) Vancomycin at a concentration of 1 to 10 mg / mL, for example, 2.5 to 7.5 mg / mL, or about 5 mg / mL, or a pharmaceutically acceptable salt thereof; D-lactic acid at a concentration of 100 to 500 mM, 100 to 300 mM, 100 to 200 mM, 100 to 150 mM, about 100 mM, or about 200 mM, or a pharmaceutically acceptable salt thereof; or DL-lactic acid at a concentration of 200 to 1000 mM, 200 to 600 mM, 200 to 400 mM, 200 to 300 mM, about 200 mM, or about 400 mM, or a pharmaceutically acceptable salt thereof; A mixture of propylene glycol at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM, and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM; wherein the combined total concentration of propylene glycol and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is 200 to 1200 mM, for example, 300 to 800 mM, said mixture; and Optionally, an inorganic salt containing a metal cation; Containing, consisting essentially of, or consisting of them: The osmolarity is 400 to 1250 mOsm / L, for example, 450 to 1250 mOsm / L, or 550 to 1250 mOsm / L; and The pH is in the range of 4.0 to 6.0, for example, about 5.0, the storage-stable aqueous solution composition according to item 1. (Item 52) The storage-stable aqueous solution composition according to any one of items 1 to 51, which is a pharmaceutical composition. (Item 53) The storage-stable aqueous solution composition according to any one of items 1 to 51 or the pharmaceutical composition according to item 52 for use in therapy. (Item 54) The storage-stable aqueous solution composition or pharmaceutical composition according to item 53 for use in the treatment of bacterial infections. (Item 55) 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 51 or the pharmaceutical composition according to item 52. (Item 56) The storage-stable aqueous solution composition for use according to item 54 or the method according to item 55, 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, multi-drug resistant Staphylococcus epidermidis, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Actinomyces spp., Lactobacillus spp., Enterococcus faecalis, and diphtheroids. (Item 57) The storage-stable aqueous solution composition or method for use according to any one of items 54 to 56 for use in combination with one or more additional therapeutic agents. (Item 58) The storage-stable aqueous solution composition or method for use according to item 57, 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 59) An administration-ready intravenous (IV) solution container, such as a bag or a bottle, containing the storage-stable aqueous solution composition according to any one of items 1 to 52.

Examples

[0109] (Example) (General method) (Reverse-phase chromatography (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 column with dimensions 250 mm × 4.6 mm, 5 μm particle size, and 80 Å pore size. Mobile phase A is a mixture of triethylamine buffer (prepared by mixing 4 mL of triethylamine and 2000 mL of water and adjusting the pH to 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. Bind the sample containing vancomycin (or a pharmaceutically acceptable salt thereof) in mobile phase A and elute it using a gradient of mobile phase A and mobile phase B. The sample volume 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.

[0110] (Visual evaluation method) Visible particles are preferably detected using the 2.9.20. European Pharmacopoeia monograph (Microscopic particles: visible particles). The required equipment consists of · 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 white light source with appropriate shading and an appropriate diffuser (an observation illuminator containing two 13 W fluorescent tubes each with a length of 525 mm is preferred) and consists of an observation table. The intensity of irradiation at the observation point is maintained between 2000 lux and 3750 lux.

[0111] All attached labels are removed from the container, and the exterior is washed and dried. The container is gently rotated or reverse rotated to ensure that no bubbles are introduced and 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 scores are 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 including larger particles Visual Score 5: >50 particles including larger particles.

[0112] Particles with visual scores of 4 and 5 in the sample are clearly detectable by a schematic visual assessment under normal light, whereas samples with visual scores of 1 - 3 generally appear as clear solutions in the same assessment. Samples with visual scores of 1 - 3 are considered "qualified"; samples with visual scores of 4 - 5 are considered "unqualified".

[0113] (Osmolality of the composition) Some of the vancomycin compositions prepared in Examples 2 - 8 have an osmolality greater than 1250 mOsm / L. These compositions, due to their high osmolality, are not embodiments of the invention per se, but exhibit trends in stability related to the use of the components of the particular compositions, which are aspects of the present invention.

[0114] (Example 1: Composition Example) The following exemplary aqueous compositions can be prepared. Example A: Vancomycin hydrochloride 5 mg / mL D - lactic acid 100 mM Propylene glycol 1000 mM pH 5.0 Osmolality 1190 mOsm / L Example B: Vancomycin hydrochloride 5 mg / mL Sodium D-lactate 200 mM Propylene glycol 800 mM pH 5.0 Osmolarity 1200 mOsm / L Example C: Vancomycin hydrochloride 5 mg / mL D-lactic acid 200 mM Sucrose 300 mM pH 5.0 Osmolarity 680 mOsm / L Example D: Vancomycin hydrochloride 5 mg / mL Sodium D-lactate 100 mM Sucrose 400 mM pH 5.0 Osmolarity 600 mOsm / L Example E: Vancomycin hydrochloride 5 mg / mL DL-lactic acid 200 mM Propylene glycol 800 mM pH 5.0 Osmolarity 1180 mOsm / L Example F: Vancomycin hydrochloride 5 mg / mL Sodium DL-lactate 400 mM Sucrose 300 mM pH 5.0 Osmolarity 1100 mOsm / L Example G: Vancomycin hydrochloride 5 mg / mL Sodium DL-lactate 200 mM Sucrose 350 mM Propylene glycol 150 mM pH 5.0 Osmolarity 900 mOsm / L Example H: Vancomycin hydrochloride 5 mg / mL D-lactic acid 100 mM Propylene glycol 800 mM Methionine 10 mM pH 5.0 Osmolarity 1000 mOsm / L Example I: Vancomycin hydrochloride 5 mg / mL Sodium D-lactate 100 mM Propylene glycol 150 mM Glycerol 450 mM pH 5.0 Osmolarity 800 mOsm / L Example J: Vancomycin hydrochloride 5 mg / mL D-lactic acid 100 mM Propylene glycol 150 mM Sucrose 350 mM pH 5.0 Osmolarity 690 mOsm / L Example K: Vancomycin hydrochloride 5 mg / mL Sodium D-lactate 200 mM Mannitol 400 mM pH 5.0 Osmolarity 800 mOsm / L Example L: Vancomycin hydrochloride 5 mg / mL D-lactic acid 100 mM Propylene glycol 1000 mM Sodium chloride 10 mM pH 5.0 Osmolarity 1210 mOsmol / L Example M: Vancomycin hydrochloride 5 mg / mL D-lactic acid 100 mM Sucrose 200 mM Propylene glycol 300 mM Sodium chloride 100 mM pH 5.0 Osmolarity 890 mOsm / L

[0115] 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 listed as a component of the composition, the stated amount of sodium chloride is added to the composition.

[0116] (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]

[0117] From Table 1, it can be seen that the pH range of 4.5 - 6.5 is the most stable, the degradation rate increases on either side of these ranges, and is very rapid at higher, more alkaline pH values. All subsequent compositions in the examples were prepared at pH 5.0.

[0118] (Example 3: Effect of composition additives on the stability of vancomycin) The effect of individual composition additives N-acetyl-D-alanine (NADA), PEG400, and lysine hydrochloride on the stability of vancomycin was 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 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 a commercially available composition of VancoReady (trademark). (Table 2: Stability of vancomycin hydrochloride (5 mg / mL) composition expressed as % impurities against time zero (T0)) [Table 2] *(VancoReady™ composition)

[0119] It can be seen from Table 2 that the removal of NADA from the VancoReady™ product led to a significant deterioration in stability (compare Compositions 7 and 8). The removal of PEG400 or lysine HCl did not seem to have a significant effect on the stability of the vancomycin composition. Thus, NADA appears to be an important stabilizing additive in VancoReady™.

[0120] (Example 4: Stability of vancomycin composition 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 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 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 commercial composition of VancoReady™. (Table 3: Vancomycin hydrochloride (5 mg / mL) composition) [Table 3] *(VancoReady™ composition) (Table 4: Stability of vancomycin hydrochloride (5 mg / mL) composition evaluated using RP-HPLC) [Table 4] *(VancoReady™ Composition) **(The analysis was not performed because the sample failed visual inspection due to precipitation of the formulation.)

[0121] 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. Even when NADA was replaced with N-acetyl-L-alanine (NALA), a significant deterioration in stability was brought about (compare Compositions 7 and 13). However, when NADA was replaced with sodium D-lactate, the decrease in composition stability was considerably less (compare Compositions 7 and 14). A similar effect was not observed in the case of sodium L-lactate, in which case the stability decreased considerably (compare Compositions 7 and 16). When the compositions containing sodium D-lactate and sodium L-lactate were modified by replacing PEG400 with propylene glycol, which is a polyol, a surprising relative increase in stability was observed (compare Compositions 14 and 15 and Compositions 16 and 17).

[0122] (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 the 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) composition) [Table 5] (Table 6: Stability of vancomycin hydrochloride (5 mg / mL) composition evaluated using RP-HPLC)

Table 6

[0123] 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).

[0124] (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

[0125] 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 provides a stabilizing effect, but the concentration has to be twice as high as when sodium D-lactate is used for the same degree of stabilizing effect (compare Compositions 28 - 30).

[0126] 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 Compositions 25 and 34) (compare Compositions 25 and 32).

[0127] (Example 7: Stability of vancomycin compositions (50 mg / mL) in the presence of various concentrations of D-lactate, DL-lactate, and polyols, and sodium chloride) The effects of various concentrations of sodium D-lactate, sodium DL-lactate, and polyols (propylene glycol (PG) or glycerol) on the stability of vancomycin compositions were investigated using the RP-HPLC method described in the general method. The effect of adding sodium chloride was 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 (compared to time zero) after storage at 2 - 8 °C for 8 weeks and at 25 °C for 8 weeks. (Table 9: Vancomycin hydrochloride (50 mg / mL) compositions)

Table 9

Table 10

[0128] 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 the polyol also results in improved composition stability (compare Compositions 23 and 24). Interestingly, the racemic form of the lactate (DL-sodium lactate) also provides a stabilizing effect, but the concentration has to be twice as high as when D-lactate is used for the same stabilizing effect (compare Compositions 24 and 28).

[0129] The addition of sodium chloride leads to an improvement in stability (compare Compositions 23 and 29). The mixture of polyols (propylene glycol and glycerol) was also confirmed to have a stabilizing effect (compare Compositions 24 and 25).

[0130] (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), and a polyol (a mixture of 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

[0131] 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.

[0132] (Example 9: Stability of vancomycin composition (5 mg / mL) in the presence of various polyols) The effect of selected polyols (propylene glycol (PG), sucrose, trehalose, glycerol, and mannitol) in the presence of 103.7 mM D - lactate on the stability of the vancomycin composition was investigated using the RP - HPLC method described in the general method. All compositions contained 5 mg / mL vancomycin hydrochloride in water for injection (WFI) and additional additives as listed in Table 13 (below) and were adjusted to pH 5.0. Table 14 shows the increase in % total impurities (compared to time zero) after storage at 25°C for 2, 4, and 6 weeks. (Table 13: Vancomycin hydrochloride (5 mg / mL) composition)

Table 13

Table 14

[0133] Comparing Compositions 36 - 40, the inventors can observe that the polyols tested have similar effects on stability at the equal molar concentrations tested. Further, comparing Formulations 36 - 40 with Formulation 35, the inventors recognize that an increase in the concentration of the polyol results in improved stability at the expense of an increase in the molar osmotic concentration. Therefore, it is necessary to specify the optimal balance between stability and molar osmotic concentration according to the requirements of the product.

[0134] (Example 10: Long - term stability of pre - prepared vancomycin composition (5 mg / mL)) Long-term stability tests for three compositions were set up at 2 - 8 °C and 25 °C. All the compositions contained 5 mg / mL of vancomycin hydrochloride and the additional additives shown in Table 15, and were adjusted to pH 5.0. The compositions were filled under aseptic conditions into Technoflex polypropylene 50 mL IV bags (Technoflex IX01001T009.029_D). 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 16 - 18 (2 - 8 °C) and Tables 19 - 21 (25 °C). (Table 15: Vancomycin hydrochloride (5 mg / mL) composition)

Table 15

Table 16

Table 17

Table 18

Table 19

Table 20

Table 21

[0135] Importantly, the United States Pharmacopeia monograph (Vancomycin Hydrochloride for Injection, United States Pharmacopeia 29) requires that vancomycin pharmaceuticals have the following purity: · Vancomycin purity of 88% or more (i.e., total impurities not exceeding 12%) · All individual impurities of 4% or less to have.

[0136] The results in Tables 16 - 21 demonstrate that the compositions tested (Composition Nos. 41 - 43) exhibit long-term storage stability and, in particular, meet the conditions enumerated in the United States Pharmacopeia monograph (United States Pharmacopeia 29) after storage at 2 - 8°C for 6 months and after short-term excursions at 25°C.

[0137] These results indicate that the compositions tested (Composition Nos. 41 - 43) 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 enumerated in the United States Pharmacopeia monograph (United States Pharmacopeia 29) after short-term excursions at 25°C.

Claims

1. Vancomycin at a concentration of 1 to 10 mg / mL or a pharmaceutically acceptable salt thereof; D-lactic acid or a pharmaceutically acceptable salt thereof; and A polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, or a mixture thereof; Comprising Having an osmolality of 400 to 1250 mOsm / L, A storage-stable aqueous solution composition.

2. The form of the vancomycin is vancomycin hydrochloride; and / or The concentration of vancomycin or a pharmaceutically acceptable salt thereof is 2.5 to 7.5 mg / mL, or about 5 mg / mL, The storage-stable aqueous solution composition according to claim 1.

3. The concentration of the D-lactic acid or a pharmaceutically acceptable salt thereof is 100 to 500 mM, for example, 100 to 300 mM, and in particular, 100 to 200 mM, for example, about 100 mM or about 200 mM, The storage-stable aqueous solution composition according to claim 1 or 2.

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.

5. The concentration of the DL-lactic acid or a pharmaceutically acceptable salt thereof is 200 to 1000 mM, for example, 200 to 600 mM, and in particular, 200 to 400 mM, for example, about 200 mM or about 400 mM, The storage-stable aqueous solution composition according to claim 4.

6. The total concentration of the polyol in the composition is 200 to 1200 mM, for example, 300 to 800 mM, The storage-stable aqueous solution composition according to any one of claims 1 to 5.

7. Comprising a single polyol selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, The storage-stable aqueous solution composition according to any one of claims 1 to 6.

8. Comprising a mixture of two polyols selected from the group consisting of propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol, The storage-stable aqueous solution composition according to any one of claims 1 to 6.

9. The storage-stable aqueous solution composition according to any one of claims 1 to 8, wherein the above or each polyol is selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol.

10. The storage-stable aqueous solution composition according to any one of claims 1 to 8, wherein the above or each polyol is selected from the group consisting of propylene glycol, sucrose, trehalose, lactose, glucose, sorbitol, and mannitol.

11. The storage-stable aqueous solution composition according to any one of claims 1 to 8, wherein the above or each polyol is selected from the group consisting of sucrose, trehalose, lactose, glucose, sorbitol, and mannitol.

12. Comprising a mixture of propylene glycol and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol; The propylene glycol is preferably present at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM; and the polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is preferably present at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM. The storage-stable aqueous solution composition according to claim 8.

13. The storage-stable aqueous solution composition according to claim 12, wherein the combined total concentration of propylene glycol and a polyol selected from the group consisting of sucrose, glycerol, trehalose, lactose, glucose, sorbitol, and mannitol is 200 to 1200 mM, for example, 300 to 800 mM.

14. The storage-stable aqueous solution composition according to claim 12, comprising a mixture of propylene glycol and glycerol, The propylene glycol is preferably present in the composition at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM, and the glycerol is preferably present in the composition at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM; and The combined total concentration of propylene glycol and glycerol is preferably 200 to 1200 mM, for example, 300 to 800 mM. The above storage-stable aqueous solution composition.

15. The storage-stable aqueous solution composition according to claim 12, comprising a mixture of propylene glycol and sucrose, wherein the propylene glycol is preferably present in the composition at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM, and the sucrose is preferably present in the composition at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM; and the combined total concentration of propylene glycol and sucrose is 200 to 1200 mM, for example, 300 to 800 mM, of the storage-stable aqueous solution composition.

16. The storage-stable aqueous solution composition according to claim 12, comprising a mixture of propylene glycol and mannitol, wherein the propylene glycol is preferably present in the composition at a concentration of 10 to 160 mM, for example, 10 to 150 mM or 10 to 125 mM, and the mannitol is preferably present in the composition at a concentration of 40 to 1190 mM, for example, 50 to 1190 mM or 75 to 1190 mM; and the combined total concentration of propylene glycol and mannitol is preferably 200 to 1200 mM, for example, 300 to 800 mM, of the storage-stable aqueous solution composition.

17. The storage-stable aqueous solution composition according to any one of claims 1 to 16, wherein the molar ratio of the vancomycin or a pharmaceutically acceptable salt thereof to the polyol is between 1:100 and 1:1000, for example, between 1:100 and 1:500, particularly between 1:100 and 1:

250.

18. The storage-stable aqueous solution composition according to any one of claims 1 to 17, wherein the osmolality concentration is 410 to 1250 mOsm / L, for example, 425 to 1250 mOsm / L, 450 to 1250 mOsm / L, 500 to 1250 mOsm / L, 550 to 1250 mOsm / L, 600 to 1250 mOsm / L, 700 to 1250 mOsm / L, 400 to 1100 mOsm / L, 410 to 1100 mOsm / L, 425 to 1100 mOsm / L, 450 to 1100 mOsm / L, 500 to 1100 mOsm / L, 550 to 1100 mOsm / L, 600 to 1100 mOsm / L, 700 to 1100 mOsm / L, 400 to 1000 mOsm / L, 410 to 1000 mOsm / L, 425 to 1000 mOsm / L, 450 to 1000 mOsm / L, 500 to 1000 mOsm / L, 550 to 1000 mOsm / L, 600 to 1000 mOsm / L, 700 to 1000 mOsm / L, 400 to 800 mOsm / L, 410 to 800 mOsm / L, 425 to 800 mOsm / L, 450 to 800 mOsm / L, 500 to 800 mOsm / L, 550 to 800 mOsm / L, 600 to 800 mOsm / L, 700 to 800 mOsm / L, 400 to 600 mOsm / L, 410 to 600 mOsm / L, 425 to 600 mOsm / L, 450 to 600 mOsm / L, 500 to 600 mOsm / L, or 500 to 600 mOsm / L.

19. The storage-stable aqueous solution composition according to any one of claims 1 to 18, which preferably contains an inorganic salt containing a metal cation, particularly a Group 1 or Group 2 metal cation, selected from the group consisting of sodium chloride, calcium chloride, sodium oxalate, and sodium sulfate, at a concentration of 1 to 500 mM, for example, 50 to 250 mM or 75 to 150 mM.

20. The storage-stable aqueous solution composition according to any one of claims 1 to 19, wherein the pH is in the range of 4.0 to 6.0, for example, about 5.

0.

21. A storage-stable aqueous solution composition according to any one of claims 1 to 20, comprising at least 80% (v / v) water, for example, at least 70% (v / v), at least 60% (v / v), at least 55% (v / v), at least 50% (v / v), at least 45% (v / v), at least 40% (v / v), at least 35% (v / v), at least 30% (v / v), at least 25% (v / v), at least 20% (v / v), at least 15% (v / v), at least 10% (v / v), at least 5% (v / v), or at least 2.5% (v / v) water, for example, water for sterile injection or bacteriostatic water for injection.

22. A storage-stable aqueous solution composition according to any one of claims 1 to 21, which is a pharmaceutical composition.

23. A storage-stable aqueous solution composition according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22, for use in therapy.

24. A storage-stable aqueous solution composition or a pharmaceutical composition according to claim 23, for use in the treatment of a bacterial infection, wherein the bacterial infection is preferably caused by a Gram-positive bacterium and preferably is 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, methicillin-resistant Staphylococcus aureus, Actinomyces spp., Lactobacillus spp., Enterococcus faecalis, and diphtheroids.

25. An intravenous (IV) solution container ready for administration, such as a bag or a bottle, containing a storage-stable aqueous solution composition according to any one of claims 1 to 22.

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