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WO2025229010A1 - Compositions comprenant de la dalbavancine - Google Patents

Compositions comprenant de la dalbavancine

Info

Publication number
WO2025229010A1
WO2025229010A1 PCT/EP2025/061747 EP2025061747W WO2025229010A1 WO 2025229010 A1 WO2025229010 A1 WO 2025229010A1 EP 2025061747 W EP2025061747 W EP 2025061747W WO 2025229010 A1 WO2025229010 A1 WO 2025229010A1
Authority
WO
WIPO (PCT)
Prior art keywords
aqueous liquid
dalbavancin
storage stable
stable aqueous
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/061747
Other languages
English (en)
Inventor
Jan Jezek
David GERRING
Joshua CREMIN
Jorge PINTO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HELM PHARMACEUTICALS GmbH
Original Assignee
HELM PHARMACEUTICALS GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by HELM PHARMACEUTICALS GmbH filed Critical HELM PHARMACEUTICALS GmbH
Publication of WO2025229010A1 publication Critical patent/WO2025229010A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the present invention relates to storage stable aqueous liquid solution compositions of dalbavancin, in particular, compositions which are diluted prior to administration, and which are non-toxic and have improved handling.
  • Dalbavancin is a second-generation lipoglycopeptide antibiotic, which is produced via a semisynthetic process in which the precursor glycopeptide complex A-40926, isolated from the actinomycete genus Nonomuraea, is selectively esterified, amidated and saponified. Dalbavancin is typically used in the form of its hydrochloride salt, which has a molecular weight of 1816.71 Da.
  • Dalbavancin has strong antibiotic activity against a number of Gram-positive bacteria including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus.
  • dalbavancin is one of the most widely used antibiotics in the treatment of methicillin-resistant Staphylococcus aureus (MRSA).
  • MRSA methicillin-resistant Staphylococcus aureus
  • dalbavancin is particularly used to treat acute bacterial skin and skin structure infections (ABSSSI), in particular when said infections are caused by the aforementioned Gram-positive bacteria, including MRSA.
  • dalbavancin binds to the C-terminal lysyl-D-alanyl-D-alanine sub-unit of expanding peptidoglycan chains, resulting in the prevention of transpeptidation of said chains. Consequently peptidoglycan elongation, and therefore, in embodiments, bacterial cell wall formation and cell reproduction are inhibited.
  • Dalbavancin is typically administered intravenously, and accordingly the present invention disclosed herein is primarily concerned with storage stable aqueous liquid solution compositions of dalbavancin which, following dilution, are suitable for intravenous administration.
  • the existing commercial dalbavancin product Xydalba®/Dalvance® is a product for intravenous use that is lyophilised. This product is presented as a lyophilised powder which must be reconstituted and subsequently diluted into an intravenous (IV) solution bag prior to administration. These requirements mean that this product is somewhat inconvenient to use.
  • Xydalba®/Dalvance® is formulated in a single-use vial and contains 500 mg dalbavancin hydrochloride, 129 mg lactose monohydrate, 129 mg mannitol, and hydrochloric acid and/or sodium hydroxide (for pH adjustment).
  • This formulation must be reconstituted with 25 mL of either sterile water for injection, USP, or 5% dextrose for injection. Following reconstitution, the pH of the resultant solution is between 5.0-7.0.
  • the present invention addresses the need for storage stable and non-toxic dalbavancin compositions, that are simply diluted prior to administration, thereby providing greater dosing flexibility and improved handling.
  • compositions comprising dalbavancin:
  • WO2018/096556A1 discloses a lyophilized pharmaceutical composition
  • a lyophilized pharmaceutical composition comprising (a) dalbavancin hydrochloride or its pharmaceutically acceptable salt and (b) a pharmaceutically acceptable amount of an amino acid as a stabilizer, wherein the ratio of dalbavancin to stabilizer is 1 :0.8 to 1 :1 by weight.
  • US7119061 B2 discloses methods and compositions for treatment of bacterial infections, including administration of dalbavancin formulations.
  • compositions comprising an alternative lipoglycopeptide antibiotic, vancomycin:
  • WO2016/071495A1 discloses solution comprising a glycopeptide antibiotic, for example vancomycin, and an amino acid or amino acid derivative, such as N-acetyl-glycine or N-acetyl-D-alanine.
  • US2022/0133845A1 discloses formulations and compositions comprising one or more glycopeptide antibiotics or a pharmaceutically acceptable salt thereof for parenteral administration, for example a liquid formulation comprising vancomycin, N-acetyl-methionine and one or more pharmaceutically acceptable excipients.
  • US10471149B2 discloses stabilized lipid-based glycopeptide antibiotic compositions and a process for producing the same.
  • US2022/0040309A1 discloses compositions and methods for delivery of therapeutic agents across a barrier, for example comprising a therapeutic agent, a permeation enhancer, and a matrix forming agent.
  • WO2020/185518A1 discloses compositions comprising a cyclic peptide, a solvent, and two or more hydroxyihydrocarbons, independently selected from (i) ethanol and glycerol or (ii) ethanol and mannitol.
  • the present invention provides, inter alia, a storage stable aqueous liquid solution composition
  • a storage stable aqueous liquid solution composition comprising:
  • dalbavancin may be present in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts include hydrochloride, citrate, formate, acetate, tartrate, sulphate, tosylate, nitrate, mesylate, napsylate, besylate, oxalate, maleate, phosphate, pamoate, fumarate, hippurate, succinate and carbonate.
  • dalbavancin is present in the composition as dalbavancin i.e. as the free base.
  • dalbavancin is present in the composition as dalbavancin hydrochloride.
  • any reference herein to “dalbavancin” is also intended to cover a pharmaceutically acceptable salt of dalbavancin, in particular the hydrochloride salt, unless stated otherwise.
  • the compositions of the present invention are concentrated solutions of dalbavancin (i.e. a composition concentrate), which require dilution into an IV solution bag or bottle prior to use.
  • the compositions of the present invention contain dalbavancin at a concentrations which is higher than that required for administration, in particular intravenous administration.
  • the compositions of the present invention are therefore typically diluted to the required concentration shortly before administration, e.g. intravenous administration.
  • the composition Prior to use, in embodiments, the composition is typically stored in a suitable container such as a sealed vial.
  • the concentration of dalbavancin or a pharmaceutically acceptable salt thereof in the compositions of the invention is 5-50 mg/mL, for example 5-40 mg/mL, for example 10-40 mg/mL, for example 10-35 mg/mL, for example 10-30 mg/mL, for example 10-25 mg/mL, for example 15-25 mg/mL, or about 20 mg/mL.
  • concentrations are based on dalbavancin and will be scaled accordingly when a salt such as the hydrochloride salt is used.
  • compositions of the present invention further comprise a non-ionic surfactant.
  • the non-ionic surfactant is suitably selected from the group consisting of a polysorbate, an alkyl glycoside, an alkyl ether of polyethylene glycol, a block copolymer of polyethylene glycol and polypropylene glycol, and an alkylphenyl ether of polyethylene glycol, and combinations thereof.
  • polysorbate surfactants i.e. polysorbates, (fatty acid esters of ethoxylated sorbitan), such as polysorbate 20, or polysorbate 80.
  • Polysorbate 20 is a mono ester formed from lauric acid and polyoxyethylene (20) sorbitan in which the number 20 indicates the number of oxyethylene groups in the molecule.
  • Polysorbate 80 is a mono ester formed from oleic acid and polyoxyethylene (20) sorbitan in which the number 20 indicates the number of oxyethylene groups in the molecule.
  • Polysorbate 20 is known under a range of brand names including in particular Tween 20, and also Alkest TW 20.
  • Polysorbate 80 is known under a range of brand names including in particular Tween 80, and also Alkest TW 80.
  • Other suitable polysorbate surfactants, i.e. polysorbates include polysorbate 40 and polysorbate 60. Therefore, in embodiments, the non-ionic surfactant is a polysorbate surfactant, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.
  • the non- ionic surfactant is a polysorbate surfactant, such as polysorbate 20 or polysorbate 80. In one preferred embodiment, the non-ionic surfactant is polysorbate 80.
  • alkyl glycosides include dodecyl maltoside, dodecyl glucoside, octyl glucoside, octyl maltoside, decyl glucoside, decyl maltoside, tridecyl glucoside, tridecyl maltoside, tetradecyl glucoside, tetradecyl maltoside, hexadecyl glucoside, hexadecyl maltoside, sucrose monooctanoate, sucrose mono decanoate, sucrose monododecanoate, sucrose monotridecanoate, sucrose monotetradecanoate and sucrose monohexadecanoate.
  • a particularly suitable alkyl glycoside is dodecyl maltoside.
  • a further suitable class of non-ionic surfactants are the alkyl ethers of polyethylene glycol, such as those known under a brand name Brij, such as selected from polyethylene glycol (2) hexadecyl ether (Brij 52), polyethylene glycol (2) oleyl ether (Brij 93) and polyethylene glycol (2) dodecyl ether (Brij L4).
  • Other suitable Brij surfactants include 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).
  • a suitable class of non-ionic surfactants are the block copolymers of polyethylene glycol and polypropylene glycol, also known as poloxamers.
  • Suitable poloxamer surfactants include poloxamer 188, poloxamer 407, poloxamer 171 and poloxamer 185.
  • Poloxamer surfactants are also known under the brand name Pluronics or the brand name Koliphors.
  • Pluronics or the brand name Koliphors.
  • poloxamer 188 is marketed as Pluronic F-68.
  • the non-ionic surfactant is a block copolymer of polyethylene glycol and polypropylene glycol, i.e. it is a poloxamer surfactant.
  • the non-ionic surfactant which is a block copolymer of polyethylene glycol and polypropylene glycol is selected from the group consisting of poloxamer 188, poloxamer 407, poloxamer 171 , and poloxamer 185.
  • the non-ionic surfactant is poloxamer 188.
  • a suitable class of non-ionic surfactants are the alkylphenyl ethers of polyethylene glycol, such as 4-(1 ,1 ,3,3-tetramethylbutyl)phenyl-polyethylene glycol, also known under the brand name Triton X-100.
  • the total concentration of the non-ionic surfactant (i.e. the one or more non- ionic surfactants) in the compositions of the invention is about 0.5 mg/mL or more, for example about 1 mg/mL or more, for example about 2 mg/mL or more, for example about 2.5 mg/mL or more, for example about 4 mg/mL or more, for example about 5 mg/mL or more.
  • the total concentration of the non-ionic surfactant (i.e. the one or more non- ionic surfactants) in the compositions of the invention is about 30 mg/mL or less, for example about 25 mg/mL or less, for example about 20 mg/mL or less, for example about 18 mg/mL or less, for example about 16 mg/mL or less, for example about 15 mg/mL or less.
  • the total concentration of the non-ionic surfactant (i.e. the one or more non- ionic surfactants) in the compositions of the invention is about 0.5-30 mg/mL, for example about 0.5-25 mg/mL, for example about 1-20 mg/mL, for example about 2-20 mg/mL, for example 5-20 mg/mL or 2-18 mg/mL, for example 5-15 mg/mL, or 2-15 mg/mL.
  • the total concentration of the non-ionic surfactant (i.e. the one or more non- ionic surfactants) in the compositions of the invention is about 10 mg/mL, or about 15 mg/mL, or about 20 mg/mL.
  • compositions of the present invention further comprise a polyol.
  • the polyol may function as an uncharged tonicity modifier, i.e. to provide a storage stable aqueous liquid solution composition with appropriate tonicity, and/or as a stabilizer, i.e. to provide a storage stable aqueous liquid solution composition of dalbavancin with improved stability.
  • the polyol is present as a stabilizer and, although the polyol contributes to tonicity, a further additional tonicity modifier (i.e. in addition to the polyol) is included in the composition of the present invention.
  • the polyol is present as a stabilizer and an uncharged tonicity modifier and no further additional tonicity modifier (i.e. in addition to the polyol) is included in the composition of the present invention.
  • any tonicity modifier for example an uncharged tonicity modifier such as a polyol, would be included in said compositions at a concentration which results in the diluted compositions having the desired tonicity, e.g. are isotonic, or slightly hypertonic
  • the polyol is selected from the group consisting of polyethylene glycol (PEG)300, PEG400 propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol and mannitol and combinations thereof.
  • the polyol is suitably selected from the group consisting of propylene glycol, glycerol, mannitol, and glucose, and combinations thereof.
  • the polyol is selected from the group consisting of glucose and propylene glycol.
  • the polyol is glucose.
  • the polyol is propylene glycol.
  • glucose is also known by the name dextrose, since it is dextrorotatory, and therefore any reference to glucose herein could equally refer to dextrose, and vice versa.
  • the polyol is not cyclodextrin.
  • the total concentration of the polyol is suitably in the range about 10-500 mM, for example about 10-450 mM, for example about 10-400 mM, for example about 20-400 mM, for example about 50-400 mM, for example about 100-400 mM, for example about 150-400 mM, for example about 150-350 mM, for example 200-350 mM, for example 250-350 mM, such as about 300 mM.
  • the pH of the storage stable aqueous liquid compositions according to the present invention is in the range of about 3.0 to 7.0, for example about 3.5 to 7.0, for example about 3.5 to 6.5, for example about 3.5 to 6.0, for example about 4.0 to 6.0, for example about 4.0 to 5.5, for example about 4.0 to 5.0, such as about 4.5 or about 5.0, or about 4.5 to 5.5, such as about 5.0 or about 5.5.
  • the pH of the composition of the present invention is about 4.5 to 5.5, such as about 5.0.
  • the storage stable aqueous liquid solution compositions of the present invention further comprise an additional salt at a total concentration of 50 mM or less, for example 40 mM or less, for example 30 mM or less, for example 20 mM or less, for example 10 mM or less, for example 5 mM or less, for example 2 mM or less.
  • the compositions of the present invention comprise an additional salt at a total concentration of 0-50 mM, for example 0-40 mM, for example 0-30 mM, for example 0-20 mM, for example 0-10 mM, for example 0-5 mM, for example 0-2 mM.
  • the compositions of the present invention comprise an additional salt at a total concentration of 0.1-50 mM, for example 0.1-40 mM, for example 0.1-30 mM, for example 0.1- 20 mM, for example 0.1-10 mM, for example 0.1-5 mM, for example 0.1-2 mM.
  • the compositions of the present invention are substantially free of, for example are free of, an additional salt.
  • an additional salt refers to any salt other than a salt which is included in the composition as a result of a specific formulation excipient being included in the composition in the salt form. That is, any salt which is included in the composition of the present invention that is not e.g.
  • a salt of dalbavancin and/or a salt of a neutral amino acid and/or a buffer salt is an additional salt, that is present in the composition at a total concentration of 50 mM or less, or that the composition is substantially free of, is sodium chloride.
  • the composition is substantially free of sodium lactate.
  • Sources of sodium chloride in the formulation which are not added as an additional salt include chloride ions and sodium ions from pH adjustment using, respectively, hydrochloric acid and sodium hydroxide as well as chloride ions from dalbavancin hydrochloride when the chloride salt is used or chloride ions and sodium ions from salt forms of the neutral amino acids present in the composition.
  • the total concentration of sodium chloride in the formulation from whatever source is 50 mM or less, for example 40 mM or less, for example 30 mM or less, for example 20 mM or less, for example 10 mM or less, for example 5 mM or less, for example 2 mM or less, e.g. is 0-20 mM e.g. 2-20 mM e.g. 5-20 mM e.g. 10-20 mM or 0-10 mM e.g. 2-10 mM e,g. 5-10 mM.
  • such additional salts may contribute to the tonicity of the composition and act as a charged tonicity modifier.
  • the storage stable aqueous liquid solution compositions of the present invention are substantially free of, for example are free of, N-acetyl-D-alanine and/or N-acetyl- glycine and/or N-acetyl-methionine.
  • the storage stable aqueous liquid solution compositions of the present invention are substantially free of, for example are free of, N- acetyl-D-alanine and N-acetyl-glycine and N-acetyl-methionine.
  • composition concentrate contains ⁇ 0.1 mg/mL of the stated component if the component is a solid at 21 °C, or ⁇ 0.01 % (v/v) if the component is a liquid at 21 °C.
  • the storage stable aqueous liquid solution compositions of the present invention are substantially free of, for example are free of, any neutral amino acid or pharmaceutically acceptable salt thereof.
  • a neutral amino acid is an amino acid the side chain of which does not contain an ionisable group which is significantly ionised (e.g. more than 5% especially more than 10% of the side chain have a negative or positive charge) at the pH of the composition.
  • the neutral amino acid does not contain a side chain with a pKa in the range 2.5-7.5 e.g. 3.0-7.0.
  • Exemplary neutral amino acids include glycine, methionine, proline, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, asparagine and glutamine. Therefore, suitably, the storage stable aqueous liquid solution compositions of the present invention are substantially free of, for example are free of glycine, methionine, proline, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, asparagine and glutamine, and pharmaceutically acceptable salts thereof.
  • compositions of the present invention may further comprise a buffer.
  • the compositions of the present invention comprise a buffer, in particular a buffer with suitable buffering capacity in the pH range of about 3.0 to about 7.0, such as in the pH range of about 4.0 to about 6.0, such as in the pH range 4.5 to 5.5.
  • the composition of the present invention comprises a buffer selected from the group consisting of maleate, sulphite, aspartame, aspartate, glutamate, tartrate, gluconate, adenine, succinate, ascorbate, benzoate, phenylacetate, gallate, cytosine, p-aminobenzoic acid, sorbate, acetate, propionate, lactate, alginate, urate, 2-(N-morpholino)ethanesulphonic acid, bicarbonate, bis(2- hydroxyethyl) iminotris(hydroxymethyl)methane, N-(2-acetamido)-2-iminodiacetic acid, 2-[(2- amino-2-oxoethyl)amino]ethanesulphonic acid, piperazine-N,N’-bis(2-ethanesulphonic acid) (PIPES), phosphate, N,N-bis(2-hydroxyethyl)-2-aminoethane
  • buffers are present in solution at the target pH in an equilibrium between a protonated and deprotonated form.
  • reference to “citrate” or “lactate” etc. as buffer will be understood to mean a mixture of that ion and the corresponding acid as buffer in a ratio according to the target pH.
  • target pH means the pH at which the composition of the present invention is intended to be buffered.
  • the protonated form predominates.
  • the deprotonated form predominates.
  • a buffer is most effective at controlling (i.e.
  • buffering pH at pH values within 2 pH units or more suitably within around 1 pH unit of the pKa of the or an ionisable group of the buffer.
  • the buffer acid e.g. citric acid, lactic acid etc
  • a base such as sodium hydroxide
  • the total concentration of the buffer i.e. the one or more buffers
  • the total concentration of the buffer is suitably in the range about 1-20 mM, for example about 2-20 mM, for example about 2-18 mM, for example about 4-16 mM, for example about 5-15 mM, for example about 5-12 mM, for example about 5-10 mM.
  • the total concentration of the buffer is about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, or about 10 mM.
  • compositions of the present invention may further comprise a tonicity modifier (i.e. in addition to the polyol defined above), particularly an uncharged tonicity modifier.
  • a tonicity modifier i.e. in addition to the polyol defined above
  • an uncharged tonicity modifier may be included in the compositions of the present invention in addition to a polyol, when said polyol is present as a stabilizer in the compositions of the present invention, despite the fact that said polyol may also contribute to tonicity as an uncharged tonicity modifier.
  • the polyol present in the compositions of the present invention may function as an uncharged tonicity modifier, optionally as well as a stabilizer, such that no further tonicity modifier is present in the compositions of the present invention.
  • an additional uncharged tonicity modifier is typically employed in the composition at a concentration of 50-1000 mM, for example 200-500 mM, such as about 300 mM.
  • an additional salt may act as a charged tonicity modifier and thus contribute to tonicity.
  • compositions of the present invention may further comprise an antioxidant.
  • the antioxidant is selected from the group consisting of monothioglycerol, butylated hydroxyanisole, glutathione (reduced), ascorbate, and cysteine.
  • Monothioglycerol is also known as 1 -thioglycerol, a-monothioglycerol, a-thioglycerol and 3-mercapto-1 ,2- propanediol.
  • the antioxidant is suitably present at a concentration of about 1 to about 100 mM, for example about 2 to about 80 mM, for example about 5 to about 50 mM, for example about 10 to about 50 mM, for example about 25 to about 50 mM.
  • the compositions of the present invention may further comprise a preservative, such as a phenolic or benzylic preservative.
  • the preservative is suitably selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, propyl paraben and methyl paraben, in particular phenol, m-cresol and benzyl alcohol, and mixtures thereof.
  • the preservative is suitably present at a concentration of about 10-100 mM, for example 20-80 mM, such as 25-50 mM.
  • the optimal concentration of the preservative in the composition is selected to ensure the composition passes the Pharmacopoeia Antimicrobial Effectiveness Test (USP ⁇ 51 >, Vol. 32).
  • the total ionic strength of the storage stable aqueous liquid solution compositions of the present invention is suitably less than 100 mM, for example less than 80 mM, for example less than 75 mM, for example less than 60 mM, for example less than 50 mM, for example less than 40 mM, less than 35 mM, less than 30 mM, less than 25 mM or less than 20 mM.
  • total ionic strength is used herein as the following function of the concentration of all ions in a solution: where c x is molar concentration of ion x (mol L' 3 ), z x is the net charge of ion c x .
  • the sum covers all ions (n) present in the solution excluding the contribution of dalbavancin or the pharmaceutically acceptable salt thereof.
  • aqueous solution refers to a solution in water, preferably distilled water, deionized water, water for injection, sterile water for injection or bacteriostatic water for injection.
  • the compositions of the present invention are aqueous liquid solution compositions and therefore, in embedments, comprise at least 75% (v/v) of water, such as at least 80% (v/v), at least 85% (v/v), at least 90% (v/v), or at least 95% (v/v) of water, e.g. sterile water for injection or bacteriostatic water for injection.
  • the present invention provides a storage stable aqueous liquid solution composition
  • a storage stable aqueous liquid solution composition comprising: dalbavancin or a pharmaceutically acceptable salt thereof, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; and a polyol, at a concentration of about 10-500 mM, for example about 50-400 mM, for example about 100-400 mM, for example 200-350 mM, for example 250-350 mM, such as about 300 mM; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant selected from the group consisting of an alkyl glycoside, a polysorbate, an alkyl ether of polyethylene glycol, a block copolymer of polyethylene glycol and polypropylene glycol, and an alkylphenyl ether of polyethylene glycol, and combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL
  • a polyol selected from the group consisting of PEG300, PEG400 propylene glycol, sucrose, glycerol, trehalose, lactose, glucose,
  • the present invention provides a storage stable aqueous liquid solution composition
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is a polysorbate surfactant, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80, and combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL
  • the present invention provides a storage stable aqueous liquid solution composition
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 20 or polysorbate 80, or combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL
  • the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of
  • the present invention provides a storage stable aqueous liquid solution composition
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 20 or polysorbate 80, or combinations thereof, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL
  • the present invention provides a storage stable aqueous liquid solution composition
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 80, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL
  • a polyol which is propylene glycol, at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM
  • the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition
  • a storage stable aqueous liquid solution composition comprising: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-15 mg/mL; and a polyol, which is propylene glycol, at a concentration of 250-350 mM, such as about 300 mM; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 80, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL
  • a polyol which is glucose, at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM
  • the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition
  • a storage stable aqueous liquid solution composition comprising: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-15 mg/mL; and a polyol, which is glucose, at a concentration of 250-350 mM, such as about 300 mM; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 80
  • a polyol which is glucose, at a concentration of 250-350 mM, such as about 300 mM
  • the present invention provides a storage stable aqueous liquid solution composition
  • a storage stable aqueous liquid solution composition comprising: dalbavancin, as dalbavancin hydrochloride, at a concentration of about 20 mg/mL; polysorbate 80 at a concentration of about 10 mg/mL; glucose at a concentration of about 300 mM; and acetate buffer at a concentration of about 10 mM; wherein the pH of the composition is about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; a polyol at a concentration of about 10-500 mM, for example about 50-400 mM, for example about 100-400 mM, for example 200-350 mM, for example 250-350 mM, such as about 300 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, selected from the group consisting of an alkyl glycoside, a polysorbate, an alkyl ether of polyethylene glycol, a block copolymer of polyethylene glycol and polypropylene glycol, and an alkylphenyl ether of polyethylene glycol, and combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; a polyol selected from the group consisting of PEG300, PEG400 propylene glycol, sucrose, glycerol, trehalose, lac
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is a polysorbate surfactant, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80, and combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; a polyol selected from the group consisting of propylene glycol, glycerol, mannitol, and glucose, and combinations thereof, at a concentration of about 10-500 mM, for example about 50-400 mM, for example about 100-400 mM, for example 200-350
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 20 or polysorbate 80, or combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; a polyol selected from the group consisting of propylene glycol and glucose at a concentration of about 10-500 mM, for example about 50-400 mM, for example about 100-400 mM, for example 200-350 mM, for example 250-350 mM, such as about 300 mM;
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 20 or polysorbate 80, or combinations thereof, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL; a polyol selected from the group consisting of propylene glycol and glucose at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM;
  • water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL; a polyol, which is propylene glycol, at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-15 mg/mL; a polyol, which is propylene glycol, at a concentration of 250-350 mM, such as about 300 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL; a polyol, which is glucose, at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-15 mg/mL; a polyol, which is glucose, at a concentration of 250-350 mM, such as about 300 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • the present invention provides a storage stable aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin, as dalbavancin hydrochloride, at a concentration of about 20 mg/mL; polysorbate 80 at a concentration of about 10 mg/mL; glucose at a concentration of about 300 mM; acetate buffer at a concentration of about 10 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is about 5.0.
  • the term “comprises”, and variations such as ‘comprises’ and ‘comprising’ means that the stated components are included in the compositions, but not to the exclusion of any other component or group of components other than those listed.
  • the term “consists of” means that no further components are included in the composition other than those listed.
  • the term “consists essentially of” means that specific further components can be present but said components do not materially affect the essential characteristics of the composition, and are typically present in a de minimis amount.
  • compositions of the invention may be considered storage stable if they meet the stability requirements for regulatory approval, for example as set out in the International Conference on Harmonization (ICH) Tripartite Guideline “Stability Testing of New Drug Substances and Products” which provides the stability testing requirements for a registration application within territories such as the European Union, Japan and the United States.
  • ICH International Conference on Harmonization
  • compositions of the invention are storage stable, i.e. they remain as a clear solution (free of visible particles) following storage.
  • the composition of the invention remains as a clear solution (e.g. as measured according to the Visual Assessment Method in the General Methods) following storage at 2-8 °C for an extended period of time, such as at least 6 months, at least 12 months, at least 18 months or at least 24 months.
  • Visible particles may be suitably detected by methods known to those skilled in the art, such as the Visual Assessment Method or RP-HPLC methods described in the General Methods section herein, or in 2.9.20. European Pharmacopoeia Monograph (Particulate Contamination: Visible Particles).
  • composition of the invention remains as a clear solution (e.g. as measured according to the Visual Assessment Method in the General Methods) following storage at 25 °C for at least 1 week, such as at least 2 weeks, at least 4 weeks or at least 8 weeks.
  • the composition of the invention comprises no more than 10% total impurities (by total weight of dalbavancin or pharmaceutically acceptable salt thereof in the composition) following storage at 2-8 °C for an extended period of time, such as at least 6 months, at least 12 months, at least 18 months or at least 24 months.
  • the composition of the invention comprises no more than 10% total impurities with (by total weight of dalbavancin or pharmaceutically acceptable salt thereof in the composition) following storage at 25 °C for at least 1 week, such as at least 2 weeks, at least 4 weeks or at least 8 weeks.
  • NDSRIs Nitrosamine Drug Substance-Related Impurities
  • NDSRIs relevant to compositions comprising dalbavancin or pharmaceutically acceptable salts thereof include, but are not limited to: /V-nitroso-dalbavancin aO; /V-nitroso-desmethyl- dalbavancin aO; /V-nitroso-dalbavancin a1 ; /V-nitroso-desmethyl-dalbavancin a1 ; /V-nitroso- dalbavancin bO; /V-nitroso-desmethyl-dalbavancin bO; /V-nitroso-dalbavancin b1 ; /V-nitroso- desmethyl-dalbavancin b1 ; and /V-nitroso-desmethyl-dalbavancin b2.
  • the nitrosamine impurities in the composition of the invention are within acceptable levels. More suitably, the level of nitrosamine impurities in the composition of the invention does not increase (e.g. does not increase more than about 20%, 10%, 5% or 1 %) compared to the level of nitrosamine impurities in the starting Active Pharmaceutical Ingredient (API).
  • the “starting API” refers to dalbavancin or the pharmaceutically acceptable salt thereof used to prepare the composition of the invention.
  • Liquid chromatography methods may be used for detecting nitrosamine impurities, such as LCMS/MS.
  • the level of nitrosamine impurities in the compositions may be expressed in parts per million (ppm) based on the weight of the drug substance containing amine.
  • MDD maximum daily dose
  • dalbavancin stability can also be tested via a microbiological bioassay that determines antibiotic potency.
  • the present invention also provides a container, containing a dose or a plurality of doses of the composition as described hereinabove.
  • the container is suitably a vial e.g. a vial made of plastic or glass.
  • a glass vial is a type 1 glass vial e.g. containing 80% silica and 10% boric oxide, with a small amount of sodium oxide and aluminium oxide.
  • the fill volume of the vial is 10 mL, 20 mL, 25 mL, 40 mL, 50 mL, 75 mL or 100 mL, for example the fill volume of the vial is 25 mL.
  • the present invention also provides an injection device containing the diluted composition as described hereinabove.
  • the injection device may be filled with a single dose of the composition as described herein.
  • the storage stable aqueous liquid solution composition of the invention is suitably diluted, in embodiments prior to administration. Once diluted, the resulting solution is usually administered by intravenous infusion.
  • a typical method for administration of a diluted composition of the invention involves transferring a volume of the storage stable aqueous liquid solution composition to a container which is suitably an intravenous (IV) solution bag or a bottle, where the volume of the diluted compositions to be administered is calculated according to the required dose and the volume of the container. Following thorough mixing of the diluted solution, the contents of the container can be administered to the patient.
  • IV intravenous
  • the container is an IV solution bag
  • it is suitably constructed from plastic such as PVC, polyolefin, polypropylene, a blend of PO and PP (polyolefin blend), polyurethane, or a material that is substantially free of PVC, plasticizers, adhesives and latex, such as DEHP (di(2- ethylhexyl) phthalate).
  • plastic such as PVC, polyolefin, polypropylene, a blend of PO and PP (polyolefin blend), polyurethane, or a material that is substantially free of PVC, plasticizers, adhesives and latex, such as DEHP (di(2- ethylhexyl) phthalate).
  • the container is a bottle
  • the volume of the IV solution bag or bottle is 50 ml to 1 L, e.g. 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 400 mL, 500
  • the storage stable aqueous liquid solution composition of the invention can be diluted in a pharmaceutically acceptable aqueous diluent such as 0.9% (w/v) saline, 5% (w/v) glucose in water, or water (e.g. sterile water for injection or bacteriostatic water for injection).
  • a pharmaceutically acceptable aqueous diluent such as 0.9% (w/v) saline, 5% (w/v) glucose in water, or water (e.g. sterile water for injection or bacteriostatic water for injection).
  • the storage stable aqueous liquid solution composition of the invention is diluted in a suitable aqueous diluent by mixing 1 volume part of the composition with 1-24 volume parts, such as 3-19 volume parts, such as 4-14 volume parts, (e.g. 9 volume parts) of the suitable aqueous diluent to achieve the described concentration of dalbavancin.
  • concentration of dalbavancin or pharmaceutically acceptable salt thereof in the resulting diluted composition is thus 2-24 times, such as 5-15 times (e.g. 10 times) lower than that in the storage stable aqueous liquid solution composition.
  • the concentration of dalbavancin or pharmaceutically acceptable salt thereof in the diluted composition is 2-25%, such as 5-15% (e.g. 10%) of the concentration in the storage stable aqueous liquid solution composition.
  • the diluted composition contains 0.5-10 mg/mL (e.g. 0.5-7.5 mg/mL, for example 1-5 mg/mL) dalbavancin (optionally in the form of a pharmaceutically acceptable salt e.g. the hydrochloride salt).
  • the present invention provides a diluted composition, i.e. a diluted form of the storage stable aqueous liquid solution composition, wherein said storage stable aqueous liquid solution composition is diluted with an aqueous diluent, for example selected from 0.9% saline, 5% glucose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection); and/or wherein the concentration of dalbavancin or pharmaceutically acceptable salt thereof in the diluted composition is 2-25%, for example 5- 25%, for example 5-15%, such as about 10% of the concentration in the storage stable aqueous liquid solution composition prior to dilution.
  • an aqueous diluent for example selected from 0.9% saline, 5% glucose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection); and/or wherein the concentration of dalbavancin or pharmaceutically acceptable salt thereof in the diluted composition is 2-25%, for example 5- 25%,
  • the present invention provides a ready-to-administer composition
  • a ready-to-administer composition comprising a storage stable liquid solution composition described herein, diluted with a diluent suitable for intravenous administration.
  • a ready-to-use or ready-to-administer composition does not require reconstitution before use, but the composition can be further diluted if present as a concentrated solution, or directly administered.
  • the ready-to-administer formulation is included at the required concentration and volume in a final administration device, such as an injection device (e.g. syringe) or infusion bag for administration to a patient.
  • the ready-to-administer or the diluted form of the composition of the invention is free of visible particles, i.e. it is clear and not opalescent as measured according to the procedures described herein.
  • the diluted composition of the invention is free of visible particles and is a colourless to slightly yellow solution.
  • the diluted composition is isotonic.
  • the diluted composition is slightly hypertonic.
  • the diluted composition is stable for at least 24 hours, preferably for at least 48 hours at 2-8 °C and room light and at least 24 hours, preferably for at least 48 hours at 25 °C and room light.
  • the present invention provides a method of preparing a solution i.e. a diluted composition, for administration, for example for intravenous administration, comprising diluting a storage stable aqueous liquid solution composition according to the invention with an aqueous diluent, for example wherein the aqueous diluent is selected from 0.9% saline, 5% glucose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection).
  • an aqueous diluent for example wherein the aqueous diluent is selected from 0.9% saline, 5% glucose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection).
  • the concentration of dalbavancin or pharmaceutically acceptable salt thereof in the diluted composition, prepared according to above-described method of the present invention is about 2 to about 25%, for example about 5 to about 15%, such as about 10% of the concentration in the storage stable aqueous liquid solution composition prior to dilution; and/or wherein the concentration of dalbavancin or a pharmaceutically acceptable salt thereof in the diluted composition, prepared according to above-described method of the present invention, is about 0.5 to about 10 mg/mL, for example about 0.5 to about 7.5 mg/mL, for example about 1 to about 5 mg/mL.
  • a diluted composition of the invention for example which is prepared from a storage stable aqueous liquid solution composition according to the invention, is for use in therapy.
  • a diluted composition of the invention for example which is prepared from a storage stable aqueous liquid solution composition according to the invention, is a pharmaceutical composition.
  • Dalbavancin (in particular dalbavancin hydrochloride) is indicated inter alia for the treatment bacterial infections, in particular bacterial infections caused by Gram-positive bacteria.
  • dalbavancin has antibiotic activity against Gram-positive bacteria including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus.
  • Dalbavancin (in particular dalbavancin hydrochloride) demonstrates antibiotic activity against Enterococcus faecium and Enterococcus faecalis.
  • dalbavancin in particular dalbavancin hydrochloride exhibits antibiotic activity against Gram-positive bacteria of the Bacillus spp., Listeria spp., and Corynebacterium spp.
  • Dalbavancin in particular dalbavancin hydrochloride
  • dalbavancin hydrochloride is one of the most widely used antibiotics in the treatment of methicillin-resistant Staphylococcus aureus (MRSA).
  • dalbavancin is particularly used to treat acute bacterial skin and skin structure infections (ABSSSI), in particular in adults, and in particular when said infections are caused by the aforementioned Gram-positive bacteria, including MRSA.
  • the present invention provides a diluted composition of the invention, for example which is prepared from a storage stable aqueous liquid solution composition according to the invention, for use in the treatment of a bacterial infection, in particular wherein the bacterial infection is caused by Gram-positive bacteria, for example wherein the Gram-positive bacteria is selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus anginosus, Streptococcus intermedius, Streptococcus viridans, Streptococcus constellatus, Streptococcus bovis, Enterococcus faecium, Enterococcus faecalis, Clostridium difficile, and Listeria monocytogenes.
  • the Gram-positive bacteria is selected from the group consisting of Staphylococcus aureus, Sta
  • the Gram-positive bacteria is suitably selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus anginosus, Streptococcus intermedius, Streptococcus viridans, Streptococcus constellatus, and Streptococcus bovis.
  • the bacterial infection is caused by methicillin-resistant and/or multidrug-resistant bacteria, such as a methicillin-resistant and/or multidrug-resistant Gram-positive bacteria, for example methicillin-resistant Staphylococcus aureus.
  • the present invention provides a diluted composition of the invention, for example which is prepared from a storage stable aqueous liquid solution composition according to the invention, for use in the treatment of acute bacterial skin and skin structure infections (ABSSSI), for example wherein said ABSSSI is caused Gram-positive bacteria.
  • ABSSSI acute bacterial skin and skin structure infections
  • the present invention provides use of a diluted composition of the invention, for example which is prepared from a storage stable aqueous liquid solution composition according to the invention, in the manufacture of a medicament for treating a bacterial infection, in particular wherein the bacterial infection is caused by Gram-positive bacteria.
  • the present invention provides use of such a diluted composition in the manufacture of a medicament for treating acute bacterial skin and skin structure infections (ABSSSI), for example wherein said ABSSSI is caused Gram-positive bacteria.
  • ABSSSSI acute bacterial skin and skin structure infections
  • the present invention provides a method of treating a bacterial infection, in particular wherein the bacterial infection is caused by Gram-positive bacteria, which comprises administering to a patient, particularly a human patient, in need thereof a therapeutically effective amount of a diluted composition described herein, which is suitably prepared from a storage stable aqueous liquid solution composition according to the invention.
  • the present invention provides a method of treating acute bacterial skin and skin structure infections (ABSSSI), for example wherein said ABSSSI is caused Gram-positive bacteria, which comprises administering to a patient, particularly a human patient, in need thereof a therapeutically effective amount of a diluted composition described herein.
  • ABSSSSI acute bacterial skin and skin structure infections
  • the diluted dalbavancin compositions of the present invention can be used as a sole therapy, or in combination with one or more further therapeutic agents.
  • the further therapeutic agent(s) is/are antibiotics, e.g. selected from the group consisting of rifampicin, an aminoglycoside (such as gentamicin), and a beta-lactam antibiotic (such as amoxicillin).
  • the present invention provides a diluted composition as described herein, which is suitably prepared from a storage stable aqueous liquid solution composition according to the invention, for use in treating a bacterial infection, in particular wherein the bacterial infection is caused by Gram-positive bacteria, with an antibiotic, e.g.
  • the present invention provides an antibiotic, e.g. selected from the group consisting of rifampicin, an aminoglycoside (such as gentamicin), and a beta-lactam antibiotic (such as amoxicillin) for use in treating a bacterial infection, in particular wherein the bacterial infection is caused by Gram-positive bacteria, with a diluted composition as described herein, which is suitably prepared from a storage stable aqueous liquid solution composition according to the invention.
  • the diluted dalbavancin compositions of the present invention may be administered (e.g. intravenously) in a therapeutically effective amount of dalbavancin or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount of dalbavancin or a pharmaceutically acceptable salt thereof can be present in an amount of, for example, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg or about 3000 mg.
  • the dalbavancin compositions of the present invention may be administered in a single dose of, for example, 1500 mg.
  • the dalbavancin compositions of the present invention can be administered in multiple doses, such as, for example, a 1000 mg dose followed by a 500 mg dose. If administered in multiple doses, administration is preferably at different time points, such as an initial dose of 1000 mg, then 500 mg after about 1 week. All physical parameters referred to herein e.g. pH, pKa etc are determined at 21 °C and standard pressure.
  • a storage stable aqueous liquid solution composition comprising:
  • Clause 2 The storage stable aqueous liquid solution composition according to clause 1 , comprising a pharmaceutically acceptable salt of dalbavancin, in particular wherein the pharmaceutically acceptable salt is selected from hydrochloride, citrate, formate, acetate, tartrate, sulphate, tosylate, nitrate, mesylate, napsylate, besylate, oxalate, maleate, phosphate, pamoate, fumarate, hippurate, succinate and carbonate.
  • the pharmaceutically acceptable salt is selected from hydrochloride, citrate, formate, acetate, tartrate, sulphate, tosylate, nitrate, mesylate, napsylate, besylate, oxalate, maleate, phosphate, pamoate, fumarate, hippurate, succinate and carbonate.
  • Clause 3 The storage stable aqueous liquid solution composition according to clause 2, comprising a pharmaceutically acceptable salt of dalbavancin, in particular dalbavancin hydrochloride.
  • Clause 4 The storage stable aqueous liquid solution composition according to any one of clauses 1 to 3, wherein the concentration of dalbavancin or a pharmaceutically acceptable salt thereof is about 5 to about 50 mg/mL, for example about 10 to about 40 mg/mL, for example about 10 to about 30 mg/mL, or about 20 mg/mL (based on weight of dalbavancin).
  • Clause 5 The storage stable aqueous liquid composition according to any one of clauses 1 to 4, wherein the non-ionic surfactant is selected from the group consisting of a polysorbate, an alkyl glycoside, an alkyl ether of polyethylene glycol, a block copolymer of polyethylene glycol and polypropylene glycol, and an alkylphenyl ether of polyethylene glycol, and combinations thereof.
  • the non-ionic surfactant is selected from the group consisting of a polysorbate, an alkyl glycoside, an alkyl ether of polyethylene glycol, a block copolymer of polyethylene glycol and polypropylene glycol, and an alkylphenyl ether of polyethylene glycol, and combinations thereof.
  • Clause 6 The storage stable aqueous liquid composition according to clause 5, wherein the non-ionic surfactant is a polysorbate surfactant, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.
  • Clause 7 The storage stable aqueous liquid composition according to clause 6, wherein the non-ionic surfactant is a polysorbate surfactant, such as polysorbate 20 or polysorbate 80.
  • Clause 8 The storage stable aqueous liquid composition according to clause 7, wherein the non-ionic surfactant is polysorbate 80.
  • Clause 9 The storage stable aqueous liquid composition according to clause 5, wherein the non-ionic surfactant is a block copolymer of polyethylene glycol and polypropylene glycol, such as poloxamer 188, poloxamer 407, poloxamer 171 and poloxamer 185.
  • the non-ionic surfactant is a block copolymer of polyethylene glycol and polypropylene glycol, such as poloxamer 188, poloxamer 407, poloxamer 171 and poloxamer 185.
  • Clause 10 The storage stable aqueous liquid composition according to clause 9, wherein the non-ionic surfactant is poloxamer 188.
  • Clause 11 The storage stable aqueous liquid composition according to any one of clauses 1 to 10, wherein the total concentration of the non-ionic surfactant is about 0.5 mg/mL or more, for example about 1 mg/mL or more, for example about 2 mg/mL or more, for example about 2.5 mg/mL or more, for example about 4 mg/mL or more, for example about 5 mg/mL or more.
  • Clause 12 The storage stable aqueous liquid composition according to any one of clauses 1 to 11 , wherein the total concentration of the non-ionic surfactant is about 30 mg/mL or less, for example about 25 mg/mL or less, for example about 20 mg/mL or less, for example about 18 mg/mL or less, for example about 16 mg/mL or less, for example about 15 mg/mL or less.
  • Clause 13 The storage stable aqueous liquid composition according to any one of clauses 1 to 12, wherein the total concentration of the non-ionic surfactant is about 0.5 to about 30 mg/mL, for example about 0.5 to about 25 mg/mL, for example about 1 to about 20 mg/mL, for example about 2 to about 20 mg/mL, for example about 5 to about 20 mg/mL or about 2- to about 18 mg/mL, for example about 5 to about 15 mg/mL, or about 2 to about 15 mg/mL.
  • the total concentration of the non-ionic surfactant is about 0.5 to about 30 mg/mL, for example about 0.5 to about 25 mg/mL, for example about 1 to about 20 mg/mL, for example about 2 to about 20 mg/mL, for example about 5 to about 20 mg/mL or about 2- to about 18 mg/mL, for example about 5 to about 15 mg/mL, or about 2 to about 15 mg/mL.
  • Clause 14 The storage stable aqueous liquid composition according to any one of clauses 1 to 13, wherein the polyol is selected from the group consisting of PEG300, PEG400 propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol and mannitol, and combinations thereof.
  • the polyol is selected from the group consisting of PEG300, PEG400 propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorbitol and mannitol, and combinations thereof.
  • Clause 15 The storage stable aqueous liquid composition according to clause 14, wherein the polyol is selected from the group consisting of propylene glycol, glycerol, mannitol, and glucose, and combinations thereof.
  • Clause 16 The storage stable aqueous liquid composition according to clause 15, wherein the polyol is selected from the group consisting of propylene glycol and glucose.
  • Clause 17 The storage stable aqueous liquid composition according to clause 16, wherein the polyol is propylene glycol.
  • Clause 18 The storage stable aqueous liquid composition according to clause 16, wherein the polyol is glucose.
  • Clause 19 The storage stable aqueous liquid composition according to any one of clauses 1 to 18, wherein the total concentration of the polyol is about 10-500 mM, for example about 10-450 mM, for example about 10-400 mM, for example about 20-400 mM, for example about 50-400 mM, for example about 100-400 mM, for example about 150-400 mM, for example about 150-350 mM, for example 200-350 mM, for example 250-350 mM, such as about 300 mM.
  • Clause 20 The storage stable aqueous liquid composition according to any one of clauses 1 to 19, wherein the pH of the composition is in the range about 3.5 to about 7.0, for example about 3.5 to about 6.5, for example about 3.5 to about 6.0, for example about 4.0 to about 6.0, for example about 4.0 to about 5.5, for example about 4.0 to about 5.0, or about 5.0 to about 5.5, or about 4.5, or about 5.0, or about 5.5.
  • Clause 21 The storage stable aqueous liquid composition according to clause 20, wherein the pH of the composition is in the range of about 4.5 to about 5.5, such as about 5.0.
  • Clause 22 The storage stable aqueous liquid composition according to any one of clauses 1 to 21 , further comprising an additional salt, that is any salt other than a salt which is included in the composition as a result of a specific formulation excipient, e.g. dalbavancin, at a total concentration of about 50 mM or less, for example about 40 mM or less, for example about 25 mM or less, for example about 10 mM or less, for example about 5 mM or less.
  • a specific formulation excipient e.g. dalbavancin
  • Clause 23 The storage stable aqueous liquid composition according to clause 22, further comprising an additional salt, that is any salt other than a salt which is included in the composition as a result of a specific formulation excipient, e.g. dalbavancin, at a total concentration of at a total concentration of 0-50 mM, for example 0-40 mM, for example 0-30 mM, for example 0-20 mM, for example 0-10 mM, for example 0-5 mM.
  • a specific formulation excipient e.g. dalbavancin
  • Clause 24 The storage stable aqueous liquid composition according to clause 22 or clause 23, wherein the composition is substantially free of, e.g. is free of, an additional salt, that is any salt other than a salt which is included in the composition as a result of a specific formulation excipient, e.g. dalbavancin.
  • an additional salt that is any salt other than a salt which is included in the composition as a result of a specific formulation excipient, e.g. dalbavancin.
  • Clause 25 The storage stable aqueous liquid composition according to any one of clauses 22 to 24, wherein the additional salt is sodium chloride, sodium lactate, or combinations thereof.
  • Clause 26 The storage stable aqueous liquid composition according to any one of clauses 1 to 25, wherein the composition is substantially free of, e.g. is free of, N-acetyl-D-alanine and/or N-acetyl-glycine and/or N-acetyl-methionine.
  • Clause 27 The storage stable aqueous liquid composition according to clause 26, wherein the composition is substantially free of, e.g. is free of, N-acetyl-D-alanine and N-acetyl-glycine and N-acetyl-methionine.
  • Clause 28 The storage stable aqueous liquid composition according to any one of clauses 1 to 27, wherein the compositions is substantially free of, e.g. is free of, any neutral amino acid or pharmaceutically acceptable salt thereof.
  • Clause 29 The storage stable aqueous liquid composition according to clause 28, wherein the compositions is substantially free of, e.g. is free of, glycine, methionine, proline, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, asparagine and glutamine, and pharmaceutically acceptable salts thereof.
  • Clause 30 The storage stable aqueous liquid composition according to any one of clauses 1 to 29, wherein the total ionic strength of the composition, excluding the contribution of dalbavancin or the pharmaceutically acceptable salt thereof, is suitably less than 100 mM, for example less than 80 mM, for example less than 75 mM, for example less than 60 mM, for example less than 50 mM, for example less than 40 mM, less than 35 mM, less than 30 mM, less than 25 mM or less than 20 mM.
  • Clause 31 The storage stable aqueous liquid composition according to any one of clauses 1 to 30, wherein the composition further comprises a buffer.
  • Clause 32 The storage stable aqueous liquid composition according to clause 31 , wherein the buffer is selected from the group consisting of maleate, sulphite, aspartame, aspartate, glutamate, tartrate, gluconate, adenine, succinate, ascorbate, benzoate, phenylacetate, gallate, cytosine, p-aminobenzoic acid, sorbate, acetate, propionate, alginate, urate, 2-(/V- morpholino)ethanesulphonic acid, bicarbonate, bis(2-hydroxyethyl) iminotris(hydroxymethyl)methane, / ⁇ /-(2-acetamido)-2-iminodiacetic acid, 2-[(2-amino-2- oxoethyl)amino]ethanesulphonic acid, piperazine-/V,/V’-bis(2-ethanesulphonic acid) (PIPES), phosphate, /V,/
  • Clause 34 The storage stable aqueous liquid composition according to clause 33, wherein the buffer is acetate buffer.
  • Clause 35 The storage stable aqueous liquid composition according to any one of clauses 31 to 34, wherein the buffer comprises ionisable groups with pK a within 2 units of the pH of the composition.
  • Clause 36 The storage stable aqueous liquid composition according to clause 35, wherein the buffer comprises ionisable groups with pK a within 1 unit of the pH of the composition.
  • Clause 37 The storage stable aqueous liquid composition according to any one of clauses 31 to 36, wherein the total concentration of the buffer is about 1 to about 20 mM, for example about 2 to about 20 mM, for example about 2 to about 18 mM, for example about 4 to about 16 mM, for example about 5 to about 15 mM, for example about 5 to about 12 mM, for example about 5 to about 10 mM.
  • Clause 38 The storage stable aqueous liquid solution composition according to any one of clauses 1 to 37, wherein the composition further comprises an antioxidant.
  • Clause 39 The storage stable aqueous liquid solution composition according to clause 38, wherein the antioxidant is selected from the group consisting of monothioglycerol, butylated hydroxyanisole, glutathione (reduced), ascorbate, and cysteine.
  • the antioxidant is selected from the group consisting of monothioglycerol, butylated hydroxyanisole, glutathione (reduced), ascorbate, and cysteine.
  • Clause 40 The storage stable aqueous liquid solution composition according to clause 38 or clause 39, wherein the antioxidant is present at a concentration of about 1 to about 100 mM, for example about 2 to about 80 mM, for example about 5 to about 50 mM, for example about 10 to about 50 mM, for example about 25 to about 50 mM.
  • Clause 41 The storage stable aqueous liquid solution composition according to any one of clauses 1 to 40, wherein the composition further comprises a preservative, such as a phenolic or benzylic preservative.
  • a preservative such as a phenolic or benzylic preservative.
  • Clause 42 The storage stable aqueous liquid solution composition according to clause 41 , wherein the preservative is selected from the group consisting of phenol, m-cresol, chlorocresol, benzyl alcohol, propyl paraben and methyl paraben.
  • Clause 43 The storage stable aqueous liquid solution composition according to clause 42, wherein the preservative is selected from the group consisting of phenol, m-cresol and benzyl alcohol, and mixtures thereof.
  • Clause 44 The storage stable aqueous liquid solution composition according to any one of clauses 41 to 43, wherein the preservative is present at a concentration of 10-100 mM, for example 20-80 mM, such as 25-50 mM.
  • the storage stable aqueous liquid solution composition according to clause 1 comprising: dalbavancin or a pharmaceutically acceptable salt thereof, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; and a polyol, at a concentration of about 10-500 mM, for example about 50-400 mM, for example about 100-400 mM, for example 200-350 mM, for example 250-350 mM, such as about 300 mM; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about 4.0 to about 6.0, such as about 5.0.
  • the storage stable aqueous liquid solution composition according to clause 1 comprising: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, selected from the group consisting of an alkyl glycoside, a polysorbate, an alkyl ether of polyethylene glycol, a block copolymer of polyethylene glycol and polypropylene glycol, and an alkylphenyl ether of polyethylene glycol, and combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; and a polyol selected from the group consisting of PEG300, PEG400 propylene glycol, sucrose, glycerol, trehalose, lactose, glucose, sorb
  • the storage stable aqueous liquid solution composition according to clause 1 comprising: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is a polysorbate surfactant, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80, and combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; and a polyol selected from the group consisting of propylene glycol, glycerol, mannitol, and glucose, and combinations thereof, at a concentration of about 10-500 mM, for example about 50-400 mM, for example about 100-400 mM, for example 200-350 mM, for example 250-350
  • the storage stable aqueous liquid solution composition according to clause 1 comprising: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 20 or polysorbate 80, or combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; and a polyol selected from the group consisting of propylene glycol and glucose at a concentration of about 10-500 mM, for example about 50-400 mM, for example about 100-400 mM, for example 200-350 mM, for example 250-350 mM, such as about 300 mM; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about
  • the storage stable aqueous liquid solution composition according to clause 1 comprising: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 20 or polysorbate 80, or combinations thereof, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL; and a polyol selected from the group consisting of propylene glycol and glucose at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 20 or polysorbate 80, or combinations
  • the storage stable aqueous liquid solution composition according to clause 1 comprising: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL; and a polyol, which is propylene glycol, at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 80
  • a polyol which is propylene glycol
  • the storage stable aqueous liquid solution composition according to clause 1 comprising: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-15 mg/mL; and a polyol, which is propylene glycol, at a concentration of 250-350 mM, such as about 300 mM; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 80
  • a polyol which is propylene glycol
  • the storage stable aqueous liquid solution composition according to clause 1 comprising: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL; and a polyol, which is glucose, at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 80
  • a polyol which is glucose, at a concentration of 100-400 mM, for example 250
  • the storage stable aqueous liquid solution composition according to clause 1 comprising: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-15 mg/mL; and a polyol, which is glucose, at a concentration of 250-350 mM, such as about 300 mM; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 80
  • a polyol which is glucose, at a concentration of 250-350 mM, such as about 300 mM
  • the pH of the composition is in the range of about
  • Clause 54 The storage stable aqueous liquid solution composition according to clause 1 comprising: dalbavancin, as dalbavancin hydrochloride, at a concentration of about 20 mg/mL; polysorbate 80 at a concentration of about 10 mg/mL; glucose at a concentration of about 300 mM; and acetate buffer at a concentration of about 10 mM; wherein the pH of the composition is about 5.0.
  • Clause 55 The storage stable aqueous liquid solution composition according to clause 1 consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; a polyol at a concentration of about 10-500 mM, for example about 50-400 mM, for example about 100-400 mM, for example 200-350 mM, for example 250-350 mM, such as about 300 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about 4.0 to about 6.0, such as about 5.0.
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant selected from the group consisting of an alkyl glycoside, a polysorbate, an alkyl ether of polyethylene glycol, a block copolymer of polyethylene glycol and polypropylene glycol, and an alkylphenyl ether of polyethylene glycol, and combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL
  • a polyol selected from the group consisting of PEG300, PEG400 propylene glycol, sucrose, glycerol, trehalose, lacto
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about 4.0 to about 6.0, such as about 5.0.
  • aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is a polysorbate surfactant, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80, and combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; a polyol selected from the group consisting of propylene glycol, glycerol, mannitol, and glucose, and combinations thereof, at a concentration of about 10-500 mM, for example about 50-400 mM, for example about 100-400 mM, for example 200-350
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about 4.0 to about 6.0, such as about 5.0.
  • Clause 58 The storage stable aqueous liquid solution composition according to clause 1 consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 5-50 mg/mL, for example 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 20 or polysorbate 80, or combinations thereof, at a concentration of 1-20 mg/mL, for example 2-20 mg/mL, for example 5-20 mg/mL, for example 5-15 mg/mL; a polyol selected from the group consisting of propylene glycol and glucose at a concentration of about 10-500 mM, for example about 50-400 mM, for example about 100-400 mM, for example 200-350 mM, for example 250-350 mM, such as about 300 mM;
  • dalbavancin or a pharmaceutically acceptable salt thereof
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 3.0 to about 7.0, for example in the range of about 4.0 to about 6.0, such as about 5.0.
  • aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 20 or polysorbate 80, or combinations thereof, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL;
  • water e.g. water for injection
  • a polyol selected from the group consisting of propylene glycol and glucose at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM
  • optionally a buffer optionally an antioxidant
  • optionally a preservative wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • dalbavancin or a pharmaceutically acceptable salt thereof e.g. dalbavancin hydrochloride
  • a non-ionic surfactant which is polysorbate 80, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL
  • a polyol which is propylene glycol, at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • aqueous liquid solution composition consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-15 mg/mL; a polyol, which is propylene glycol, at a concentration of 250-350 mM, such as about 300 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • Clause 62 The storage stable aqueous liquid solution composition according to clause 1 consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-20 mg/mL, for example 5-15 mg/mL; a polyol, which is glucose, at a concentration of 100-400 mM, for example 250-350 mM, such as about 300 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • Clause 63 The storage stable aqueous liquid solution composition according to clause 1 consisting of, or consisting essentially of: dalbavancin or a pharmaceutically acceptable salt thereof, e.g. dalbavancin hydrochloride, at a concentration of 10-30 mg/mL, or about 20 mg/mL; a non-ionic surfactant, which is polysorbate 80, at a concentration of 5-15 mg/mL; a polyol, which is glucose, at a concentration of 250-350 mM, such as about 300 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is in the range of about 4.0 to about 6.0, such as about 5.0.
  • Clause 64 The storage stable aqueous liquid solution composition according to clause 1 consisting of, or consisting essentially of: dalbavancin, as dalbavancin hydrochloride, at a concentration of about 20 mg/mL; polysorbate 80 at a concentration of about 10 mg/mL; glucose at a concentration of about 300 mM; acetate buffer at a concentration of about 10 mM;
  • - water e.g. water for injection; optionally a buffer; optionally an antioxidant; and optionally a preservative; wherein the pH of the composition is about 5.0.
  • Clause 65 A diluted form of the storage stable aqueous liquid solution composition according to any one of clauses 1 to 64, wherein the storage stable aqueous liquid solution composition is diluted with an aqueous diluent, for example selected from 0.9% saline, 5% glucose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection).
  • an aqueous diluent for example selected from 0.9% saline, 5% glucose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection).
  • Clause 66 The diluted form of the storage stable aqueous liquid solution composition according to clause 65, wherein the concentration of dalbavancin or pharmaceutically acceptable salt thereof in the diluted composition is about 2 to about -25%, for example about 5 to about 15%, such as about 10% of the concentration in the storage stable aqueous liquid solution composition prior to dilution.
  • Clause 67 The diluted form of the storage stable aqueous liquid solution composition according to clause 65 or clause 66, wherein the concentration of dalbavancin or pharmaceutically acceptable salt thereof in the diluted composition is about 0.5 to about 10 mg/mL, for example about 0.5 to about 7.5 mg/mL, for example about 1 to about 5 mg/mL.
  • Clause 68 The diluted form of the storage stable aqueous liquid solution composition according to any one of clauses 65 to 67, wherein the diluted composition is a pharmaceutical composition.
  • Clause 69 The diluted form of the storage stable aqueous liquid solution composition according to any one of clauses 65 to 68, wherein the diluted composition is for use in therapy.
  • Clause 70 The diluted form of the storage stable aqueous liquid solution composition for use according to clause 69, for use in the treatment of a bacterial infection.
  • Clause 71 The diluted form of the storage stable aqueous liquid solution composition for use according to clause 70, wherein the bacterial infection is caused by Gram-positive bacteria, in particular wherein the Gram-positive bacteria is selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus anginosus, Streptococcus intermedius, Streptococcus viridans, Streptococcus constellatus, Streptococcus bovis, Enterococcus faecium, Enterococcus faecalis, Clostridium difficile, and Listeria monocytogenes.
  • Gram-positive bacteria is selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Strept
  • Clause 72 The diluted form of the storage stable aqueous liquid solution composition for use according to clause 71 , wherein the bacterial infection is caused Gram-positive bacteria selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus anginosus, Streptococcus intermedius, Streptococcus viridans, Streptococcus constellatus, and Streptococcus bovis.
  • Gram-positive bacteria selected from the group consisting of Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus anginosus, Streptococcus intermedius, Streptococcus virid
  • Clause 73 The diluted form of the storage stable aqueous liquid solution composition for use according to any one of clauses 70 to 72, wherein the bacterial infection is caused by methicillin-resistant and/or multidrug-resistant bacteria.
  • Clause 74 The diluted form of the storage stable aqueous liquid solution composition for use according to clause 73, wherein the bacterial infection is caused by methicillin-resistant Staphylococcus aureus (MRSA).
  • MRSA methicillin-resistant Staphylococcus aureus
  • Clause 76 A method of treating a bacterial infection, in particular wherein said bacterial infection is caused by Gram-positive bacteria, which comprises administering to a patient in need thereof a therapeutically effective amount of a diluted form of the storage stable aqueous liquid solution composition according to any one of clauses 65 to 68.
  • Clause 77 Use of a diluted form of the storage stable aqueous liquid solution composition according to any one of clauses 65 to 68, in the manufacture of a medicament for treating a bacterial infection, in particular wherein said bacterial infection is caused by Gram-positive bacteria.
  • Clause 78 The diluted form of the storage stable aqueous liquid solution composition for use, method, or use, according to any one of clauses 69 to 77, for use in combination with one or more other therapeutic agents.
  • Clause 79 The diluted form of the storage stable aqueous liquid solution composition for use, method, or use, according to clause 78, wherein the further therapeutic agent(s) is/are antibiotics, e.g. selected from the group consisting of rifampicin, an aminoglycoside (such as gentamicin), and a beta-lactam antibiotic (such as amoxicillin).
  • antibiotics e.g. selected from the group consisting of rifampicin, an aminoglycoside (such as gentamicin), and a beta-lactam antibiotic (such as amoxicillin).
  • Clause 80 A method of preparing a solution for intravenous administration by diluting a storage stable aqueous liquid solution composition according to any one of clauses 1 to 64, with an aqueous diluent, for example selected from 0.9% saline, 5% glucose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection).
  • an aqueous diluent for example selected from 0.9% saline, 5% glucose in water, and water (e.g. sterile water for injection or bacteriostatic water for injection).
  • Clause 81 The method according to clause 80, wherein the concentration of dalbavancin or pharmaceutically acceptable salt thereof in the diluted composition is about 2 to about 25%, for example about 5 to about 15%, such as about 10% of the concentration in the storage stable aqueous liquid solution composition prior to dilution.
  • Clause 82 The method according to clause 80 or clause 81 , wherein the concentration of dalbavancin or a pharmaceutically acceptable salt thereof in the diluted composition is about 0.5 to about 10 mg/mL, for example about 0.5 to about 7.5 mg/mL, for example about 1 to about 5 mg/mL.
  • a vial which is suitably a glass vial, containing the storage stable aqueous liquid solution composition according to any one of clauses 1 to 64.
  • An intravenous (IV) solution bag which is suitably constructed from plastic such as PVC, polyolefin, polypropylene, a blend of PO and PP (polyolefin blend), polyurethane, or a material that is substantially free of PVC, plasticizers, adhesives and latex, such as DEHP (di(2- ethylhexyl) phthalate), containing the diluted composition according to any one of clauses 65 to 68.
  • plastic such as PVC, polyolefin, polypropylene, a blend of PO and PP (polyolefin blend), polyurethane, or a material that is substantially free of PVC, plasticizers, adhesives and latex, such as DEHP (di(2- ethylhexyl) phthalate), containing the diluted composition according to any one of clauses 65 to 68.
  • Clause 86 An injection device containing the diluted composition according to any one of clauses 65 to 68. Examples
  • High performance reverse phase chromatography is performed using a C18 column and a UV detector (280 nm).
  • the sample comprising dalbavancin (or pharmaceutically acceptable salt thereof) is injected into Mobile Phase A and subsequently eluted using a gradient of Mobile Phase A and Mobile Phase B.
  • Mobile Phase A is a mixture of 25 mM sodium dihydrogen phosphate buffer and acetonitrile in a volume per volume ratio of 86:14.
  • Mobile Phase B is a mixture of 25 mM sodium dihydrogen phosphate buffer and acetonitrile in a volume per volume ratio of 72:28.
  • Visible particles are suitably detected using the 2.9.20. European Pharmacopoeia Monograph (Particulate Contamination: Visible Particles).
  • the apparatus required consists of a viewing station comprising:
  • an adjustable lampholder fitted with a suitable, shaded, white-light source and with a suitable light diffuser (a viewing illuminator containing two 13 W fluorescent tubes, each 525 mm in length, is suitable).
  • the intensity of illumination at the viewing point is maintained between 2000 lux and 3750 lux.
  • any adherent labels are removed from the container and the outside washed and dried.
  • the container is gently swirled or inverted, ensuring that air bubbles are not introduced, and observed for about 5 s in front of the white panel.
  • the procedure is repeated in front of the black panel. The presence of any particles and opalescence is recorded.
  • the visual scores are ranked as follows:
  • HIAC is performed via Light Obscuration using a Beckman-Coulter HIAC 9703.
  • the sample comprising dalbavancin (or pharmaceutically acceptable salt thereof) at 20 mg/mL is subjected to light obscuration to determine particle size.
  • the particle size threshold tested in the Examples below is >10 pm. Results are expressed as number of particles >10 pm per 25 mL container.
  • Multi-Angle Dynamic Light Scattering was performed using a Malvern Zetasizer Ultra Red (ZSU3305).
  • MADLS uses three different angles (back 173°, side 90° and forward 13° scattering detection) and combines the information obtained into one size distribution plot.
  • the sample comprising dalbavancin (or pharmaceutically acceptable salt thereof) is placed in a ZEN2112 cuvette and subjected to MADLS at 20 mg/mL. Results are expressed as the wavelength (nm) of the highest intensity peak observed.
  • Example 1 Effect of pH on the stability of dalbavancin compositions
  • Table 1 Stability of dalbavancin (as hydrochloride, 20 mg/mL) compositions assessed using RP-HPLC.
  • Example 2 Effect of a non-ionic surfactant on the stability of dalbavancin compositions
  • Table 2 Stability of dalbavancin (as hydrochloride, 20 mg/mL) compositions assessed using RP-HPLC.
  • a non-ionic surfactant which is either polysorbate 80 or poloxamer 188
  • each of polysorbate 80 and poloxamer 188 provides a similar increase in dalbavancin stability.
  • non-ionic surfactants, as represented by polysorbate 80 improve the stability of dalbavancin compositions in a concentration-dependent manner. It should be noted that such an improvement in dalbavancin stability is specifically observed in the presence of a polyol, in particular propylene glycol.
  • Example 3 Effect of charged species, such as charged tonicity modifiers, on the stability of dalbavancin compositions
  • Table 3 Stability of dalbavancin (as hydrochloride, 20 mg/mL) compositions assessed using the Visual Assessment Method.
  • Example 4 Effect of a polyol on the stability of dalbavancin compositions
  • Example 5 Predicting the effect of a further polyol on the stability of dalbavancin compositions
  • the present inventors sought to further investigate the predicted effect of a further polyol, glucose, on the stability of dalbavancin compositions following storage for 4 weeks at 40 °C.
  • the present inventors have performed a design of experiments (DOE) study which is a well understood tool for predicting the effect of specific excipients on the stability of formulations, such as the dalbavancin compositions described herein, based on input experimental data.
  • DOE design of experiments
  • dalbavancin composition F16 Stability of dalbavancin composition F16 was followed for up to 4 weeks at 40 °C and 26 weeks at 2-8 °C using analytical methods described in General Methods.
  • the composition contained 20 mg/mL dalbavancin (as hydrochloride) and 10 mM acetate buffer and was adjusted to pH 5.0.
  • Table 5 shows additional formulation ingredients of formulation F16 and the increase in % impurities (RP-HPLC) observed in the composition following storage for 4 weeks at 40 °C and 26 weeks at 2-8 °C.
  • Table 5 Stability of a dalbavancin (as hydrochloride, 20 mg/mL) composition assessed using RP-HPLC.
  • composition F16 Stability of composition F16 is presented in more detail in Table 6, using additional analytical methods. To provide the most comprehensive summary of dalbavancin stability the results are presented as absolute values at each time-point in Table 6.
  • Table 6 Stability of a dalbavancin (as hydrochloride, 20 mg/mL) composition assessed using RP-HPLC, Visual Analysis, MADLS and HIAC.
  • Formulation F16 has a very good stability in terms of total impurities (assessed by RP-HPLC), particle size (assessed by DLS) and very low count of subvisible particles.
  • Example 7 Effect of N-acetyl-D-alanine on the solubility of dalbavancin compositions
  • N-acetyl-D-alanine was studied in the presence of mannitol (i.e. a polyol).
  • Formulations F17 and F18 contained 20 mg/mL dalbavancin (as hydrochloride) and 5 mM acetate buffer and were adjusted to pH 4.0.
  • Table 7 shows additional formulation ingredients of formulations F17 and F18 and the visual observation following the preparation of the formulations.
  • the presence of N-acetyl-D-alanine resulted in immediate opalescence and dalbavancin precipitation. N-acetyl-D-alanine is thus detrimental to dalbavancin stability.
  • Formulations F19 and F20 contained 20 mg/mL dalbavancin (as hydrochloride) and 5 mM acetate buffer and were adjusted to pH 4.0. D/L-lactic acid was added to the desired concentration. Due to the pH adjustment (pH 4.0) and the pKa of lactic acid (3.7) more than 50% of this additive will be present in the form of sodium D/L-lactate.
  • Table 8 shows additional formulation ingredients of formulations F19 and F20 as well as the increase in total impurities after 4 weeks at 40°C following the preparation of the formulations.
  • Table 8 Stability of dalbavancin (as hydrochloride, 20 mg/mL) compositions assessed using RP-HPLC.
  • a dalbavancin composition with improved stability is provided by the presence of (i) a non-ionic surfactant, such as a polysorbate or poloxamer surfactant, and (ii) a polyol, such as propylene glycol or glucose.
  • a non-ionic surfactant such as a polysorbate or poloxamer surfactant
  • a polyol such as propylene glycol or glucose
  • a non-ionic surfactant specifically polysorbate 80 or poloxamer 188
  • a polyol specifically propylene glycol
  • glucose an alternative polyol
  • DAE robust design of experiments

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Abstract

L'invention concerne des compositions de dalbavancine stables au stockage. En particulier, la composition stable au stockage est une solution liquide aqueuse comprenant : de la dalbavancine ou un sel pharmaceutiquement acceptable de celle-ci ; un tensioactif non ionique ; et un polyol, le pH de la composition étant dans la plage d'environ 3,0 à environ 7,0.
PCT/EP2025/061747 2024-04-29 2025-04-29 Compositions comprenant de la dalbavancine Pending WO2025229010A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040224908A1 (en) * 2002-11-18 2004-11-11 Vicuron Pharmaceuticals, Inc. Stable compositions of dalbavancin
US7119061B2 (en) 2002-11-18 2006-10-10 Vicuron Pharmaceuticals, Inc. Dalbavancin compositions for treatment of bacterial infections
WO2016071495A1 (fr) 2014-11-06 2016-05-12 Xellia Pharmaceuticals Aps Compositions de glycopeptides
WO2018096556A1 (fr) 2016-11-23 2018-05-31 Gufic Biosciences Limited Compositions pharmaceutiques lyophilisées de dalbavancine
US10471149B2 (en) 2012-11-29 2019-11-12 Insmed Incorporated Stabilized vancomycin formulations
US20200171124A1 (en) * 2016-04-15 2020-06-04 Lupin Limited Topical compositions for ophthalmic and otic use
WO2020185518A1 (fr) 2019-03-08 2020-09-17 Emphascience, Inc. Formulations pharmaceutiques stables de médicaments peptidiques et protéiques
US20220040309A1 (en) 2015-08-05 2022-02-10 Children's Medical Center Corporation Compositions with permeation enhancers for drug delivery
US20220133845A1 (en) 2020-10-30 2022-05-05 Somerset Therapeutics, Llc Glycopeptide antibiotics liquid formulations and methods and uses thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040224908A1 (en) * 2002-11-18 2004-11-11 Vicuron Pharmaceuticals, Inc. Stable compositions of dalbavancin
US7119061B2 (en) 2002-11-18 2006-10-10 Vicuron Pharmaceuticals, Inc. Dalbavancin compositions for treatment of bacterial infections
US10471149B2 (en) 2012-11-29 2019-11-12 Insmed Incorporated Stabilized vancomycin formulations
WO2016071495A1 (fr) 2014-11-06 2016-05-12 Xellia Pharmaceuticals Aps Compositions de glycopeptides
US20220040309A1 (en) 2015-08-05 2022-02-10 Children's Medical Center Corporation Compositions with permeation enhancers for drug delivery
US20200171124A1 (en) * 2016-04-15 2020-06-04 Lupin Limited Topical compositions for ophthalmic and otic use
WO2018096556A1 (fr) 2016-11-23 2018-05-31 Gufic Biosciences Limited Compositions pharmaceutiques lyophilisées de dalbavancine
WO2020185518A1 (fr) 2019-03-08 2020-09-17 Emphascience, Inc. Formulations pharmaceutiques stables de médicaments peptidiques et protéiques
US20220133845A1 (en) 2020-10-30 2022-05-05 Somerset Therapeutics, Llc Glycopeptide antibiotics liquid formulations and methods and uses thereof

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