Liquid Dalbavancin Compositions

Abstract

The present disclosure relates to stable aqueous compositions of dalbavancin, processes for making such compositions, and the use of such compositions for the treatment of patients in need thereof.

Description

[Technical Field]

[0001] The present disclosure relates to stable aqueous compositions of dalbavancin, processes for making such compositions, and the use of such compositions for the treatment of patients in need thereof. Such compositions provide good stability. [Background technology]

[0002] Dalbavancin is a semisynthetic lipoglycopeptide that exerts its bactericidal effect by disrupting cell wall biosynthesis. It binds to D-alanyl-D-alanyl residues on growing peptidoglycan chains, preventing transpeptidation and preventing peptidoglycan elongation and cell wall formation.

[0003] Dalbavancin is produced by fermenting selected strains of the genus Nonomuraea to produce the natural glycopeptide complex A-40926. This precursor is then selectively esterified at the carboxyl groups of its sugar moiety, amidated at its peptidyl carboxyl groups, and saponified at the esters of the N-acylaminoglucuronic acid carboxyl groups. The result is a complex mixture of two closely related structural families—A and B—that can be further subdivided into a total of five subtypes (Table 1).

[0004] The structure of dalbavancin is shown below.

[0005] [ka]

[0006] [Table 1]

[0007] Dalbavancin is commercially available under the trade name DALVANCE® in the United States and XYDALBA® in Europe. The commercial product is a lyophilized powder containing dalbavancin hydrochloride, lactose monohydrate, and mannitol. It may also contain sodium hydroxide and / or hydrochloric acid. The lyophilized powder must be reconstituted and diluted before administration to patients. The DALVANCE® (dalbavancin) injection package insert instructs users to use either Sterile Water for Injection (USP) or 5% Dextrose Injection (USP) to reconstitute the lyophilized product, followed by dilution with 5% Dextrose Injection (USP) alone to a final concentration of 1 mg / mL to 5 mg / mL.

[0008] The total time between reconstitution and dilution and administration should not exceed 48 hours. Dalbavancin is marketed for the treatment of adult and pediatric patients with acute bacterial skin and skin structure infections (ABSSSIs) caused by specified susceptible strains of Gram-positive organisms. Summary of the Invention [Problem to be solved by the invention]

[0009] What is needed is a stable liquid composition of dalbavancin that does not require reconstitution and / or dilution prior to administration and that is stable over extended periods of time. [Means for solving the problem]

[0010] The liquid compositions of dalbavancin described herein have been found to have surprisingly improved stability. In particular, certain liquid compositions have been found to be stable at room temperature for extended periods of time.

[0011] Aqueous solutions of dalbavancin containing at least one excipient and / or at least one solubilizing agent selected from N-acetyl-D-amino acids or N-acetyl-glycine have been found to be stable for certain periods of time.

[0012] These aqueous solutions of dalbavancin have also been found to have low levels of mannosyl aglycone impurities. These aqueous solutions of dalbavancin in water have been found to have good chemical and physical stability for periods of time at room temperature. DETAILED DESCRIPTION OF THE INVENTION

[0013] Detailed Description (including definitions) As used herein, the terms "pharmaceutical composition," "pharmaceutical formulation," "composition," and "formulation" are used interchangeably.

[0014] The term "aqueous solution" is understood to mean any solution in which water is present at 50% v / v or greater, such as a solution containing about 50% v / v to about 100% v / v water, etc. Thus, aqueous solutions include solutions containing about 50% v / v or greater, about 60% v / v or greater, about 70% v / v or greater, about 75% v / v or greater, about 80% v / v or greater, about 85% v / v or greater, about 90% v / v or greater, about 95% v / v or greater, or about 100% v / v water.

[0015] "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrathoracic injection, infusion, etc. Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersing agents, wetting agents, suspending agents and / or solubilizing agents.

[0016] The term "ready-to-administer" is synonymous with "ready-to-infuse" or "ready-to-inject" and should not be read as the term "ready-to-use" aqueous solution.

[0017] The term "ready-to-use" includes aqueous preconcentrates that require a single dilution step with an aqueous diluent fluid, such as water for injection or saline, prior to administration. The term "ready-to-administer" also distinguishes them from lyophilized products that require two steps: a first step of reconstitution to form a preconcentrate, and then a second step in which the preconcentrate is subjected to dilution with an aqueous infusion fluid. "Ready-to-administer" parenteral dosage forms according to the present disclosure avoid the inconvenience of reconstituting or diluting a concentrated parenteral formulation in an infusion diluent prior to injection, eliminating the risk of any potential calculation or dilution errors, as well as the risk of microbial contamination during handling.

[0018] The aqueous dalbavancin formulations described herein can be ready-to-use or ready-to-administer solutions that can be filled into flexible plastic containers or in vials or bottles.

[0019] As used herein, the term "flexible plastic container" means a flexible polymeric IV bag or other polymeric container. Exemplary flexible plastic containers are made from polyolefins such as polyethylene, polypropylene, their copolymers and derivatives, with or without other additives.

[0020] Typically, the compound of the present disclosure is administered in an amount effective for treating the disease states described herein.The compound of the present disclosure is administered by any suitable route, in the form of a pharmaceutical composition adapted to such route, in an amount effective for intended treatment.The therapeutically effective dose of the compound required for treating the progression of medical condition can be easily ascertained by those skilled in the art using preclinical and clinical approaches well known in the medical field.

[0021] As used herein, the term "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition sufficient to produce a desired activity upon administration to a subject in need thereof. An "effective amount" refers to the amount of a compound or pharmaceutical composition according to the present disclosure that, when administered to a patient for treating an infection or disease, is sufficient to achieve such treatment. The "effective amount" will vary depending on the active ingredient, the state of infection, the disease or condition being treated and its severity, and the age, weight, physical condition and responsiveness of the mammal being treated.

[0022] Dalbavancin is prone to degradation, the most significant impurity being the mannosyl aglycone (MAG) impurity shown below.

[0023] [ka]

[0024] The terms "stability," "chemical stability," or "stable" mean that a product, composition, or formulation exhibits an acceptable amount of dalbavancin or that no more than a specified amount of dalbavancin is degraded after a specified period of time. Thus, a stable product, solution, or formulation avoids unacceptable degradation of the active agent.

[0025] Stability can be expressed as the purity or assay of dalbavancin in a composition according to the present disclosure. If a composition initially contains dalbavancin of a particular purity or assay, the stability of the composition is reflected by the reduction of dalbavancin in the product, formulation, or composition over time; a stable composition contains dalbavancin of a particular chromatographic purity or assay after a given period of time. For example, MAG formation is reduced in a stable product.

[0026] For example, a stable composition can be one that has an assay loss / decrease of dalbavancin of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or less after a predetermined period of time when analyzed by liquid chromatography, e.g., HPLC, UHPLC, or LC / MS.

[0027] Therefore, "stability" can also be defined by the total or individual amounts of impurities produced after a certain period of time. The amount of impurity present can be expressed as a percentage, for example, as a peak area percentage in an HPLC chromatogram, or calculated according to a standard solution.

[0028] Degradation of dalbavancin to produce a mannosyl aglycone impurity can be identified based on the relative retention times (RRTs) of dalbavancin and the mannosyl aglycone impurity in an HPLC chromatogram.

[0029] As used herein, the increase (Δ) in mannosyl aglycone impurity is measured from the time of preparation and storage of the formulation up to a specified time (eg, 3 months and 6 months). For example, a stable composition can be one in which the amount of mannosyl aglycone impurity increases by no more than 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0% after storage at 25°C for 3 months.

[0030] In addition to chemical stability, the physical stability of the composition can be monitored. Physical stability is defined as the appearance of the formulation and includes visual inspection of the solution for sedimentation, clarity, and color. The color is L * a * b * Using the color space method, USP <1061> It can be determined spectrophotometrically by calculating ΔE according to

[0031] In liquid, ready-to-administer pharmaceutical products, it is important to have a formulation that is free of visible particles or sediment. In certain embodiments, aqueous dalbavancin formulations according to the present disclosure are stable for a period of time at temperatures between 2°C and 8°C. In certain embodiments, aqueous dalbavancin formulations according to the present disclosure are stable for a period of time under room temperature conditions. As used herein, the term "room temperature" means 20°C to 27°C. In certain embodiments, aqueous dalbavancin formulations according to the present disclosure are stable for a period of time at 40°C. In certain embodiments, aqueous dalbavancin formulations described herein are stable for a period of 7 days (1 week), 14 days (2 weeks), 30 days (1 month), 60 days (2 months), 3 months, 4 months, 180 days (6 months), 9 months, 12 months (1 year), 14 months, 16 months, 18 months, 20 months, 24 months, or more under certain temperature conditions.

[0032] The formulations disclosed herein can be sterilized by means known in the art, including, for example, sterile filtration. The formulations disclosed herein are suitable for parenteral administration.

[0033] The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of the present disclosure with an acid whose anion is generally considered suitable for human use, or with a base whose cation is generally considered suitable for human use.

[0034] As used herein, the term "dalbavancin" refers to dalbavancin or a pharmaceutically acceptable salt of dalbavancin. Dalbavancin is a mixture of two closely related structural compound families—A and B—which can be further subdivided into a total of five subtypes, as shown in the table above. B0 is the major component of the mixture, with components A0, A1, B1, and B2 present in lesser amounts. Pharmaceutically acceptable salts of dalbavancin may be salts derived from inorganic or organic acids.

[0035] In one embodiment, the pH of the aqueous dalbavancin formulation is in the range of 3.0 to 6.5. In some embodiments, the pH is in the range of 4.0 to 6.5. In other embodiments, the pH is in the range of 5.0 to 6.0. In other embodiments, the pH is 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5.

[0036] "pH" is the conventional unit of measure of hydrogen ion activity in an aqueous or other liquid solution at room temperature, unless another temperature is specified. In certain embodiments, the pH values ​​are given for the formulations immediately after preparation (meaning at the start of the stability study).

[0037] The pH of the formulation can be adjusted by any suitable method.The pH can be adjusted with one or more pH adjusting agents that can be selected from acid or base.Examples of pH adjusting agents include hydrochloric acid and sodium hydroxide, and combinations thereof.

[0038] In one embodiment, the aqueous dalbavancin formulation does not contain a buffer. In one embodiment, the aqueous dalbavancin formulation does not include a phosphate buffer. In one embodiment, the aqueous dalbavancin formulation does not include an acetate buffer.

[0039] In one embodiment, the aqueous dalbavancin formulation does not include a citrate buffer. For an intravenous product to be acceptable for administration to humans, such a product must have an appropriate osmolality.

[0040] The aqueous dalbavancin formulations described herein may optionally include an osmolality adjusting agent. The osmolality adjusting agent may be dextrose.

[0041] In one embodiment, the osmolality adjusting agent is dextrose. In some embodiments, the concentration of the osmolality adjusting agent in the product is an amount that provides an isotonic ready-to-administer or ready-to-use product.

[0042] In some embodiments, the aqueous dalbavancin formulation has an osmolality within the physiological osmolality of blood, which, according to the literature, as used herein, is in the range of 270 to 340 mOsmol / kg.

[0043] In certain embodiments, the concentration of the osmolality-adjusting agent in the aqueous dalbavancin formulation should be an amount that achieves a product osmolality within the target range of 270-340 mOsmol / kg.

[0044] In some embodiments, the aqueous dalbavancin formulation is isotonic and has an osmolality within the physiological osmolality of blood, as described above. In certain embodiments, the compositions described herein comprise an N-acetyl-D-amino acid.

[0045] N-acetyl-D-amino acids are compounds represented by the following structure:

[0046] [ka]

[0047] where R1 is the side chain of an α-amino acid. Alpha-amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and ornithine.

[0048] The term "N-acetyl-D-amino acid" is also meant to include any salts thereof, particularly pharmaceutically acceptable salts. N-acetyl-glycine is a compound represented by the following structure:

[0049] [ka]

[0050] It can exist as the acid or in deprotonated form. The term "N-acetyl-glycine" is also meant to encompass salts thereof, particularly pharmaceutically acceptable salts. The term "solubilizer" refers to an agent included in a formulation that helps ensure that the dalbavancin solution remains clear, with no precipitates present in the solution. Solubilizers include organic molecules, such as polyamino acid-based amphiphilic polymers, polysorbates, castor oil, sodium cholesteryl sulfate (SCS), polyvinylpyrrolidone (povidone, PVP), polyoxyl-15-hydroxystearate, N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, diacylglycerol, monoglycerol, propylene glycol, polyethylene glycol (PEG), and cyclodextrins, such as PEG 400 and hydroxypropyl beta-cyclodextrin, as well as combinations of solubilizers.

[0051] Stable liquid dalbavancin compositions are described herein. In one embodiment, the composition comprises dalbavancin hydrochloride. The concentration of dalbavancin in the composition can range from 1 mg / ml to 25 mg / ml. In one embodiment, the concentration of dalbavancin ranges from 1 mg / ml to 10 mg / ml, 1 mg / ml to 7 mg / ml, or 3 mg / ml to 6 mg / ml. In some embodiments, the concentration of dalbavancin ranges from 4 mg / ml to 6 mg / ml. In another embodiment, the concentration of dalbavancin is 4.0 mg / ml, 4.1 mg / ml, 4.2 mg / ml, 4.3 mg / ml, 4.4 mg / ml, 4.5 mg / ml, 4.6 mg / ml, 4.7 mg / ml, 4.8 mg / ml, 4.9 mg / ml, 5.0 mg / ml, 5.1 mg / ml, 5.2 mg / ml, 5.3 mg / ml, 5.4 mg / ml, 5.5 mg / ml, 5.6 mg / ml, 5.7 mg / ml, 5.8 mg / ml, 5.9 mg / ml, or 6.0 mg / ml. In yet another embodiment, the concentration of dalbavancin is 5 mg / ml. In some embodiments, the concentration of dalbavancin ranges from 10 mg / ml to 25 mg / ml. In one embodiment, the concentration of dalbavancin ranges from 15 mg / ml to 22 mg / ml. In another embodiment, the concentration of dalbavancin ranges from 18 mg / ml to 22 mg / ml. In another embodiment, the concentration of dalbavancin is 18 mg / ml, 19 mg / ml, 20 mg / ml, 21 mg / ml, or 22 mg / ml.

[0052] When specific amounts or amount ranges of dalbavancin are given in this application, all values ​​are calculated based on the dalbavancin base. In some embodiments, the composition comprises dalbavancin hydrochloride, a cyclodextrin, and water.

[0053] In some embodiments, the cyclodextrin is hydroxypropyl beta cyclodextrin. Hydroxypropyl-β-cyclodextrin is a partially substituted poly(2-hydroxypropyl) ether of β-cyclodextrin. In one embodiment, the molar substitution of the hydroxypropyl beta-cyclodextrin is 0.4 to 1.5. In one embodiment, the molar substitution of the hydroxypropyl beta-cyclodextrin is 0.5 to 1.1. In another embodiment, the molar substitution of the hydroxypropyl beta-cyclodextrin is 0.6 to 1.0. In another embodiment, the molar substitution of the hydroxypropyl beta-cyclodextrin is 0.6 to 0.9. In another embodiment, the molar substitution of the hydroxypropyl beta-cyclodextrin is 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or 1.1.

[0054] In some embodiments, the molar ratio of dalbavancin to hydroxypropyl beta cyclodextrin ranges from 1:0.5 to 1:10. In some embodiments, the molar ratio of dalbavancin to hydroxypropyl beta cyclodextrin ranges from 1:0.5 to 1:5.

[0055] In some embodiments, the molar ratio of dalbavancin to hydroxypropyl beta cyclodextrin ranges from 1:0.6 to 1:2. In some embodiments, the molar ratio of dalbavancin to hydroxypropyl beta cyclodextrin ranges from 1:0.6 to 1:1.

[0056] In some embodiments, the molar ratio of dalbavancin to hydroxypropyl beta cyclodextrin ranges from 1:0.7 to 1:0.9. In some embodiments, the molar ratio of dalbavancin to hydroxypropyl beta cyclodextrin is 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:2, 1:3, 1:4, or 1:5.

[0057] In some embodiments, the composition comprises dalbavancin, an N-acetyl-D-amino acid or N-acetyl-glycine, and water. In some embodiments, the N-acetyl-D-amino acid is selected from N-acetyl-D-alanine, N-acetyl-D-leucine, N-acetyl-D-methionine, or a combination thereof. In one embodiment, the N-acetyl-D-amino acid is N-acetyl-D-alanine.

[0058] In certain embodiments, the molar ratio of dalbavancin to N-acetyl-D-amino acid can range from 1:1 to 40:1. In some embodiments, the molar ratio of dalbavancin to N-acetyl-glycine can range from 1:1 to 40:1.

[0059] In some embodiments, the composition comprises dalbavancin and a mixture of an N-acetyl-D-amino acid and a solubilizing agent. In some embodiments, the composition comprises dalbavancin and a mixture of an N-acetyl-D-amino acid and a solubilizing agent, wherein the N-acetyl-D-amino acid is N-acetyl-D-alanine.

[0060] In some embodiments, the composition comprises dalbavancin and a mixture of an N-acetyl-D-amino acid and a solubilizing agent, wherein the solubilizing agent is PEG. In some embodiments, the composition comprises dalbavancin and a mixture of an N-acetyl-D-amino acid and a solubilizing agent, wherein the solubilizing agent is PEG400.

[0061] In some embodiments, the composition comprises dalbavancin and a mixture of an N-acetyl-D-amino acid and a solubilizing agent, wherein the solubilizing agent is a cyclodextrin. In some embodiments, the composition comprises dalbavancin and a mixture of an N-acetyl-D-amino acid and a solubilizing agent, wherein the solubilizing agent is hydroxypropyl beta-cyclodextrin.

[0062] In some embodiments, the composition comprises dalbavancin and a mixture of an N-acetyl-D-amino acid and a solubilizing agent, wherein the N-acetyl-D-amino acid is N-acetyl-D-alanine and the solubilizing agent is PEG.

[0063] In some embodiments, the composition comprises dalbavancin and a mixture of an N-acetyl-D-amino acid and a solubilizing agent, wherein the N-acetyl-D-amino acid is N-acetyl-D-alanine and the solubilizing agent is PEG400.

[0064] In some embodiments, the composition comprises dalbavancin and a mixture of an N-acetyl-D-amino acid and a solubilizing agent, wherein the N-acetyl-D-amino acid is N-acetyl-D-alanine and the solubilizing agent is a cyclodextrin.

[0065] In some embodiments, the composition comprises dalbavancin and a mixture of an N-acetyl-D-amino acid and a solubilizing agent, wherein the N-acetyl-D-amino acid is N-acetyl-D-alanine and the solubilizing agent is hydroxypropyl beta-cyclodextrin.

[0066] In some embodiments, the molar ratio of dalbavancin to N-acetyl-D-alanine to hydroxypropyl beta-cyclodextrin is 1:0.5:0.5 to 1:10:4. In some embodiments, the molar ratio of dalbavancin to N-acetyl-D-alanine to hydroxypropyl beta-cyclodextrin is 1:0.1:0.1 to 1:10:4.

[0067] In some embodiments, the composition comprises dalbavancin and a mixture of N-acetyl-D-alanine and hydroxypropyl beta-cyclodextrin, wherein the molar ratio of dalbavancin to N-acetyl-D-alanine is 1:0.1 to 1:10; 1:0.5 to 1:10; 1.1 to 1:10; 1:1 to 1:4.5; 1:1 to 1:3; 1:4 to 1:6; 1:4.5 to 1:6; 1:6 to 1:10; 1:7 to 1:10, or 1:8 to 1:10.

[0068] In some embodiments, the composition comprises dalbavancin and a mixture of N-acetyl-D-alanine and hydroxypropyl beta-cyclodextrin, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is 1:1 to 1:2.

[0069] In some embodiments, the aqueous solution comprises dalbavancin and a mixture of N-acetyl-D-alanine and hydroxypropyl beta-cyclodextrin, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is 1:1 to 1:2, the molar ratio of dalbavancin to N-acetyl-D-alanine is 1:1 to 1:10, and the concentration of dalbavancin is 1 mg / ml to 25 mg / ml.

[0070] In some embodiments, the aqueous solution comprises dalbavancin and a mixture of N-acetyl-D-alanine and hydroxypropyl beta-cyclodextrin, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is 1:1 to 1:2, the molar ratio of dalbavancin to N-acetyl-D-alanine is 1:1 to 1:10, and the concentration of dalbavancin is 1 mg / ml to 7 mg / ml.

[0071] In some embodiments, the aqueous solution comprises dalbavancin and a mixture of N-acetyl-D-alanine and hydroxypropyl beta-cyclodextrin, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is 1:1 to 1:2, the molar ratio of dalbavancin to N-acetyl-D-alanine is 1:1 to 1:10, and the concentration of dalbavancin is 15 mg / ml to 22 mg / ml.

[0072] In some embodiments, the aqueous solution of dalbavancin exhibits less than an 8% increase in the mannosyl aglycone impurity as measured by HPLC. In some embodiments, an aqueous solution of dalbavancin exhibits less than a 2% increase in mannosyl aglycone impurity as measured by HPLC after 3 months of storage at room temperature.

[0073] In some embodiments, an aqueous solution of dalbavancin exhibits less than a 1.5% increase in mannosyl aglycone impurity as measured by HPLC after 3 months of storage at room temperature. In one embodiment, the compositions described above can be used to treat adult and pediatric patients with acute bacterial skin and skin structure infections (ABSSSIs) caused by designated susceptible strains of Gram-positive microorganisms. [Example]

[0074] Example (method, results, discussion) After preparation, the initial levels of active pharmaceutical ingredient and impurities were determined by high performance liquid chromatography (HPLC), after which the containers were loaded into stability chambers at different storage conditions, 40°C and 25°C.

[0075] To determine the stability of the active pharmaceutical ingredient in a formulation according to the present disclosure, containers were removed from the stability chamber at various time points, such as 28 days, 1 month, 2 months, 3 months, and 6 months, and analyzed by HPLC.

[0076] The assay of the active pharmaceutical ingredient was determined by a gradient HPLC method using an internal standard and a DAD detector. Impurities were determined using the same HPLC method, and the amount was determined by area percentage. In parallel with the assay and impurities, the component distribution was also determined by area percentage for five major homologues (A0, A1, B0, B1, and B2). In all cases, a reversed-phase C18 column was used.

[0077] HPLC Assay and Impurity Method Mobile phase A: A mixture of phosphate buffer and acetonitrile (85 / 15) Mobile phase B: A mixture of phosphate buffer and acetonitrile (35 / 65) Mode:LC Detector: UV230nm Column: 2.1 x 5 mm; 3.5 μm packing Column temperature: 45°C.

[0078] Samples are prepared by diluting to 0.3 mg / ml. All sample sequences are run with injections of the internal impurity ID standard, as well as replicate injections of the blank dilution solution. The system is periodically cleaned due to potential backpressure buildup.

[0079] Calculate the percent labeled amount of dalbavancin.

[0080]

number

[0081] A s - Peak response of dalbavancin (as the sum of the five homologues) from the sample solution. A std -Peak response of dalbavancin (as the sum of the five homologues) from standard solution.

[0082] c std - Dalbavancin concentration in standard solution (mg / mL) c s -Nominal concentration of dalbavancin in the sample solution (mg / mL) The impurity content is given as area % of the total area, calculated using the following formula: A i - Peak response of impurities from sample solution A tot - the sum of all peak responses from the sample solution

[0083]

number

[0084] A h -Peak response of homologues from sample solution A d - The sum of the peak responses of all homologues (A0, A1, B0, B1 and B2) from the sample solution.

[0085] Preparation of Exemplary Formulations: Water for injection or 5% dextrose solution (90% of the final volume) was added to the vessel and stirring was initiated.

[0086] Excipients required for different formulations were added. Dalbavancin hydrochloride was added in an amount to obtain a final concentration of 5 mg / ml. The solution was stirred until all dry ingredients were dissolved. The pH was adjusted to the target pH value by adding the required amount of HCl or NaOH (1 M solution). Additional water for injection or 5% dextrose solution was added to the solution to reach the final volume. The solution was filtered through a 0.22 μm filter and filled into containers such as glass vials or plastic bags.

[0087] Example 1 This example demonstrates the evolution of mannosyl aglycone impurities in a 5 mg / ml formulation of dalbavancin hydrochloride with N-acetyl-D-alanine (NADA) in water for injection at different pH levels.

[0088] Data shown is after 3 and 6 months of storage at 25°C.

[0089] [Table 2]

[0090] Example 2 This example demonstrates the evolution of mannosyl aglycone impurities in a formulation of 5 mg / ml dalbavancin hydrochloride with hydroxypropyl beta-cyclodextrin in water for injection (WFI) at pH 4.

[0091] Data shown is after 3 and 6 months of storage at 25°C and 4 weeks at 40°C.

[0092] [Table 3]

[0093] Example 3 This example shows the evolution of mannosyl aglycone impurities in a 5 mg / ml formulation of dalbavancin hydrochloride containing a combination of hydroxypropyl beta-cyclodextrin and NADA in a 5% dextrose solution at pH 4. The table shows data after 3 months at 25° C.

[0094] [Table 4]

[0095] Example 4 This example shows the evolution of mannosyl aglycone impurities in formulations of 5 mg / ml dalbavancin hydrochloride with different molar ratios of hydroxypropyl beta-cyclodextrin in a 5% dextrose solution at pH 4. The table shows data after 3 months at 25°C.

[0096] [Table 5]

[0097] Example 5 This example shows the evolution of mannosyl aglycone impurities in a 20 mg / ml formulation of dalbavancin hydrochloride with a combination of hydroxypropyl beta-cyclodextrin and NADA in a 5% dextrose solution at pH 4. The table shows data after 4 weeks at 25° C. and 40° C.

[0098] [Table 6]

[0099] Example 6: The following numbered items represent embodiments of liquid pharmaceutical formulations containing active ingredients: Item 1. An aqueous formulation comprising dalbavancin or a pharmaceutically acceptable salt thereof, a hydroxypropyl beta-cyclodextrin solubilizer, an excipient selected from N-acetyl-D-amino acids, N-acetyl-glycine, and combinations thereof, wherein the aqueous formulation has a pH in the range of 3.0 to 6.5.

[0100] Item 2. The aqueous formulation according to Item 1, wherein the solution is a sterile aqueous solution. Item 3. The aqueous formulation according to Item 1 or Item 2, wherein the solution is an aqueous sterile solution for parenteral administration.

[0101] Item 4. The aqueous formulation according to any one of Items 1 to 3, wherein the concentration of dalbavancin is in the range of 1 mg / ml to 25 mg / ml. Item 5. The aqueous formulation according to Item 4, wherein the concentration of dalbavancin is in the range of 1 mg / ml to 7 mg / ml.

[0102] Item 6. The aqueous formulation according to Item 4, wherein the concentration of dalbavancin is in the range of 15 mg / ml to 22 mg / ml. Item 7. The aqueous formulation according to Item 5, wherein the concentration of dalbavancin is in the range of 2 mg / ml to 6 mg / ml.

[0103] Item 8. The aqueous formulation according to Item 7, wherein the concentration of dalbavancin is in the range of 4 mg / ml to 6 mg / ml. Item 9. The aqueous formulation according to Item 6, wherein the concentration of dalbavancin is in the range of 18 mg / ml to 22 mg / ml.

[0104] Item 10. The aqueous formulation according to any one of Items 1 to 9, wherein the solution exhibits an increase in mannosyl aglycone impurity of less than 8% when measured by HPLC. Item 11. The aqueous formulation according to any one of Items 1 to 9, wherein the increase in mannosyl aglycone impurity is less than 2% when the solution is stored at room temperature for 3 months as measured by HPLC.

[0105] Item 12. The aqueous formulation of any one of Items 11, wherein the mannosyl aglycone impurity increases by less than 1.5% when measured by HPLC after storing the solution at room temperature for 3 months.

[0106] Item 13. The aqueous formulation of any one of Items 11, wherein the increase in mannosyl aglycone impurity is less than 1.0% when measured by HPLC after storing the solution at room temperature for 3 months.

[0107] Item 14. The aqueous formulation of any one of Items 11, wherein the increase in mannosyl aglycone impurity is less than 0.8% when measured by HPLC after storing the solution at room temperature for 3 months.

[0108] Item 15. The aqueous formulation according to any one of items 1 to 14, wherein the solution comprises the excipient N-acetyl-D-alanine. Item 16. The aqueous formulation according to any one of items 1 to 14, wherein the solution further comprises the solubilizer PEG400.

[0109] Item 17. The aqueous formulation according to Item 15, wherein the molar ratio of dalbavancin to N-acetyl-D-alanine is in the range of 1:1 to 1:40. Item 18. The aqueous formulation according to Item 17, wherein the molar ratio of dalbavancin to N-acetyl-D-alanine is in the range of 1:1 to 1:30.

[0110] Item 19. The aqueous formulation according to Item 17, wherein the molar ratio of dalbavancin to N-acetyl-D-alanine is in the range of 1:1 to 1:20. Item 20. The aqueous formulation according to Item 17, wherein the molar ratio of dalbavancin to N-acetyl-D-alanine is in the range of 1:1 to 1:10.

[0111] Item 21. The aqueous formulation according to Item 1, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:10. Item 22. The aqueous formulation according to Item 21, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:8.

[0112] Item 23. The aqueous formulation according to Item 21, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:5. Item 24. The aqueous formulation of Item 21, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:6.

[0113] Item 25. The aqueous formulation according to Item 21, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:4. Item 26. The aqueous formulation according to Item 1, wherein the pH of the formulation is in the range of 3.5 to 6.0.

[0114] Item 27. The aqueous formulation according to Item 26, wherein the pH of the formulation is in the range of 3.5 to 5.5. Item 28. The aqueous formulation according to Item 26, wherein the pH of the formulation is in the range of 3.5 to 5.0. Item 29. The aqueous formulation according to Item 26, wherein the pH of the formulation is in the range of 3.5 to 4.5.

[0115] Item 30. An aqueous formulation comprising dalbavancin or a pharmaceutically acceptable salt thereof, a hydroxypropyl beta-cyclodextrin solubilizer, an excipient selected from N-acetyl-D-amino acids, N-acetyl-glycine, and combinations thereof, wherein the aqueous formulation has a pH in the range of 3.0 to 6.5.

[0116] Item 31. The aqueous formulation according to Item 30, wherein the solution is a sterile aqueous solution. Item 32. The aqueous formulation according to Item 30 or 31, wherein the solution is an aqueous sterile solution for parenteral administration.

[0117] Item 33. The aqueous formulation according to any one of Items 30 to 32, wherein the concentration of dalbavancin is in the range of 1 mg / ml to 25 mg / ml. Item 34. The aqueous formulation according to Item 33, wherein the concentration of dalbavancin is in the range of 1 mg / ml to 7 mg / ml.

[0118] Item 35. The aqueous formulation according to Item 33, wherein the concentration of dalbavancin is in the range of 15 mg / ml to 22 mg / ml. Item 36. The aqueous formulation according to Item 34, wherein the concentration of dalbavancin is in the range of 2 mg / ml to 6 mg / ml.

[0119] Item 37. The aqueous formulation according to Item 36, wherein the concentration of dalbavancin is in the range of 4 mg / ml to 6 mg / ml. Item 38. The aqueous formulation according to Item 35, wherein the concentration of dalbavancin is in the range of 18 mg / ml to 22 mg / ml.

[0120] Item 39. The aqueous formulation according to any one of Items 30 to 38, wherein the solution exhibits an increase in mannosyl aglycone impurity of less than 8% when measured by HPLC. Item 40. The aqueous formulation according to any one of Items 30 to 38, wherein the increase in mannosyl aglycone impurity is less than 2% when the solution is stored at room temperature for 3 months as measured by HPLC.

[0121] Item 41. The aqueous formulation of any one of Items 40, wherein the increase in mannosyl aglycone impurity is less than 1.5% when measured by HPLC after storing the solution at room temperature for 3 months.

[0122] Item 42. The aqueous formulation of any one of Items 40, wherein the increase in mannosyl aglycone impurity is less than 1.0% when measured by HPLC after storing the solution at room temperature for 3 months.

[0123] Item 43. The aqueous formulation of any one of Items 40, wherein the increase in mannosyl aglycone impurity is less than 0.8% when measured by HPLC after storing the solution at room temperature for 3 months.

[0124] Item 44. The aqueous formulation according to any one of Items 301 to 43, wherein the solution comprises the excipient N-acetyl-D-alanine. Item 45. The aqueous formulation according to any one of Items 30 to 43, wherein the solution further comprises the solubilizer PEG400.

[0125] Item 46. The aqueous formulation according to Item 44, wherein the molar ratio of dalbavancin to N-acetyl-D-alanine is in the range of 1:1 to 1:40. Item 47. The aqueous formulation according to Item 46, wherein the molar ratio of dalbavancin to N-acetyl-D-alanine is in the range of 1:1 to 1:30.

[0126] Item 48. The aqueous formulation according to Item 46, wherein the molar ratio of dalbavancin to N-acetyl-D-alanine is in the range of 1:1 to 1:20. Item 49. The aqueous formulation according to Item 46, wherein the molar ratio of dalbavancin to N-acetyl-D-alanine is in the range of 1:1 to 1:10.

[0127] Item 50. The aqueous formulation according to Item 30, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:10. Item 51. The aqueous formulation according to Item 50, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:8.

[0128] Item 52. The aqueous formulation according to Item 50, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:5. Item 53. The aqueous formulation according to Item 50, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:6.

[0129] Item 54. The aqueous formulation according to Item 50, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:4. Item 55. The aqueous preparation according to Item 30, wherein the pH of the solution is in the range of 3.5 to 6.0.

[0130] Item 56. The aqueous preparation according to Item 55, wherein the pH of the solution is in the range of 3.5 to 5.5. Item 57. The aqueous preparation according to Item 55, wherein the pH of the solution is in the range of 3.5 to 5.0. Item 58. The aqueous preparation according to Item 55, wherein the pH of the solution is in the range of 3.5 to 4.5.

[0131] Item 59. The aqueous formulation according to items 1 to 58, wherein the formulation further comprises dextrose. Item 60. A method for treating an acute bacterial infection caused by vancomycin-susceptible isolates of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus, or Enterococcus faecalis, comprising the step of administering an aqueous preparation defined in items 1 to 59 to a patient in need thereof.

[0132] Item 61. Aqueous preparations as defined in items 1 to 59 for use in the treatment of acute bacterial infections caused by vancomycin-susceptible isolates of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, the Streptococcus anginosus group, or Enterococcus faecalis.

[0133] Item 62. A method for producing an aqueous dalbavancin formulation according to any one of Items 1 to 59, comprising mixing dalbavancin or a pharmaceutically acceptable salt thereof, at least one excipient selected from N-acetyl-D-amino acids or N-acetyl-lysine, and a hydroxypropyl beta-cyclodextrin solubilizer with water, wherein the pH of the solution is in the range of 3.0 to 6.5.

[0134] Item 63. An aqueous formulation comprising dalbavancin or a pharmaceutically acceptable salt thereof and a hydroxypropyl beta-cyclodextrin solubilizer, wherein the pH of the solution is in the range of 3.0 to 6.5.

[0135] Item 64. The aqueous formulation according to Item 63, wherein the solution is an aqueous sterile solution. Item 65. The aqueous formulation according to Item 63 or 64, wherein the formulation is an aqueous sterile formulation for parenteral administration.

[0136] Item 66. The aqueous formulation according to any one of Items 63 to 65, wherein the concentration of dalbavancin is in the range of 1 mg / ml to 25 mg / ml. Item 67. The aqueous formulation according to Item 66, wherein the concentration of dalbavancin is in the range of 1 mg / ml to 7 mg / ml.

[0137] Item 68. The aqueous formulation according to Item 66, wherein the concentration of dalbavancin is in the range of 15 mg / ml to 22 mg / ml. Item 69. The aqueous formulation according to Item 67, wherein the concentration of dalbavancin is in the range of 2 mg / ml to 6 mg / ml.

[0138] Item 70. The aqueous formulation according to Item 69, wherein the concentration of dalbavancin is in the range of 4 mg / ml to 6 mg / ml. Item 71. The aqueous formulation according to Item 68, wherein the concentration of dalbavancin is in the range of 18 mg / ml to 22 mg / ml.

[0139] Item 72. The aqueous formulation of any one of Items 63 to 71, wherein the increase in mannosyl aglycone impurity as measured by HPLC is less than 8%. Item 73. The aqueous formulation according to any one of Items 63 to 71, wherein the formulation exhibits less than a 2% increase in mannosyl aglycone impurity when measured by HPLC after storage at room temperature for 3 months.

[0140] Item 74. The aqueous formulation of any one of Items 73, wherein the mannosyl aglycone impurity increases by less than 1.5% when measured by HPLC after storing the formulation at room temperature for 3 months.

[0141] Item 75. The aqueous formulation of any one of Items 73, wherein the mannosyl aglycone impurity increases by less than 1.0% when measured by HPLC after storing the formulation at room temperature for 3 months.

[0142] Item 76. The aqueous formulation of any one of Items 73, wherein the mannosyl aglycone impurity increases by less than 0.8% when measured by HPLC after storing the formulation at room temperature for 3 months.

[0143] Item 77. The aqueous formulation according to Item 63, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:10. Item 78. The aqueous formulation according to Item 77, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:8.

[0144] Item 79. The aqueous formulation according to Item 77, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:5. Item 80. The aqueous formulation according to Item 77, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:6.

[0145] Item 81. The aqueous formulation according to Item 77, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:4. Item 82. The aqueous formulation of Item 77, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.6 to 1:2.

[0146] Item 83. The aqueous formulation of Item 77, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.6 to 1:1. Item 84. The aqueous formulation according to Item 77, wherein the molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.7 to 1:0.9.

[0147] Item 85. The aqueous preparation according to Item 66, wherein the pH of the solution is in the range of 3.5 to 6.0. Item 86. The aqueous preparation according to Item 85, wherein the pH of the solution is in the range of 3.5 to 5.5. Item 87. The aqueous preparation according to Item 85, wherein the pH of the solution is in the range of 3.5 to 5.0.

[0148] Item 88. The aqueous preparation according to Item 85, wherein the pH of the solution is in the range of 3.5 to 4.5. Item 89. The aqueous formulation according to Items 63 to 88, wherein the formulation further comprises dextrose. Item 90. A method for treating an acute bacterial infection caused by a vancomycin-susceptible isolate of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group, or Enterococcus faecalis, comprising the step of administering an aqueous preparation as defined in Items 63 to 89 to a patient in need thereof.

[0149] Item 91. Aqueous preparations as defined in items 63 to 89 for use in the treatment of acute bacterial infections caused by vancomycin-susceptible isolates of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group or Enterococcus faecalis.

[0150] Item 92. A method for producing an aqueous dalbavancin formulation according to any one of Items 63 to 89, comprising mixing dalbavancin or a pharmaceutically acceptable salt thereof and a hydroxypropyl beta-cyclodextrin solubilizer with water, wherein the pH of the solution is in the range of 3.0 to 6.5.

[0151] Item 93. The method of producing an aqueous dalbavancin formulation according to Items 62 and 92, wherein the formulation is further sterile filtered.

Claims

1. Darbabansin or a pharmaceutically acceptable salt thereof, Hydroxypropyl beta-cyclodextrin and an aqueous formulation containing, The concentration of dalbavancin is in the range of 1 mg / ml to 7 mg / ml. The molar ratio of dalbavancin to hydroxypropyl beta-cyclodextrin is in the range of 1:0.5 to 1:10, and The aqueous formulation is an aqueous formulation that does not contain a buffer.

2. The aqueous formulation according to claim 1, wherein the formulation is an aqueous sterilization solution.

3. The aqueous formulation according to claim 1, wherein the formulation is an aqueous sterile solution for parenteral administration.

4. The aqueous formulation according to claim 1, wherein the pH of the formulation is in the range of 3.0 to 6.5 when measured at 25°C.

5. The aqueous formulation according to claim 1, wherein the formulation exhibits an increase of less than 8% in mannosyl aglycone impurities as measured by HPLC.

6. The aqueous formulation according to claim 1, wherein the formulation shows an increase of less than 2% in mannosyl aglycone impurities when measured by HPLC after being stored at room temperature for three months.

7. An aqueous formulation according to any one of claims 1 to 6, for use in the treatment of acute bacterial infections caused by vancomycin-sensitive isolates of Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group, or Enterococcus faecalis.