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 formulations of dalbavancin in water having a pH in the range of 4.8 to 5.9 and optionally an osmolality adjuster have been found to be stable at room temperature for periods of time. These aqueous formulations of dalbavancin have also been found to have low levels of mannosyl aglycone impurities.

[0012] These aqueous formulations of dalbavancin 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 degrease / decrease of dalbavancin of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or less after a predetermined period of time as 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 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.

[0033] 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.

[0034] In one embodiment, the pH of the liquid dalbavancin formulation is in the range of 4.8 to 5.9. In some embodiments, the pH is in the range of 5.0 to 5.8. In other embodiments, the pH is in the range of 5.2 to 5.7 or in the range of 5.0 to 5.5. In other embodiments, the pH is 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, or 5.9.

[0035] "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).

[0036] 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.

[0037] For aqueous dalbavancin formulations, it is important to maintain a stable pH over time, e.g., to minimize pH shifts over time. As used herein, the term "shift in pH" refers to the change in pH in a formulation from immediately after it is manufactured, as well as the measured pH after a specified time, e.g., 3 months, 6 months, 9 months, 12 months, 16 months, 18 months, 24 months, or more.

[0038] Formulations that experience no or little shift in pH over time have improved chemical and physical stability. In some embodiments, the pH in the formulation does not shift by more than 1.0 pH unit after storage at room temperature for at least 6 months.

[0039] In some embodiments, the pH in the formulation does not shift more than 0.8 pH units after storage at room temperature for at least 6 months. In some embodiments, the pH in the formulation does not shift more than 0.6 pH units after storage at room temperature for at least 6 months.

[0040] For an intravenous product to be acceptable for administration to humans, such a product must have an appropriate osmolality. The aqueous dalbavancin formulations described herein may optionally include an osmolality adjusting agent. The osmolality adjusting agent may be dextrose.

[0041] In some embodiments, 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. As mentioned above, it is important to maintain a stable pH in the formulation over time. To reduce pH shifts in the formulation, pH-stabilizing agents can be included in the formulation. It is also known to be important to obtain an aqueous dalbavancin formulation that is free of visible particles.

[0045] By including at least one amino acid in an aqueous dalbavancin formulation, the inventors have discovered that pH shifts can be stabilized and / or aid in the physical stability of the solution.

[0046] Aqueous dalbavancin formulations containing at least one amino acid experience less pH shift and therefore less degradation of dalbavancin, and the formulation remains clear. The term "amino acid" refers to any amino acid, including but not limited to the 20 amino acids naturally occurring in peptides in both D and L form, and is also meant to encompass any salts thereof, particularly pharmaceutically acceptable salts. For example, the term "amino acid" includes alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, and ornithine, and any configurations thereof.

[0047] Thus, the term "amino acid" includes L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine and L-ornithine.

[0048] Thus, D-alanine, D-arginine, D-asparagine, D-aspartic acid, D-cysteine, D-glutamic acid, D-glutamine, D-histidine, D-isoleucine, D-leucine, D-lysine, D-methionine, D-phenylalanine, D-proline, D-serine, D-threonine, D-tryptophan, D-tyrosine, D-valine and D-ornithine are included.

[0049] In some embodiments, the amino acid is in the L-form. In certain embodiments, the formulation comprises one or more amino acids. In certain embodiments, the formulation comprises one or more L-amino acids.

[0050] In some embodiments, the aqueous dalbavancin formulation does not contain a buffer. In some embodiments, the aqueous dalbavancin formulation does not include a phosphate buffer. In some embodiments, the aqueous dalbavancin formulation does not include an acetate buffer.

[0051] In some embodiments, the aqueous dalbavancin formulation does not include a citrate buffer. The term "solubilizer" refers to an agent included in a formulation that helps the dalbavancin formulation remain clear and free of precipitates. The solubilizer can be an organic molecule; for example, the solubilizer can be a polyethylene glycol (PEG), such as PEG400.

[0052] In some embodiments, the composition comprises dalbavancin hydrochloride. In some embodiments, the composition comprises dalbavancin hydrochloride and water. The concentration of dalbavancin in the composition can range from 1 mg / ml to 25 mg / ml. In some embodiments, 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 some embodiments, 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.

[0053] 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 aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, and has a pH of 4.8 to 5.9.

[0054] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, and has a pH of 4.8 to 5.9.

[0055] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, one or more amino acids, and water, and has a pH between 4.8 and 5.9.

[0056] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, has a pH of 4.8 to 5.9, and a concentration of dalbavancin in the range of 1 mg / ml to 25 mg / ml.

[0057] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 1 mg / ml to 25 mg / ml.

[0058] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, one or more amino acids, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 1 mg / ml to 25 mg / ml.

[0059] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, has a pH of 4.8 to 5.9, and a concentration of dalbavancin in the range of 15 mg / ml to 22 mg / ml.

[0060] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 15 mg / ml to 22 mg / ml.

[0061] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, one or more amino acids, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 15 mg / ml to 22 mg / ml.

[0062] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 1 mg / ml to 7 mg / ml.

[0063] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 1 mg / ml to 7 mg / ml.

[0064] In some embodiments, the aqueous dalbavancin composition comprises dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, one or more amino acids, and water, with a pH of 4.8 to 5.9 and a dalbavancin concentration ranging from 1 mg / ml to 7 mg / ml.

[0065] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, and has a pH between 4.8 and 5.9. In some embodiments, the aqueous dalbavancin composition consists of dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, and has a pH between 4.8 and 5.9.

[0066] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, and has a pH of 4.8 to 5.9.

[0067] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality-adjusting agent, one or more amino acids, and water, and has a pH between 4.8 and 5.9.

[0068] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, and has a pH between 4.8 and 5.9.

[0069] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, one or more amino acids, and water, and has a pH between 4.8 and 5.9.

[0070] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration ranging from 1 mg / ml to 25 mg / ml.

[0071] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration ranging from 1 mg / ml to 25 mg / ml.

[0072] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 1 mg / ml to 7 mg / ml.

[0073] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration ranging from 1 mg / ml to 7 mg / ml.

[0074] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 15 mg / ml to 22 mg / ml.

[0075] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 15 mg / ml to 22 mg / ml.

[0076] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration ranging from 1 mg / ml to 25 mg / ml.

[0077] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 1 mg / ml to 7 mg / ml.

[0078] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 15 mg / ml to 22 mg / ml.

[0079] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, one or more amino acids, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 1 mg / ml to 25 mg / ml.

[0080] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, one or more amino acids, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 1 mg / ml to 7 mg / ml.

[0081] In some embodiments, the aqueous dalbavancin composition consists essentially of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, a stabilizer, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 15 mg / ml to 22 mg / ml.

[0082] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration ranging from 1 mg / ml to 25 mg / ml.

[0083] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration ranging from 1 mg / ml to 7 mg / ml.

[0084] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 15 mg / ml to 22 mg / ml.

[0085] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, one or more amino acids, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration ranging from 1 mg / ml to 25 mg / ml.

[0086] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, a stabilizer, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 1 mg / ml to 7 mg / ml.

[0087] In some embodiments, the aqueous dalbavancin composition consists solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, one or more amino acids, and water, has a pH of 4.8 to 5.9, and a dalbavancin concentration in the range of 15 mg / ml to 22 mg / ml.

[0088] In some embodiments, the aqueous dalbavancin formulation exhibits less than an 8% increase in the mannosyl aglycone impurity as measured by HPLC. In some embodiments, the aqueous dalbavancin formulation exhibits less than a 4% increase in mannosyl aglycone impurity as measured by HPLC after 6 months of storage at room temperature.

[0089] In some embodiments, the aqueous dalbavancin formulation exhibits less than a 2% increase in mannosyl aglycone impurity as measured by HPLC after 3 months of storage at room temperature. In certain embodiments, the above-described formulations 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]

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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.

[0094] 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.

[0095] Calculate the percent labeled amount of dalbavancin.

[0096]

number

[0097] 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.

[0098] 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

[0099]

number

[0100] 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.

[0101] Preparation of Exemplary Formulations: Water for injection (90% of the final volume) was added to the vessel and stirring was initiated. 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.

[0102] 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 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.

[0103] Example 1 This example demonstrates the evolution of mannosyl aglycone impurities in a 5 mg / ml formulation of dalbavancin hydrochloride in water for injection under two different storage conditions and at different pHs.

[0104] [Table 2]

[0105] Example 2 This example shows the change in total impurities in a 5 mg / ml formulation of dalbavancin hydrochloride in 5% dextrose after 3 and 6 months of storage at 25° C. The two formulations have a pH shift of 0.3 and 0.5 pH units, respectively.

[0106] [Table 3]

[0107] Example 3 This example shows the change in total impurities in a 5 mg / ml formulation of dalbavancin hydrochloride in 5% dextrose after 3 and 6 months of storage at 25° C. The example includes a formulation containing dextrose only, 10 mM histidine, 10 mM aspartic acid, 10 mM glutamic acid, 10 mM isoleucine acid, and 10 mM succinic acid.

[0108] [Table 4]

[0109] Example 4 This example demonstrates the evolution of mannosyl aglycone impurities in formulations of dalbavancin hydrochloride at 20 mg / ml in 5% dextrose solution at different pH values ​​under two different storage conditions.

[0110] [Table 5]

[0111] Example 5 The following numbered items represent embodiments of liquid pharmaceutical formulations containing active ingredients: Item 1. An aqueous dalbavancin formulation comprising dalbavancin or a pharmaceutically acceptable salt of dalbavancin, and optionally an osmolality-adjusting agent, wherein the formulation has a pH in the range of 4.8 to 5.9.

[0112] Item 2. An aqueous dalbavancin formulation consisting solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin and an osmolality-adjusting agent, the formulation having a pH in the range of 4.8 to 5.9.

[0113] Item 3. An aqueous dalbavancin formulation comprising dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and optionally a pH stabilizer, wherein the formulation has a pH in the range of 4.8 to 5.9.

[0114] Item 4. An aqueous dalbavancin formulation comprising dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality adjuster, and at least one amino acid, wherein the formulation has a pH in the range of 4.8 to 5.9.

[0115] Item 5. An aqueous dalbavancin formulation consisting solely of dalbavancin or a pharmaceutically acceptable salt of dalbavancin, an osmolality-adjusting agent, and at least one amino acid, wherein the formulation has a pH in the range of 4.8 to 5.9.

[0116] Item 6. The aqueous dalbavancin formulation of items 1 to 5, wherein the osmolality adjuster is dextrose. Item 7. The aqueous dalbavancin formulation of items 4 and 5, wherein the amino acid is an L-amino acid.

[0117] Item 8. The aqueous dalbavancin formulation of Item 7, wherein the amino acid is L-histidine. Item 9. The aqueous dalbavancin formulation of Item 7, wherein the amino acid is L-glutamic acid.

[0118] Item 10. The aqueous dalbavancin formulation of Item 7, wherein the amino acid is L-isoleucine. Item 11. The aqueous dalbavancin formulation according to Items 1 to 10, wherein the concentration of dalbavancin is in the range of 1 mg / ml to 25 mg / ml.

[0119] Item 12. The aqueous dalbavancin formulation of Item 11, wherein the concentration of dalbavancin is in the range of 1 mg / ml to 7 mg / ml. Item 13. The aqueous dalbavancin formulation of Item 11, wherein the concentration of dalbavancin is in the range of 15 mg / ml to 22 mg / ml.

[0120] Item 14. The aqueous dalbavancin formulation of Item 11, wherein the concentration of dalbavancin is in the range of 3 mg / ml to 6 mg / ml. Item 15. The aqueous dalbavancin formulation of Item 11, wherein the concentration of dalbavancin is in the range of 18 mg / ml to 22 mg / ml.

[0121] Item 16. The aqueous dalbavancin formulation according to Items 1 to 15, having a pH in the range of 5.0 to 5.9. Item 17. The aqueous dalbavancin formulation according to Items 1 to 15, having a pH in the range of 5.2 to 5.9.

[0122] Item 18. The aqueous dalbavancin formulation according to Items 1 to 15, having a pH in the range of 5.3 to 5.9. Item 19. The aqueous dalbavancin formulation of items 1 to 18, wherein the formulation exhibits less than an 8% increase in mannosyl aglycone impurity as measured by HPLC.

[0123] Item 20. The aqueous dalbavancin formulation of items 1 to 18, wherein the solution exhibits less than a 4% increase in mannosyl aglycone impurity as measured by HPLC after storage at room temperature for 3 months.

[0124] Item 21. The aqueous dalbavancin formulation of items 1 to 20, wherein the solution exhibits less than a 2% increase in mannosyl aglycone impurity when measured by HPLC after storage at room temperature for 3 months.

[0125] Item 22. The aqueous dalbavancin formulation of items 1 to 20, wherein the pH shift is 1.0 pH unit or less after storage at room temperature for at least 6 months. Item 23. The aqueous dalbavancin formulation of Item 22, wherein the pH shift is 0.8 pH units or less after storage at room temperature for at least 6 months.

[0126] Item 24. The aqueous dalbavancin formulation of Item 22, wherein the pH shift is 0.6 pH units or less after storage at room temperature for at least 6 months. Item 25. The aqueous dalbavancin formulations described in Items 1 to 24 are for parenteral use.

[0127] Item 26. 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 the aqueous solution according to Items 1 to 25 to a patient in need thereof.

[0128] Item 27. An aqueous dalbavancin formulation according to items 1 to 25 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.

Claims

1. An aqueous dalbavancin preparation that can be administered immediately, Darbavancin or a pharmaceutically acceptable salt of darbavancin, A weight osmolality adjusting agent, One or more amino acids, Includes, The aforementioned formulation has a pH in the range of 4.8 to 5.

9. The concentration of dalbavancin is in the range of 1 to 7 mg / ml, and The formulation is an aqueous dalbavancin formulation, which is a clear solution free of visible particles after being stored at room temperature for at least six months.

2. The aqueous dalbavancin formulation according to claim 1, wherein the formulation shows an increase of less than 8% in mannosyl aglycone impurities when measured by HPLC.

3. The aqueous dalbavancin formulation according to claim 1, wherein the solution, after being stored at room temperature for six months, shows an increase of less than 4% in mannosyl aglycone impurities when measured by HPLC.

4. The aqueous dalbavancin formulation according to claim 1, wherein the weight osmolality adjusting agent contains dextrose.

5. The aqueous dalbavancin formulation according to claim 1, wherein the formulation contains an L-amino acid.

6. The aqueous dalbavancin formulation according to claim 1, wherein the formulation comprises an L-amino acid selected from L-histidine, L-aspartic acid, L-glutamic acid, and L-isoleucine.

7. The aqueous dalbavancin formulation according to claim 1, wherein the formulation comprises L-aspartic acid.

8. The aqueous dalbavancin formulation according to claim 1, wherein the formulation contains 10 mM L-amino acid.

9. An aqueous dalbavancin formulation according to any one of claims 1 to 8, for parenteral use in the treatment of bacterial infections.

10. An aqueous dalbavancin formulation according to any one of claims 1 to 8, 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.