A stable dalbavancin pharmaceutical composition as an immediately dilutable formulation

Abstract

The present invention relates to a stable, aqueous, ready-to-dilute composition comprising dalbavancin or a physiologically acceptable salt thereof, suitable for intravenous administration. The aqueous formulation of the present invention provides enhanced long-term stability during storage and does not require reconstitution prior to administration. The present invention relates to a stable aqueous dalbavancin composition and its use in the treatment of bacterial infections.

Description

Technology Field

[0001] The present invention relates to a stable aqueous ready-to-dilute pharmaceutical composition comprising dalbavancin or a physiologically acceptable salt thereof, and other pharmaceutically acceptable excipients such as stabilizers, isotonic agents / co-solvents, and solvents. The formulation consists of a minimal number of components and exhibits an acceptable impurity profile under long-term stability conditions. Background Technology

[0002] Dalbavancin is a second-generation lipoglycopeptide bactericidal antibiotic approved for the treatment of acute bacterial skin and soft tissue infections (ABSSSI) caused by certain Gram-positive strains, including methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), in adult and pediatric patients. Like other glycopeptide antibiotics, dalbavancin exerts its bactericidal effect by interfering with cell wall biosynthesis.

[0003] Dalbavancin is derived from natural glycopeptides by amination of 3-(dimethylamino)-1-propylamine to the peptide carboxyl group at amino acid 7. The introduction of this substituent increases efficacy against Staphylococcus aureus, particularly coagulase-negative staphylococci.

[0004] Dalbavancin is a mixture of five closely related active congeners or factors (A0, A1, B0, B1, and B2), all of which are active (bactericidal) against various Gram-positive bacteria. These congeners all share the same core structure but differ in the presence of an additional methyl group (R2) on the fatty acid side chain (R1) and / or terminal amino group of the N-acylaminoglucuronic acid moiety (as shown below). Among these, factor B0 accounts for the main component of the active substance.

[0005]

[0006]

[0007] Anhydrous free base

[0008] Structural formula and substitution pattern of dalbavancide hydrochloride homologues

[0009] Glycopeptides, particularly dalbavancin, are highly unstable in aqueous solutions due to glycosidic linkages, and the major degradation product of dalbavancin in aqueous solution is a non-homologous component called mannosyl aglycone (MAG). Mannosyl aglycone (MAG) is the primary degradation product of dalbavancin. The likely cause of MAG formation is a hydrolysis mechanism in which the oxygen of the phenyl ring is protonated by acid or water, followed by a nucleophilic attack by water on the anomeric carbon of the glycone sugar. MAG is primarily formed under acidic and high-temperature conditions.

[0010] Dalbavancin is currently marketed in the United States under the trade name DALVANCE® and in Europe under the trade name XYDALBA®. As a lyophilized formulation in a glass vial, it is a sterile, lyophilized, preservative-free solid ranging from white to grayish-white to pale yellow. Each vial contains dalbavancin HCl, equivalent to 500 mg of dalbavancin, as a free base, and lactose monohydrate (129 mg) and mannitol (129 mg) as excipients. Sodium hydroxide or hydrochloric acid may be added to adjust the pH during preparation. After reconstitution, the powder is further diluted with United States Pharmacopoeia (USP) 5% dextrose injection solution for intravenous infusion (IV).

[0011] According to the patient information leaflet, DALVANCE® / XYDALBA® must be reconstituted with 25 mL of USP water for injection or USP 5% dextrose injection solution. Additionally, this solution is diluted in an intravenous bag containing USP 5% dextrose injection solution so that the final dalbavancin concentration is between 1 mg / mL and 5 mg / mL. Reconstitution of the lyophilized vial may take approximately 5 minutes to obtain a clear, colorless to yellowish solution (see: xydalba-epar-product-information_en). Furthermore, during reconstitution, the lyophilized formulation tends to form bubbles within the reconstituted solution. This warrants essential precautions regarding further dilution and additional inspection for the presence of foam or bubbles in the intravenous bag.

[0012] MAG is a result of the hydrolysis of the glycoside bonds of dalbavancin, which produces a component with lower bactericidal activity lacking an acylglucuronamine moiety. To minimize this degradation, a product is sold in the United States in the form of a powder vial for reconstitution. This contains dalbavancin hydrochloride (free base 500 mg), lactose monohydrate (129 mg), and mannitol (129 mg) in the form of a lyophilized powder. According to the patient information leaflet, instructions are provided to reconstitute the lyophilized product with USP sterile water for injection or USP 5% dextrose injection solution, and then dilute using only USP 5% dextrose injection solution to a final concentration of 1 mg / mL to 5 mg / mL. The labeling guidelines specify that the reconstituted vial or diluted intravenous bag may be stored at a refrigerated temperature (2°C to 8°C) or controlled room temperature (20°C to 25°C), and that the total time from reconstitution through dilution to administration must not exceed 48 hours. The European XYDALBA® product is also a single-use vial containing dalbavancin, lactose monohydrate, and mannitol, which is reconstituted in water and then diluted in 5% dextrose injection solution. Additionally, the XYDALBA® label specifies that the use of sodium chloride-containing solutions will cause precipitation and should not be used for reconstitution or dilution. Importantly, the XYDALBA® label explicitly states that for both the reconstituted and diluted solutions, the stability during chemical and physical use has been proven to be 48 hours at 25°C or below.

[0013] U.S. Patent No. 8,143,212 and U.S. Patent No. 7,115,564 disclose lyophilized dalbavancin formulations comprising mannitol and lactose monohydrate.

[0014] U.S. Patent No. 7,119,061 B2 describes a freeze-dried powder formulation having a ratio of dalbavancin and a stabilizer of 2:1, in which the formulation contains about 4% or less of MAG by weight after storage at 40°C for about 3 months.

[0015] WO 2023 / 211501 A1 describes ready-to-administer heat-stable aqueous dalbavancin formulations containing buffers, metal ions, and / or cyclodextrins, having an enhanced stability profile. However, formulations containing (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) and sulfo-butyl ether-β-cyclodextrin (SBE-β-CD) in particular may be hazardous to humans. All cyclodextrin-based excipients have been proven to exhibit nephrotoxicity upon intravenous administration. Additionally, HP-β-CD exhibits greater nephrotoxicity than SBE-β-CD. The formulations further contain certain metal ions that may cause additional complications and toxicity issues during excretion via the kidneys. Examples of HP-β-CD use at concentrations of 55 mM to 110 mM, exceeding the limits of the Inactive Ingredients Database (IIG) provided by the U.S. Food and Drug Administration (USFDA), are described. Considering a maximum daily dose of dalbavancin of 1500 mg, a 20 mg / mL solution contains 55 mM (6 g) of HP-β-CD, whereas the acceptable limit for intravenous use is 1.33 g.

[0016] In addition, it has been established that dalbavancin is unstable in aqueous solutions, and accordingly, currently commercially available formulations are in freeze-dried form. The problem to be solved

[0017] Therefore, there is still an unmet need to develop a stable and ready-to-dilute dalbavancin composition that can be safely administered to the human body, contains minimal excipients with a simple manufacturing process, and provides an enhanced and sustained stability profile in an aqueous form. means of solving the problem

[0018] Summary of the Invention

[0019] The present invention relates to a stable and ready-to-dilute aqueous pharmaceutical composition for parenteral administration, comprising dalbavancin or a pharmaceutically acceptable salt thereof as an active pharmaceutical ingredient, and a pharmaceutically acceptable excipient. The aqueous formulation does not contain preservatives and exhibits excellent storage stability in the aqueous form. An additional advantage of the present invention is that it is less cumbersome for healthcare workers as there is no need to reconstitute the solution, and it provides greater flexibility and ease in emergency situations compared to known conventional lyophilized formulations.

[0020] In the first aspect of the present invention, a stable and immediately dilutable aqueous pharmaceutical composition for intravenous administration comprises dalbavancin or a pharmaceutically acceptable salt thereof, at least one stabilizer, at least one isotonic agent and / or co-solvent, at least one solvent, and at least one acidifying agent and / or alkalizing agent sufficient to adjust the pH of the aqueous formulation composition.

[0021] In another aspect of the present invention, a stable and immediately dilutable aqueous dalbavancin composition comprises one or more stabilizers (preferably sugars), one or more isotonic agents or cosolvents such as sugar alcohols, one or more solvents such as water or buffers, and one or more acidifying agents and / or alkalizing agents sufficient to adjust the pH of the solution to a range of about 4.0 to 6.0.

[0022] In one example of the first phase, dalbavansine is dalbavansine hydrochloride.

[0023] In one example of the first phase, dalbavance hydrochloride is present in an amount of about 50 mg / mL to 200 mg / mL.

[0024] In another example of the first phase, the stabilizer includes, but is not limited to, sugar.

[0025] In another example of the first phase, the stabilizer is a sugar, and is a sugar including but not limited to mannitol, lactose monohydrate, sucrose, sorbitol, cellulose, trehalose, maltose, dextrose, or a mixture thereof.

[0026] In a preferred example of the first phase, the sugar is selected from mannitol and / or lactose monohydrate.

[0027] In one example of the first phase, the stabilizer is present at a concentration of about 10 to 80 mg / mL, preferably 10 to 50 mg / mL.

[0028] In one example of the first phase, the isotonic agent and / or cosolvent comprises, but is not limited to, sodium chloride, potassium chloride, acetate buffer, benzyl alcohol, propylene glycol, polyethylene glycol, dimethylacetamide (DMA), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), sugar alcohols, e.g., anhydrous glycerol (glycerin), glycerol monohydrate, glycerin derivatives, glycerin conjugated polyols, and physical mixtures of glycerin and other polyols or mixtures thereof.

[0029] In another example of the first phase, the isotonic agent / co-solvent is anhydrous glycerol.

[0030] In one example of the first phase, the isotonic agent / co-solvent is present at a concentration of about 10 mg / mL (1% w / v) to 800 mg / mL (80% w / v).

[0031] In one example of the first phase, the isotonic agent and / or co-solvent is present at a concentration of about 10 to 80 mg / mL, preferably 10 to 50 mg / mL.

[0032] In another example of the first phase, the solvent includes, but is not limited to, water or a pharmaceutically acceptable buffer.

[0033] In another example of the first phase, the pharmaceutically acceptable buffer comprises, but is not limited to, an acetate buffer, a phosphate buffer, a citrate buffer, or a mixture thereof with a pH of 3.5 to 7.5, preferably 4.5.

[0034] In a preferred example of the first phase, the buffer solution has a concentration in the range of about 1 mM to 100 mM, preferably 1 mM to 50 mM, more preferably 20 mM.

[0035] In another example of the first phase, the ratio of isotonic agent / co-solvent to solvent is selected from about 10:90 v / v to 90:10 v / v, and more preferably, said ratio is selected from 30:70, 40:60, 50:50 or 20:80.

[0036] In an additional example of the first phase, the acidifying agent and / or alkalizing agent includes, but is not limited to, hydrochloric acid, sodium hydroxide, or a buffer solution.

[0037] In one example of the first aspect of the present invention, the pH of the composition may optionally range from 1 to 7, more preferably from 2 to 6, more preferably from 3 to 5, more preferably from 4 to 5, and more preferably about 4.5.

[0038] In a further aspect of the present invention, the dalbavancin pharmaceutical composition does not contain a preservative.

[0039] In a further aspect of the present invention, the aqueous formulation exhibits a promising impurity profile along with excellent stability over long-term conditions. Specific details for implementing the invention

[0040] The subject matter of the present invention may be more easily understood by referring to the following detailed description, which forms part of the present invention. The present invention is not limited to the specific methods, conditions, or parameters described and / or illustrated herein, and it should be understood that the terms used herein are for illustrative purposes only and are not intended to limit the claimed invention.

[0041] Unless otherwise defined herein, scientific and technical terms used in connection with this application shall have the meaning generally understood by those skilled in the art. Additionally, unless otherwise required by the context, singular terms shall include the plural and plural terms shall include the singular.

[0042] As used in this specification and the appended claims, the singular forms “one (a),” “one (an),” and “the” include multiple referents unless the context clearly indicates otherwise.

[0043] As used herein, the term “about” means that the amount, size, formulation, parameters, and other quantities and characteristics are not precise and do not need to be precise, but may be approximated and / or larger or smaller as intended to account for tolerances, conversion factors, rounding, measurement errors, and other factors. As used herein, a range may be expressed from one “about” specific value and / or another “about” specific value. As used herein, the term “about” means ±5%, ±10%, or ±20% of the modified value.

[0044] "Optional" or "optionally" means that the event or situation described below may or may not occur, and that the above description includes cases where the event or situation occurs and cases where it does not occur.

[0045] The term "stable formulation" or "stabilized formulation" refers to any formulation of dalbavancin having sufficient physical and chemical stability to allow storage at a convenient temperature for a reasonable period of time.

[0046] The terms "stability," "chemical stability," or "stable" indicate that an acceptable amount of API is present in a product, composition, or formulation, or that API has not degraded beyond a certain amount after a certain period. Accordingly, in a stable product, solution, or formulation, unacceptable degradation of the active agent is prevented.

[0047] Stability can be expressed as the purity or content (assay) of dalbavancin in the composition according to the present invention. If the composition initially contains dalbavancin of a specific purity or content, the stability of the composition is reflected by the decrease of the same component in the product, formulation, or composition over time, and a stable composition will contain a specific content of dalbavancin even after a predetermined period. For example, in a stable product, the formation of MAG is reduced.

[0048] Therefore, "stability" may be defined by the total amount of impurities or individual impurities generated after a certain period. The amount of present impurities can be expressed as a percentage, for example, as the percentage of peak areas in an HPLC chromatogram, or calculated based on standard solutions.

[0049] The dalbavancin formulation of the present invention may be intended for intravenous or parenteral administration. The immediately dilutable formulation is a sterile liquid injectable formulation that does not require reconstitution before use, and thus the formulation may be further diluted when present as a concentrated solution. The immediately dilutable liquid formulation may be stored in a pharmaceutically suitable container, e.g., a glass vial, ampoule, bottle, or syringe, or a plastic intravenous bag.

[0050] As used herein, the term “ready-to-dilute” refers to a formulation of dalbavancin or a pharmaceutically acceptable salt thereof that can be administered to a patient after being directly diluted with an infusion medium (e.g., dextrose solution, water for injection, a suitable non-aqueous solvent, or any other infusion medium). For example, a ready-to-dilute formulation may be stored in a container such as a vial, syringe, or injector and may be further diluted to the required concentration and transferred to a final administration device such as a syringe or infusion bag before being administered to a patient.

[0051] The present invention relates to a stable aqueous formulation for intravenous administration comprising dalbavancin or a pharmaceutically acceptable salt thereof, at least one stabilizer, at least one isotonic agent and / or co-solvent, at least one solvent, and at least one acidifying agent and / or alkalizing agent sufficient to control the pH of the composition. The aqueous dalbavancin formulation of the present invention exhibits enhanced stability in an aqueous form.

[0052] In a first embodiment of the present invention, a stable and immediately dilutable aqueous dalbavancin composition comprises one or more stabilizers (preferably sugars), one or more isotonic agents or cosolvents such as sugar alcohols, one or more solvents such as water or buffers, and one or more acidifying agents and / or alkalizing agents sufficient to adjust the pH of the solution to a range of about 4.0 to 6.0.

[0053] In a preferred embodiment of the present invention, dalbavancin exists in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt is preferably dalbavancin hydrochloride.

[0054] In one embodiment of the present invention, dalbavance hydrochloride is present in an amount of about 20 mg / mL to about 200 mg / mL, preferably 50 mg / mL to 200 mg / mL.

[0055] In one embodiment, the stabilizer includes, but is not limited to, sugars.

[0056] In one embodiment, the stabilizer is a sugar comprising, but not limited to, mannitol, lactose monohydrate, sucrose, sorbitol, cellulose, trehalose, maltose, dextrose, or a mixture thereof.

[0057] In a preferred embodiment, the sugar is selected from mannitol and / or lactose monohydrate.

[0058] In one embodiment, the stabilizer is present at a concentration of about 10 mg / mL to 80 mg / mL, preferably at a concentration of 10 mg / mL to 50 mg / mL.

[0059] In one embodiment, the isotonic agent / co-solvent comprises, but is not limited to, sodium chloride, potassium chloride, acetate buffer, benzyl alcohol, propylene glycol, polyethylene glycol, dimethylacetamide (DMA), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), sugar alcohols, e.g., anhydrous glycerol (glycerin), glycerol monohydrate, glycerin derivatives, glycerin conjugated polyols, and physical mixtures of glycerin and other polyols.

[0060] In a preferred embodiment, the isotonic agent / co-solvent is anhydrous glycerol.

[0061] In one example of the first phase, the isotonic agent / co-solvent is present at a concentration of about 10 mg / mL (1% w / v) to 800 mg / mL (80% w / v).

[0062] In another embodiment, the isotonic agent / co-solvent is present at a concentration of about 10 to 80 mg / mL, preferably 10 to 50 mg / mL.

[0063] In one embodiment, the solvent comprises, but is not limited to, a pharmaceutically acceptable buffer, water, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene, glycolin, or a mixture thereof.

[0064] In a preferred embodiment, the pharmaceutically acceptable buffer comprises, but is not limited to, an acetate buffer, a phosphate buffer, a citrate buffer, or a mixture thereof having a pH of 3.5 to 7.5, more preferably 4.5.

[0065] In a preferred embodiment, the buffer has a concentration in the range of about 1 to 100 mM, preferably 1 to 50 mM, and more preferably 20 mM.

[0066] In another example of the first phase, the ratio of isotonic agent / co-solvent to solvent is selected from about 10:90 v / v to 90:10 v / v, and more preferably, said ratio is selected from 30:70, 40:60, 50:50 or 20:80.

[0067] In another embodiment, the formulation may further comprise one or more acidifying agents and / or alkalizing agents, e.g., an acid or a base. The acidifying agents and / or alkalizing agents serve to help control the pH of the aqueous formulation.

[0068] In a preferred embodiment, the acidifying agent and / or alkalizing agent comprises, but is not limited to, hydrochloric acid, sodium hydroxide, or a buffer solution, and is preferably hydrochloric acid and / or sodium hydroxide. The concentration of the acidifying agent and / or alkalizing agent may be any concentration suitable for adjusting the pH.

[0069] In one embodiment, the pH of the composition may optionally range from 1 to 7, more preferably from 2 to 6, more preferably from 3 to 5, more preferably from 4 to 5, and more preferably about 4.5.

[0070] In another embodiment, the formulation is in an aqueous form.

[0071] In another embodiment of the present invention, the formulation is in a form that can be immediately diluted.

[0072] In another embodiment, the route of administration is intravenous.

[0073] In a further embodiment of the present invention, the dalbavancin pharmaceutical composition does not contain a preservative.

[0074] In a further embodiment of the present invention, the aqueous formulation exhibits a promising impurity profile along with excellent stability over long-term conditions.

[0075] In another embodiment of the present invention, the composition of the present invention is stable against decomposition impurities such as commercially known impurities such as impurity 1 (MAG), impurity 2 and impurity 3.

[0076] Impurity 1 -(MAG) or ((3S,15R,18R,34R,35S,38S,48R,50aR)-5,31-dichloro-38-{[3-(dimethylamino)propyl]carbamoyl}-6,11,34,40,44,56-hexahydroxy-42-(α-D-mannopyranosyloxy)-15-(methylamino)-2,16,36,50,51,59-hexaoxo-2,3,16,17,18,19,35,36 ,37,38,48,49,50,50a-tetradecahydro-1H,15H,34H-20,23:30,33-dieteno-3,18:35,48-bis(iminometano)-4,8:10,14:25,28:43,47-tetrametheno[1,14,6,22]dioxadiazcyclooctacosino[4,5-m][10,2,16]benzoxadiazcyclotetracosine)

[0077] Impurities 2 - (2-deoxy-1-O-{[(3S,15R,18R,34R,35S,38S,48R,50aR)-5,31-dichloro-38-{[3-(dimethylamino)propyl]carbamoyl}-6,11,34,40,44-pentahydroxy-42-(α-D-mannopyranosyloxy)-15-(methylamino)-2,16,36,50,51,59-hexaoxo-2,3,16,17,18,19,35,36,37,38,48,49,5 0,50a-tetradecahydro-1H,15H,34H-20,23:30,33-dieteno-3,18:35,48-bis(iminometano)-4,8:10,14:25,28:43,47-tetrametheno[1,14,6,22]dioxadiazcyclooctacosino[4,5-m][10,2,16]benzoxadiazcyclotetracosin-56-yl]}-2-[(10-methylundecanoyl)]-β-D-glucopyranuronic acid)

[0078] Impurity 3 -(2-deoxy-1-O-{[(3S,15R,18R,34R,35S,38S,48R,50aR)-5,31-dichloro-38-{[3-(dimethylamino)propyl]carbamoyl}-6,11,34,40,44-hexahydroxy-15-(methylamino)-2,16,36,50,51,59-hexaoxo-2,3,16,17,18,19,35,36,37,38,48,49,50,50a-tetrade Carhydro-1H,15H,34H-20,23:30,33-dieteno-3,18:35,48-bis(iminometano)-4,8:10,14:25,28:43,47-tetrametheno[1,14,6,22]dioxadiazcyclooctacosino[4,5-m][10,2,16]benzoxadiazcyclotetracosin-56-yl]}-2-[(10-methylundecanoyl)amino]-β-D-glucopyranuronic acid)

[0079] The liquid formulation of the present invention is stable or exhibits stability upon storage, and includes formulation characteristics that may be affected by storage conditions, e.g., the content or concentration of the active ingredient, impurities (e.g., various degrading impurities), visual appearance characteristics (e.g., color, transparency, turbidity, haze, precipitates, etc.), and osmolality. Storage conditions that may affect stability may include, e.g., storage temperature, humidity (e.g., relative humidity), and storage period.

[0080] In one or more embodiments of the present invention, stability may be evaluated by the amount of total decomposition impurities, the visual appearance of the formulation, the results of content analysis of the prepared formulation, the components of dalbavancin, etc. A stable formulation is an essentially transparent solution and has no or essentially no traces of visual contamination by foreign substances and / or particulates.

[0081] In a further embodiment of the present invention, the osmolality of a solution diluted or admixtured in 5% dextrose injection was investigated. Osmolality represents the concentration of all particles dissolved in the solution. Generally, for intravenous drip infusion, the osmolality range of the diluted solution should be less than 900 mOsm / L.

[0082] To demonstrate the implementation of the present invention, the following examples were prepared and tested. However, these examples should not be construed as limiting the scope of the present invention. The claims will serve to define the present invention.

[0083] Examples

[0084] Manufacturing of various Dalbabanshin formulations

[0085] A mixture of anhydrous glycerol and water for injection was prepared according to the ratios in Table 1. USP lactose monohydrate (25.8 mg) and USP mannitol (25.8 mg) were added to the mixture. Dalbavance hydrochloride was slowly added to the mixture to prepare a clear solution. The pH of the prepared solution was adjusted to a range of 4.0 to 5.0 based on a target pH of 4.50 using a 1.0 N sodium hydroxide solution / 1.0 N hydrochloric acid solution, and the final volume was adjusted to 1 mL using a mixture of anhydrous glycerol and water for injection. The pH of the final solution was checked.

[0086] Some formulations may also be prepared according to the following method using the same excipients and amounts as mentioned in Table 1 (Example 7).

[0087] Mannitol was added to a preparation vessel with stirring in about 40 to 50% of water for injection or pH 4.5 acetate buffer. A clear solution was obtained. Lactose monohydrate was added to the preparation vessel with stirring to obtain a clear solution. Glycerol or pH 4.5 acetate buffer was added to the preparation vessel with stirring to obtain a clear solution. Dalbavance hydrochloride was added to the preparation vessel and stirred until a clear solution was obtained. The pH of the bulk solution was adjusted to a range of 3.5 to 6.0, preferably 4.0 to 5.0. Subsequently, the final volume was adjusted to a batch volume using water for injection or pH 4.5 acetate buffer. The prepared solution was filtered through a hydrophilic capsule filter. The filtered solution was aseptically filled into vials (5 mL per vial per unit volume). The vials were plugged and sealed. The vials were stored at 2°C to 8°C.

[0088] Various Dalba Bansin formulations furtherance Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Dalbavancin hydrochloride (mg / mL) 100 50 100 100 100 100 100 Lactose monohydrate (USP) (mg / mL) 25.8 Mannitol (USP) (mg / ml) 25.8 Sodium hydroxide NF Add an appropriate amount to adjust the pH to 4.0-5.0 Hydrochloric acid NF Add an appropriate amount to adjust the pH to 4.0-5.0 Anhydrous glycerol : Water for injection (30:70 v / v) Add an appropriate amount to adjust to 1 mL Add an appropriate amount to adjust to 1 mL - - - - Add an appropriate amount to adjust to 1 mL Glycerol anhydrous: Acetate buffer pH 4.5 (30:70 v / v) - - Add an appropriate amount to adjust to 1 mL - - - - Anhydrous glycerol : Water for injection (40:60 v / v) - - - Add an appropriate amount to adjust to 1 mL - - - Anhydrous glycerol : Water for injection (20:80 v / v) - - - - Add an appropriate amount to adjust to 1 mL - - Anhydrous glycerol : Water for injection (50:50 v / v) - - - - - Add an appropriate amount to adjust to 1 mL -

[0089] HPLC method for analyzing degradation products, content, and component distribution of dalbavancin in dalbavancin formulations

[0090] Instrument: High-performance liquid chromatography (HPLC) equipped with UV / PDA detector

[0091] Mobile phase A: Mixture of ammonium dihydrogen phosphate buffer and acetonitrile (95:5)

[0092] Mobile phase B: Mixture of ammonium dihydrogen phosphate buffer and acetonitrile (30:70)

[0093] Exudation method: Gradient

[0094] Detector: UV 210 nm

[0095] Column: C18 column (250 x 4.6 mm, 3 μm)

[0096] Column temperature: 55℃

[0097] Injection volume: 10 μl

[0098] The sample was prepared by diluting with a mixture of water and orthophosphoric acid at a ratio of 1000:2 (v / v).

[0099] Analysis of decomposition products

[0100] An HPLC method for the quantitative determination of known and individual unknown impurities in dalbavancin injectable pharmaceuticals has been developed and validated. This method is specific for separating all process-derived and degradation impurities from the active ingredient peak present in the pharmaceutical and other raw materials (placebo). The degradation product method using HPLC (HPLC equipped with a UV / PDA detector) is capable of separating all known impurities and has been validated as a stability indicator.

[0101] After excluding the peaks attributable to the blank test, the content (%) of each specific known impurity and unknown impurity is calculated using the following formula.

[0102] Content of known impurities (%) =

[0103]

[0104] Content of unknown impurities (%) =

[0105]

[0106] In the above equation,

[0107] A Spl1 : Area of ​​known / unknown impurities in the sample preparation solution

[0108] A Std : Average area of ​​Dalbavanshin B0 in standard solution

[0109] W Std : Weight of dalbavancin HCl standard / API taken from standard preparation (mg)

[0110] D Std : Dilution factor of standard solution

[0111] W spl : Weight of the sample taken (g)

[0112] D Spl : Dilution factor of sample preparation solution

[0113] P : Potency of Dalbavansin HCl as absolute Dalbavansin B0 content (based on spot)

[0114] LC : Label claim for dalbavancin (100 mg / mL)

[0115] RF : Response coefficient

[0116] Total impurities: Sum of all known impurities + Sum of all unknown impurities

[0117] Table 2 below shows the pH and degradation product analysis results of the dalbavancin formulation in anhydrous glycerol and water (30:70 v / v) prepared as described above (Example 1). The formulation was stored at 2°C to 8°C and under 25°C / 60% RH conditions.

[0118] Analysis of pH and degradation products of 100 mg / mL dalbavancin formulation in anhydrous glycerol and water (30:70 v / v) parameters beginning (2-8℃) (25℃ / 60%RH) 1M 3M 5M 1M 2M 3M explanation CCS CCS CCS CCS CCS CCS CCS pH 4.42 4.46 4.37 4.50 4.45 4.44 4.33 decomposition products Impurity 1 (MAG) 0.15 0.22 0.38 0.59 0.55 1.24 1.92 Impurities 2 BQL BQL BQL BQL BQL BQL BQL Impurity 3 BQL BQL BQL BQL BQL BQL BQL arbitrary individual unknown impurities BQL BQL BQL BQL BQL BQL BQL Total impurities 0.15 0.22 0.38 0.59 0.55 0.55 1.92

[0119] CCS: Clear Colorless Solution

[0120] BQL: Below Quantification Level

[0121] MAG: Mannosyl Aglycone

[0122] As shown in Table 2, the 100 mg / mL dalbavancin formulation in anhydrous glycerol and water (30:70 v / v) was found to be stable in terms of appearance, pH, and total degradation impurities when stored for at least 5 months at 2°C to 8°C and for at least 3 months at 25°C / 60% RH.

[0123] When the above solution was further diluted with USP dextrose injection solution, the osmolality was found to be 335 mOsmol / Kg.

[0124] Table 3 below shows the pH and degradation product analysis results of the dalbavancin formulation in anhydrous glycerol and water (30:70 v / v) prepared as described above (Example 2). The formulation was stored at 2°C to 8°C and under 25°C / 60% RH conditions.

[0125] Analysis of pH and degradation products of 50 mg / mL dalbavancin formulation in anhydrous glycerol and water for injection (30:70 v / v) parameters beginning (2-8℃) (25℃ / 60%RH) 1 M 3 M 1 M 3 M explanation CCS CCS CCS CCS CCS pH 4.57 4.55 4.56 4.59 4.58 decomposition products Impurity 1 (MAG) 0.6 0.42 0.6 1.65 4.09 Impurities 2 BQL BQL BQL BQL BQL Impurity 3 BQL BQL BQL BQL BQL arbitrary individual unknown impurities BQL BQL BQL BQL BQL Total impurities 0.6 0.42 0.6 1.65 4.09

[0126] CCS: Transparent, colorless solution

[0127] BQL: Below the limit of quantification

[0128] MAG: Mannosyl aglycone

[0129] As shown in Table 3, the 50 mg / mL dalbavancin formulation in anhydrous glycerol and water (30:70 v / v) was found to be stable in terms of appearance, pH, and total degradation impurities when stored for at least 3 months at 2°C to 8°C and for at least 3 months at 25°C / 60% RH.

[0130] When the above solution was further diluted with USP dextrose injection solution, the osmolality was found to be 335 mOsmol / Kg.

[0131] Table 4 below shows the pH and degradation product analysis results of the dalbavancin formulation in anhydrous glycerol and acetate buffer (30:70 v / v) prepared as described above (Example 3). The formulation was stored at 2°C to 8°C and under 25°C / 60% RH conditions.

[0132] Analysis of pH and degradation products of 100 mg / mL dalbavancin formulation in anhydrous glycerol and acetate buffer (30:70 v / v) parameters beginning (2-8℃) (25℃ / 60%RH) 1 M 2 M 1 M 2 M explanation CCS CCS CCS CCS CCS pH 4.32 4.44 4.44 4.42 4.45 decomposition products Impurity 1 (MAG) 0.57 0.54 0.71 1.83 4.27 Impurities 2 BQL BQL BQL BQL BQL Impurity 3 BQL BQL BQL BQL BQL arbitrary individual unknown impurities BQL BQL BQL BQL BQL Total impurities 0.57 0.54 0.71 1.83 4.27

[0133] CCS: Transparent, colorless solution

[0134] BQL: Below the limit of quantification

[0135] MAG: Mannosyl aglycone

[0136] As shown in Table 4, the 100 mg / mL dalbavancin formulation in anhydrous glycerol and acetate buffer (30:70) was found to be stable in terms of appearance, pH, and total degradation impurities when stored for at least 2 months at 2°C to 8°C and for at least 2 months at 25°C / 60% RH.

[0137] When the above solution was further diluted with USP dextrose injection solution, the osmolality was found to be 419 mOsmol / Kg.

[0138] Table 5 below shows the pH and degradation product analysis results of the dalbavancin formulation in anhydrous glycerol and water (40:60 v / v) prepared as described above (Example 4). The formulation was stored at 2°C to 8°C and under conditions of 25°C / 60% RH.

[0139] Analysis of pH and degradation products of 100 mg / mL dalbavancin formulation in anhydrous glycerol and water for injection (40:60 v / v) parameters beginning 3 M (2-8℃) 1 M (25℃ / 60%RH) explanation CCS CCS CCS pH 4.68 4.62 4.62 decomposition products Impurity 1 (MAG) 0.88 1.21 2.94 Impurities 2 BQL ND BQL Impurity 3 BQL BQL BQL arbitrary individual unknown impurities BQL BQL BQL Total impurities 0.88 1.21 2.94

[0140] CCS: Transparent, colorless solution

[0141] BQL: Below the limit of quantification

[0142] MAG: Mannosyl aglycone

[0143] ND: Not detected

[0144] As shown in Table 5, the 100 mg / mL dalbavancin formulation in anhydrous glycerol and water (40:60 v / v) was found to be stable in terms of appearance, pH, and total degradation impurities when stored for at least 3 months at 2°C to 8°C and for at least 1 month at 25°C / 60% RH.

[0145] When the above solution was further diluted with USP dextrose injection solution, the osmolality was found to be 548 mOsmol / Kg.

[0146] Table 6 below shows the pH and degradation product analysis results of the dalbavancin formulation in anhydrous glycerol and water (20:80 v / v) prepared as described above (Example 5). The formulation was stored at 2°C to 8°C and under 25°C / 60% RH conditions.

[0147] Analysis of pH and degradation products of 100 mg / mL dalbavancin formulation in anhydrous glycerol and water for injection (20:80 v / v) parameters beginning 3 M (2-8℃) 1 M (25℃ / 60%RH) explanation CCS CCS CCS pH 4.65 4.64 4.58 decomposition products Impurity 1 (MAG) 0.84 1.1 2.55 Impurities 2 BQL BQL BQL Impurity 3 BQL BQL BQL arbitrary individual unknown impurities BQL BQL BQL Total impurities 0.84 1.1 2.55

[0148] CCS: Transparent, colorless solution

[0149] BQL: Below the limit of quantification

[0150] MAG: Mannosyl aglycone

[0151] As shown in Table 6, the 100 mg / mL dalbavancin formulation in anhydrous glycerol and water (20:80 v / v) was found to be stable in terms of appearance, pH, and total degradation impurities when stored for at least 3 months at 2°C to 8°C and for at least 1 month at 25°C / 60% RH.

[0152] When the above solution was further diluted with USP dextrose injection solution, the osmolality was found to be 395 mOsmol / Kg.

[0153] Table 7 below shows the pH and degradation product analysis results of the dalbavancin formulation in anhydrous glycerol and water (50:50) prepared as described above (Example 6). The formulation was stored at 2°C to 8°C and under 25°C / 60% RH conditions.

[0154] Analysis of pH and degradation products of 100 mg / mL dalbavancin formulation in anhydrous glycerol and water for injection (50:50) parameters beginning 3 M (2-8℃) 1 M (25℃ / 60%RH) explanation CCS CCS CCS pH 4.60 4.63 4.55 decomposition products Impurity 1 (MAG) 0.36 0.62 2.31 Impurities 2 BQL BQL BQL Impurity 3 BQL BQL BQL arbitrary individual unknown impurities BQL BQL BQL Total impurities 0.36 0.62 2.31

[0155] CCS: Transparent, colorless solution

[0156] BQL: Below the limit of quantification

[0157] MAG: Mannosyl aglycone

[0158] As shown in Table 7, the 100 mg / mL dalbavancin formulation in anhydrous glycerol and water (50:50 v / v) was found to be stable in terms of appearance, pH, and total degradation impurities when stored for at least 3 months at 2°C to 8°C and for at least 1 month at 25°C / 60% RH.

[0159] When the above solution was further diluted with USP dextrose injection solution, the osmolality was found to be 553 mOsmol / Kg.

[0160] Table 8 below shows the pH and degradation product analysis results of the dalbavancin formulation in anhydrous glycerol and water (30:70) prepared as described above (Example 7). The formulation was stored at 2°C to 8°C and at 25°C / 60% RH.

[0161] Analysis of pH and degradation products of 100 mg / mL dalbavancin formulation in anhydrous glycerol and water for injection (30:70) parameters beginning (2-8℃) (25℃ / 60%RH) 1M 3M 6M 1M 3M explanation CCS CCS CCS CCS CCS CCS pH 4.42 4.46 4.37 4.50 4.45 4.44 decomposition products Impurity 1 (MAG) 0.55 0.54 0.62 0.71 1.89 4.62 Impurities 2 BQL BQL BQL ND ND BQL Impurity 3 BQL BQL BQL BQL BQL BQL arbitrary individual unknown impurities BQL BQL BQL BQL 0.11 0.16 Total impurities 0.55 0.54 0.71 0.71 1.89 4.78

[0162] CCS: Transparent, colorless solution

[0163] BQL: Below the limit of quantification

[0164] MAG: Mannosyl aglycone

[0165] ND: Not detected

[0166] As shown in Table 8, the 100 mg / mL dalbavancin formulation in anhydrous glycerol and water (30:70 v / v) was found to be stable in terms of appearance, pH, and total degradation impurities when stored at 2°C to 8°C for at least 6 months.

[0167] When the above solution was further diluted with USP dextrose injection solution, the osmolality was found to be 300 to 500 mOsmol / Kg.

[0168] Content test of Dalbavancin formulation

[0169] Content testing of the dalbavancin drug was performed using an HPLC equipped with a UV / PDA detector. This method is specific for separating all dalbavancin components (A0, A1, B0, B1, and B2) from impurities and other raw materials (placebo) present in the drug. Since B0 is the main component, the content value is calculated using B0 as the standard substance. To ensure that the drug complies with content stability limits, the release specifications and regulatory specifications for the finished product are proposed to be 92.0% to 105.0% and 90.0% to 110.0% of the labeled amount, respectively.

[0170] The content was calculated according to the following formula:

[0171]

[0172] In the above equation,

[0173] A Spl : Sum of the peak areas of Dalbavansin A0, A1, B0, B1, and B2 in the sample preparation solution

[0174] A Std : Average area of ​​the Dalbavansine B0 peak in Standard Solution-2, measured 5 times repeatedly.

[0175] W Std : Weight (mg) of ingested Dalbavansin HCl Standard-2

[0176] W spl : Weight of the sample taken (g)

[0177] P : Potency of Dalbavansin HCl as absolute Dalbavansin B0 content (based on spot)

[0178] Content test of 100 mg / mL dalbavancin formulation in anhydrous glycerol and water (30:70 v / v) condition beginning (2-8℃) (25℃ / 60%RH) 1M 3M 6M 1M 3M 6M Content (%) 95.80 93.60 95.60 95.80 92.00 91.20 86.60

[0179] Data for the components [(A0+A1), B0, and (B1+B2)] of the Dalbavansin component distribution

[0180] Dalbavancin is a mixture of five closely related active homologues (A0, A1, B0, B1, and B2), and component B0 is the main component of dalbavancin. The HPLC method is used in this test. This method is specific for separating all dalbavancin components (A0, A1, B0, B1, and B2). Acceptance criteria for each component are proposed based on stability data obtained during the development phase.

[0181] Calculate the components according to the Area Normalization method.

[0182]

[0183] In the above equation,

[0184] AT: Sum of all peak response values ​​in the sample chromatogram.

[0185] Distribution of dalbavancin components of a 100 mg / mL dalbavancin formulation in anhydrous glycerol and water (30:70 v / v). Ingredients (%) condition beginning (2-8℃) (25℃ / 60%RH) 1 M 3 M 6 M 1 M 3 M 6 M A0+A1 (%) 3.20 3.18 3.19 3.15 3.06 2.98 2.73 B0 90.14 90.17 89.77 89.68 87.89 83.18 76.80 B1+B2 5.56 5.47 5.71 5.44 5.37 5.26 4.74

Claims

Claim 1 A stable and ready-to-dilute aqueous pharmaceutical composition for intravenous administration, comprising dalbavancin or a pharmaceutically acceptable salt thereof, at least one stabilizer, at least one isotonic agent / cosolvent, and a pH adjuster. Claim 2 A pharmaceutical composition according to claim 1, wherein the dalbavancin is dalbavancin hydrochloride. Claim 3 A pharmaceutical composition according to claim 1, wherein the stabilizer is selected from the group consisting of mannitol, lactose monohydrate, sucrose, sorbitol, cellulose, trehalose, maltose, dextrose, or mixtures thereof. Claim 4 A pharmaceutical composition according to claim 1, wherein the isotonic agent / co-solvent is selected from the group consisting of sodium chloride, potassium chloride, acetate buffer, benzyl alcohol, propylene glycol, polyethylene glycol, dimethylacetamide (DMA), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), sugar alcohols, e.g., anhydrous glycerol (glycerin), glycerol monohydrate, glycerin derivatives, glycerin conjugated polyols, and physical mixtures of glycerin and other polyols or mixtures thereof. Claim 5 A pharmaceutical composition according to claim 1, wherein the pH adjuster is selected from the group consisting of hydrochloric acid, sodium hydroxide, buffer solution, or a mixture thereof. Claim 6 A pharmaceutical composition according to claim 1, wherein the solvent is selected from the group consisting of water or pharmaceutically acceptable buffer solutions. Claim 7 A pharmaceutical composition according to claim 1, wherein the isotonic agent / co-solvent and solvent are present in a ratio of 10:90 v / v to 90:10 v / v. Claim 8 In claim 1, the method for preparing the stable and immediately dilutable aqueous pharmaceutical composition comprises the following steps: (a) a step of preparing a clear solution by adding a stabilizer to about 40 to 50% of water for injection and stirring; (b) a step of preparing a clear solution by adding an isotonic agent / co-solvent and stirring; (c) a step of preparing a clear solution by adding dalbavancin to the solution and stirring; and (d) a step of adjusting the pH to a range of 4.0 to 5.0 and then adjusting the final volume with water for injection. Claim 9 A pharmaceutical composition having about 5% or less of MAG impurities after being stored at about 2°C to 8°C for at least 6 months in any preceding claim.

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