Daptomycin formulation

Abstract

To provide a solid pharmaceutically acceptable formulation of daptomycin having an improved reconstitution time.SOLUTION: This solid formulation comprises daptomycin, arginine, histidine, and at least one branched aliphatic amino acid selected from the group consisting of leucine, isoleucine, valine, and pharmaceutically acceptable salts thereof. In the solid formulation, the molar ratio of the at least one branched aliphatic amino acid to daptomycin is from 0.5:1 to 5:1.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to solid formulations of daptomycin comprising at least one branched aliphatic amino acid. The solid daptomycin formulations of the present disclosure exhibit improved reconstitution times. The present disclosure further relates to methods for preparing solid daptomycin formulations according to the present disclosure. [Background technology]

[0002] Daptomycin is the first cyclic lipopeptide antibiotic approved by the U.S. Food and Drug Administration (FDA) in 2003 for the treatment of infections caused by Gram-positive pathogens, including methicillin- and vancomycin-resistant strains. Due to its unique mechanism of action, which differs from all other antibacterial agents available on the market, daptomycin can overcome the acquired resistance mechanisms of many resistant strains. Given that clinical resistance to daptomycin has rarely been reported, this drug has become extremely important for current clinical practice.

[0003] [ka]

[0004] Daptomycin is currently available only in the form of a lyophilized powder for intravenous infusion (Cubicin® and Cubicin RF®), which requires reconstitution and subsequent dilution before administration to patients. Given that the reconstitution and dilution steps before patient administration are often time-consuming, it is important that both steps occur as quickly and smoothly as possible.

[0005] Based on available information for current commercially available lyophilized daptomycin products, the reconstitution step often takes approximately 30 minutes or more for Cubicin® and several minutes for Cubicin RF® (Non-Patent Document 1).

[0006] Reconstitution time plays an important role for injectable powders. Typically, reconstitution time increases with increasing active compound dosage. Therefore, a short reconstitution time is an important goal for the development of large-volume lyophilized active compound formulations. A short reconstitution time is preferable for both medical personnel and patients. If the reconstitution time is too long, the time required for preparation and drug administration to patients will increase.

[0007] A need remains for lyophilized daptomycin compositions that exhibit improved reconstitution characteristics, such as rapid reconstitution times with a pharmaceutically acceptable solution for reconstitution. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Frankenfeld et al.,Drug Des Devel Ther,vol.12,2018,p1953-1958 Summary of the Invention

[0009] The present disclosure relates to solid pharmaceutically acceptable formulations of daptomycin having improved reconstitution times comprising at least one branched aliphatic amino acid, or a pharmaceutically acceptable salt or derivative thereof.

[0010] In accordance with the present disclosure, it has been discovered that solid formulations of daptomycin containing at least one excipient selected from a branched aliphatic amino acid, or a pharmaceutically acceptable salt thereof, or a derivative thereof, have improved reconstitution properties. In particular, solid pharmaceutically acceptable formulations of daptomycin according to the present disclosure have improved reconstitution times. Furthermore, in one embodiment, solid pharmaceutically acceptable formulations of daptomycin may also have other improved properties, such as reduced foaming and reduced pH dependence of reconstitution times. Furthermore, in one embodiment, the improved reconstitution times of solid formulations of daptomycin according to the present disclosure do not change significantly during storage.

[0011] According to the present disclosure, branched aliphatic amino acids may include leucine, isoleucine, and valine. In one aspect of the present disclosure, the stability of a solid daptomycin formulation including a branched aliphatic amino acid as an excipient to reduce reconstitution time may be comparable to the stability of the same solid daptomycin formulation without any excipient to reduce reconstitution time. DETAILED DESCRIPTION OF THE INVENTION

[0012] Detailed Description of the Disclosure The present disclosure relates to solid pharmaceutically acceptable formulations of daptomycin having improved reconstitution times. The solid pharmaceutically acceptable formulations of daptomycin of the present disclosure include at least one excipient selected from branched aliphatic amino acids or pharmaceutically acceptable salts or derivatives thereof to decrease reconstitution times.

[0013] As used herein, the term "reconstitution excipient" is understood to mean an excipient that reduces the time required to reconstitute a dried formulation. According to the present disclosure, the reconstitution excipient may reduce the reconstitution time to 150 seconds or less. According to the present disclosure, the reduction in reconstitution time is also achieved when the reconstitution excipient is included in the pre-drying formulation at a concentration of 2.5% w / V or less. According to the present disclosure, the terms "reconstitution excipient" and "reconstitution time-reducing excipient" are used interchangeably. According to the present disclosure, the reconstitution excipient comprises a branched-chain amino acid.

[0014] As used herein, "branched-chain amino acid" is understood to mean an amino acid having a branched aliphatic side chain, i.e., a central carbon atom of which is attached to three or more carbon atoms. In particular, the branched-chain amino acid is selected from the group consisting of valine, leucine, and isoleucine, according to one embodiment of the present disclosure.

[0015] As used herein, the term "pharmaceutical formulation" or "pharmaceutically acceptable formulation" means a composition that is suitable for veterinary as well as human pharmaceutical use, and such compositions are generally safe, relatively non-toxic, do not cause unacceptable side effects, and contain pharmaceutically acceptable excipients such as, but not limited to, solvents, carriers, antioxidants, surfactants, lipids, sugars, amino sugars, organic acids, complexing agents, preservatives, stabilizers, bulking agents, buffers, diluents, vehicles, solubilizers, and binders.

[0016] As used herein, the terms "pharmaceutical composition," "pharmaceutical formulation," "composition," and "formulation" are used interchangeably. In one embodiment, the branched aliphatic amino acids include valine, isoleucine and leucine, pharmaceutically acceptable salts thereof, or derivatives thereof.

[0017] In one embodiment, pharmaceutically acceptable salts of branched aliphatic amino acids may include their hydrochloride, acetate, citrate, phosphate, succinate, tartrate and sulfate salts. In one embodiment, the at least one branched aliphatic amino acid is selected from L-valine, L-leucine, and L-isoleucine, their pharmaceutically acceptable salts, or their derivatives. In one embodiment, the at least one branched aliphatic amino acid is L-isoleucine, its pharmaceutically acceptable salts, or their derivatives. In yet another embodiment, the at least one excipient is L-valine, its pharmaceutically acceptable salts, or their derivatives. In one embodiment, the at least one branched aliphatic amino acid is L-leucine, its pharmaceutically acceptable salts, or their derivatives.

[0018] As used herein, "reconstitution time" is the time measured from the time the reconstitution solution is added until the entire solid mass of the solid daptomycin formulation has dissolved. Unless otherwise specified, the term "addition of reconstitution solution" refers to the addition of the entire specified volume of reconstitution solution.

[0019] Reconstitution time can be determined by adding, for example, 10 mL of sterile water for injection, 0.9% sodium chloride, or bacteriostatic water for injection to a unit-dose vial containing the daptomycin pharmaceutical formulation. A timer is started immediately after adding the appropriate reconstitution solution (e.g., water, saline, etc.). The vial is rotated or swirled for a period of time, as necessary, to obtain a completely reconstituted solution. At that point, the timer is stopped and the reconstitution time is confirmed.

[0020] Improved reconstitution time of a solid pharmaceutical formulation of daptomycin of the present disclosure may be expressed as a percentage reduction in reconstitution time of a solid pharmaceutical formulation of daptomycin comprising at least one branched aliphatic amino acid according to the present disclosure compared to the reconstitution time of another solid pharmaceutical formulation of daptomycin.

[0021] As used herein, the terms "improved reconfiguration time" and "reduced reconfiguration time" are used interchangeably. The other solid daptomycin formulation may be the commercially available reference daptomycin product or another commercially available generic daptomycin product. Additionally, other solid daptomycin formulations that may be used for purposes of reconstitution time comparison may be the same daptomycin formulation but may not contain an excipient for shortening reconstitution time selected from branched aliphatic amino acids or their pharmaceutically acceptable salts or derivatives thereof.

[0022] The improved reconstruction time can also be interpreted as the time required for reconstruction. The reduced reconstitution time may be characterized by a reconstitution time of not more than 300 seconds, or not more than 240 seconds, or not more than 180 seconds, or not more than 150 seconds, or not more than 120 seconds, or not more than 90 seconds, or not more than 80 seconds, or not more than 60 seconds, or not more than 50 seconds.

[0023] In one embodiment, the improved reconstitution time of the solid daptomycin formulation does not exceed 150 seconds. In one embodiment, the improved reconstitution time of the solid daptomycin formulation does not exceed 120 seconds.

[0024] In one embodiment, the improved reconstitution time of the solid daptomycin formulation is 90 seconds or less. In one embodiment, the improved reconstitution time of the solid daptomycin formulation does not exceed 1 minute.

[0025] In one embodiment, the improved reconstitution time for 500 mg of a solid pharmaceutical daptomycin formulation of the present disclosure in 10 mL of reconstitution solution at controlled room temperature is less than 120 seconds. In one embodiment, the improved reconstitution time for 500 mg of a solid pharmaceutical daptomycin formulation of the present disclosure in 10 mL of 0.9% sodium chloride at controlled room temperature is less than 120 seconds.

[0026] As used herein, the term "controlled room temperature" refers to the <659> The temperature is controlled at room temperature, i.e., 20-25°C. In one embodiment, the improved reconstitution time of 500 mg of a solid pharmaceutically acceptable daptomycin formulation of the present disclosure in 10 mL of 0.9% sodium chloride at controlled room temperature is 1 minute or less.

[0027] In yet another embodiment, the reconstitution time of 500 mg of a solid pharmaceutically acceptable daptomycin formulation of the present disclosure in 10 mL of 0.9% sodium chloride at controlled room temperature can be 55 seconds, 50 seconds, 45 seconds, 40 seconds, 35 seconds, or 30 seconds.

[0028] In one embodiment, the improved reconstitution time of 500 mg of a solid pharmaceutically acceptable daptomycin formulation of the present disclosure in 10 mL of water for injection at controlled room temperature is 120 seconds or less.

[0029] In one embodiment, the improved reconstitution time of 500 mg of a solid pharmaceutically acceptable daptomycin formulation of the present disclosure in 10 mL of water for injection at controlled room temperature is 1 minute or less.

[0030] In yet another embodiment, the reconstitution time of 500 mg of a solid pharmaceutically acceptable daptomycin formulation of the present disclosure in 10 mL of water for injection at controlled room temperature can be 55 seconds, 50 seconds, 45 seconds, 40 seconds, 35 seconds, or 30 seconds.

[0031] In another embodiment, the reconstitution time of 350 mg of a solid pharmaceutically acceptable daptomycin formulation in 7 mL of 0.9% sodium chloride at controlled room temperature is less than 50 seconds. In yet another embodiment of the present disclosure, the reconstitution time of 350 mg of a solid pharmaceutically acceptable daptomycin formulation in 7 mL of 0.9% sodium chloride at controlled room temperature can be 55 seconds, 50 seconds, 45 seconds, 40 seconds, 35 seconds, or 30 seconds.

[0032] In yet another embodiment, the reconstitution time of 350 mg of a solid pharmaceutically acceptable daptomycin composition in 7 mL of water for injection at controlled room temperature can be 55 seconds, 50 seconds, 45 seconds, 40 seconds, 35 seconds, or 30 seconds.

[0033] In another embodiment, the reconstitution time of 3500 mg of a solid pharmaceutically acceptable daptomycin formulation in 70 mL of water for injection at controlled room temperature is 120 seconds or less. In yet another embodiment, the reconstitution time of 3500 mg of a solid pharmaceutically acceptable daptomycin composition in 70 mL of water for injection at controlled room temperature can be 90 seconds or less.

[0034] In various embodiments, the solid pharmaceutically acceptable formulations of the present disclosure are characterized by a reconstitution time of not more than 50 seconds. In some embodiments, the maximum reconstitution time of the solid pharmaceutically acceptable formulations of daptomycin of the present disclosure does not exceed 45 seconds.

[0035] In some embodiments, the maximum reconstitution time for solid pharmaceutically acceptable formulations of daptomycin disclosed herein does not exceed 40 seconds. In further embodiments, the maximum reconstitution time for solid pharmaceutically acceptable formulations of daptomycin disclosed herein does not exceed 35 seconds.

[0036] In one embodiment, the reconstitution time of 500 mg of daptomycin in a solid pharmaceutical formulation according to the present disclosure with L-valine or L-isoleucine in 10 mL of water for injection at controlled room temperature is 120 seconds or less.

[0037] In one embodiment, the reconstitution time of 500 mg of daptomycin in a solid pharmaceutical formulation according to the present disclosure with L-valine or L-isoleucine in 10 mL of 0.9% sodium chloride at controlled room temperature is 120 seconds or less.

[0038] In one embodiment, a solid formulation of daptomycin containing a branched aliphatic amino acid may have a reconstitution time that is reduced by 96% to 60% compared to the reconstitution time of Cubicin® RLD.

[0039] According to this disclosure, the term "Cubicin® RLD" refers to a commercially available solid formulation of daptomycin that is stored under refrigerated conditions and has sodium hydroxide for pH adjustment as the only inactive ingredient.

[0040] In one embodiment, a solid formulation of daptomycin containing a branched aliphatic amino acid can be stored under refrigerated conditions and have a reconstitution time that is reduced by 96% to 60% compared to the reconstitution time of a solid daptomycin formulation having only sodium hydroxide for pH adjustment as an inactive ingredient.

[0041] In one embodiment, a solid formulation of daptomycin containing a branched aliphatic amino acid can be stored under refrigerated conditions and have a reconstitution time that is reduced by 96% to 80% compared to the reconstitution time of a solid daptomycin formulation having only sodium hydroxide for pH adjustment as an inactive ingredient.

[0042] In one embodiment, a solid formulation of daptomycin comprising a branched aliphatic amino acid may have a reconstitution time that is reduced by 96% to 60% compared to the reconstitution time of a solid daptomycin formulation that does not include an excipient for reconstitution.

[0043] In one embodiment, a solid formulation of daptomycin that includes a branched aliphatic amino acid may have a reconstitution time that is reduced by 96% to 60% compared to the reconstitution time of a solid daptomycin formulation that does not include a branched aliphatic amino acid.

[0044] In one embodiment, a solid formulation of daptomycin containing a branched aliphatic amino acid may have a reconstitution time that is reduced by 96% to 80% compared to the reconstitution time of Cubicin® RLD.

[0045] In one embodiment, a solid formulation of daptomycin comprising a branched aliphatic amino acid may have a reconstitution time that is reduced by 96% to 82% compared to the reconstitution time of Cubicin® RLD.

[0046] In one embodiment, a solid formulation of daptomycin that includes a branched aliphatic amino acid may have a reconstitution time that is reduced by 10% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include a branched aliphatic amino acid.

[0047] In one embodiment, a solid formulation of daptomycin that includes a branched aliphatic amino acid may have a reconstitution time that is reduced by 25% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include a branched aliphatic amino acid.

[0048] In one embodiment, a solid formulation of daptomycin that comprises a branched aliphatic amino acid has a reconstitution time that is reduced by 50% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not comprise a branched aliphatic amino acid.

[0049] In one embodiment, a solid formulation of daptomycin that comprises a branched aliphatic amino acid has a reconstitution time that is reduced by at least 70% compared to the reconstitution time of the same solid formulation of daptomycin that does not comprise a branched aliphatic amino acid.

[0050] In one embodiment, a solid formulation of daptomycin that includes L-isoleucine may have a reconstitution time that is reduced by 25% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include L-isoleucine.

[0051] In one embodiment, a solid formulation of daptomycin that includes L-isoleucine may have a reconstitution time that is reduced by 35% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include L-isoleucine.

[0052] In one embodiment, a solid formulation of daptomycin that includes L-isoleucine may have a reconstitution time that is reduced by 50% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include L-isoleucine.

[0053] In one embodiment, a solid formulation of daptomycin that includes L-isoleucine may have a reconstitution time that is reduced by 70% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include L-isoleucine.

[0054] In one embodiment, a solid formulation of daptomycin that includes L-valine may have a reconstitution time that is reduced by 25% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include L-valine.

[0055] In one embodiment, a solid formulation of daptomycin that includes L-valine may have a reconstitution time that is reduced by 50% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include L-valine.

[0056] In one embodiment, a solid dosage form of daptomycin that includes L-valine may have a reconstitution time that is reduced by 70% or more compared to the reconstitution time of the same solid dosage form of daptomycin that does not include L-valine.

[0057] In one embodiment, a solid formulation of daptomycin that includes L-leucine may have a reconstitution time that is reduced by 25% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include L-leucine.

[0058] In one embodiment, a solid formulation of daptomycin that includes L-leucine may have a reconstitution time that is reduced by 35% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include L-leucine.

[0059] In one embodiment, a solid formulation of daptomycin that includes L-leucine may have a reconstitution time that is reduced by 50% or more compared to the reconstitution time of the same solid formulation of daptomycin that does not include L-leucine.

[0060] In one embodiment, a solid dosage form of daptomycin that includes L-leucine may have a reconstitution time that is reduced by 70% or more compared to the reconstitution time of the same solid dosage form of daptomycin that does not include L-leucine.

[0061] According to the present disclosure, pre-drying solid daptomycin formulations contain low amounts of excipients to reduce reconstitution time. The term "low amount" of excipients to reduce reconstitution time according to the present disclosure refers to a concentration of excipients for the reconstitution time included in the pre-drying daptomycin formulation of 2.5% w / v or less. Low concentrations of reconstitution excipients are useful for various reasons, including their impact on osmolality and providing a final product with a lower overall excipient concentration. The latter may have patient safety implications for patients requiring administration of daptomycin. Furthermore, low concentrations of excipients useful for reducing reconstitution time according to the present disclosure may be useful when selecting a reconstitution solution, for example, with respect to increasing the variety of any type of reconstitution solution and / or the amount of reconstitution solution required.

[0062] Furthermore, the branched aliphatic amino acids used in the present disclosure as reconstitution time-saving excipients may be safer for use in a broader patient population than the reconstitution time-saving excipients used in other commercially available daptomycin formulations.

[0063] In one embodiment, the daptomycin formulation before drying contains 2.5% w / V or less of excipients to shorten reconstitution time. In one embodiment, the daptomycin formulation before drying contains 2.4% w / V or less of excipients to improve reconstitution time. In one embodiment, the daptomycin formulation before drying contains 2.4%, 2.3%, 2%, 1.8%, 1.6%, 1.5%, 1.3%, 1.2%, 1.1%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% w / V or less of excipients to shorten reconstitution time.

[0064] In one embodiment, the daptomycin formulation before drying may contain 1.5% w / v or less of excipients for reduced reconstitution time. In one embodiment, the daptomycin formulation before drying may contain 1% w / v or less of excipients for reduced reconstitution time. In one embodiment, the daptomycin formulation before drying may contain 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% w / v or less of excipients for reduced reconstitution time.

[0065] In one embodiment, the daptomycin formulation contains 1% w / v or less L-isoleucine before drying. In one embodiment, the daptomycin formulation contains 0.8% w / v or less L-isoleucine before drying. In one embodiment, the daptomycin formulation contains 10% w / v daptomycin and 0.8% w / v L-isoleucine before drying.

[0066] In one embodiment, the daptomycin formulation contains 2.2% w / v or less L-valine before drying. In one embodiment, the daptomycin formulation contains 0.7% w / v or less L-valine before drying. In one embodiment, the daptomycin formulation contains 10% w / v daptomycin and 2.2% w / v L-valine before drying.

[0067] In one embodiment, the daptomycin formulation before drying comprises 10% w / V daptomycin and 0.8% w / V L-isoleucine and has a reconstitution time after drying of 120 seconds or less.

[0068] In one embodiment, the daptomycin formulation contains between 100 mg / mL and 400 mg / mL of daptomycin before drying. As used herein, the term "% w / V" is defined as the percent concentration by weight per volume of solution, i.e., grams of solute per 100 mL of solution (g / 100 mL).

[0069] In one embodiment, the at least one branched aliphatic amino acid is included in the solid formulation of daptomycin in a molar ratio to daptomycin of 0.5:1 to 5:1. In one embodiment, the at least one branched aliphatic amino acid is included in the solid formulation of daptomycin at a molar ratio to daptomycin of 0.5:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, or 5:1.

[0070] In one embodiment, the at least one excipient for reconstitution is included in the solid formulation of daptomycin in a molar ratio to daptomycin of 1:1 to 3:1. In one embodiment, L-isoleucine is included in the solid formulation of daptomycin at a molar ratio to daptomycin of 1:1 to 3:1.

[0071] In one embodiment, L-isoleucine is included in the solid formulation of daptomycin at a molar ratio to daptomycin of 1:1, 1:2, or 3:1. In one embodiment, L-isoleucine is included in the solid formulation of daptomycin at a 1:1 molar ratio to daptomycin.

[0072] In one embodiment, L-valine is included in the solid formulation of daptomycin at a molar ratio to daptomycin of 1:1 to 3:1. In one embodiment, L-valine is included in the solid formulation of daptomycin at a molar ratio to daptomycin of 1:1, 1:2, or 3:1.

[0073] In one embodiment, the daptomycin formulation before drying contains no more than 1% w / V L-isoleucine, and the molar ratio of L-isoleucine to daptomycin is 1:1. In one embodiment, the daptomycin formulation before drying contains no more than 1% w / V L-valine and the molar ratio of L-valine to daptomycin is 1:1.

[0074] In one embodiment, the daptomycin formulation before drying contains no more than 1% w / V L-valine and a 1:1 molar ratio of L-leucine to daptomycin. In one embodiment, the solid formulation of daptomycin comprises L-isoleucine, the molar ratio of daptomycin to the excipient, i.e., Dapt:Ile, is 1:0.5, and the reconstitution time of a 500 mg solid formulation of daptomycin in 10 mL of 0.9% sodium chloride injection at controlled room temperature (i.e., 20-25 degrees Celsius) is 90 seconds or less.

[0075] In one embodiment, the solid formulation of daptomycin comprises L-isoleucine, the molar ratio of daptomycin to the excipient, i.e., Dapt:Ile, is 1:1, and the reconstitution time of a 500 mg solid formulation in 10 mL of 0.9% sodium chloride injection at controlled room temperature (i.e., 20-25 degrees Celsius) is 120 seconds or less.

[0076] In one embodiment, the solid formulation of daptomycin comprises isoleucine, the molar ratio of daptomycin to the excipient, i.e., Dapt:Ile, is 1:3, and the reconstitution time of a 500 mg solid daptomycin formulation in 10 mL of 0.9% sodium chloride at controlled room temperature (i.e., 20-25 degrees Celsius) is 150 seconds or less.

[0077] Solid compositions of the present disclosure are obtained by art-known drying manufacturing processes, such as lyophilization, spray drying, or bed drying of liquid formulations of daptomycin according to the present disclosure. In one embodiment, the solid formulation of the present disclosure is obtained by lyophilization.

[0078] The terms "lyophilization," "lyophilized," and "freeze-dried" refer to a process in which the material to be dried is first frozen and then the ice or freezing solvent is removed by sublimation in a vacuum environment. Various excipients may be included in the pre-lyophilized formulation, including excipients to improve reconstitution time and excipients to stabilize the formulation.

[0079] In one embodiment, the reconstitution time of a solid formulation of daptomycin containing a branched aliphatic amino acid is substantially unaffected by changes in pH at a predetermined pH ratio. According to the present disclosure, the term "predetermined pH ratio" refers to the pH ratio of the daptomycin formulation before drying. In one embodiment, the predetermined pH ratio may be from 4.5 to 9. In yet another embodiment, the predetermined pH ratio may be from 4.5 to 7. In yet another embodiment, the predetermined pH ratio may be from 5.0 to 6.5.

[0080] In one embodiment, the target pH of an aqueous formulation according to the present disclosure before drying is from 4.5 to 9. In one embodiment, the target pH of an aqueous formulation according to the present disclosure before drying is from 4.5 to 7.0.

[0081] In one embodiment, the daptomycin formulation before drying contains 2.4% w / V or less of at least one branched aliphatic amino acid, and the target pH of an aqueous formulation according to the present disclosure before drying is from 4.5 to 7.0.

[0082] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 4.5 to 7.0, and the solid formulation of daptomycin has an improved reconstitution time, demonstrated as a 60% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0083] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 4.5 to 7.0, and the solid formulation of daptomycin has an improved reconstitution time, demonstrated as an 80% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0084] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less of at least one branched aliphatic amino acid, and the target pH of an aqueous formulation according to the present disclosure before drying is from 4.5 to 7.0.

[0085] In one embodiment, the daptomycin formulation before drying contains no more than 2.4% w / V L-isoleucine, and the target pH of an aqueous formulation according to the present disclosure before drying is from 4.5 to 7.0.

[0086] In one embodiment, the daptomycin formulation prior to drying contains no more than 2.4% w / V L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is from 4.5 to 7.0.

[0087] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure before drying is from 4.5 to 7.0.

[0088] In one embodiment, the daptomycin formulation before drying contains no more than 2.4% w / V L-valine, and the target pH of an aqueous formulation according to the present disclosure before drying is from 4.5 to 7.0. In one embodiment, the daptomycin formulation prior to drying contains no more than 2.4% w / V L-valine, the molar ratio of L-valine to daptomycin is 1:3, and the target pH of an aqueous formulation according to the present disclosure prior to drying is from 4.5 to 7.0.

[0089] In one embodiment, the daptomycin formulation prior to drying contains no more than 2.4% w / V L-valine, the molar ratio of L-valine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is from 4.5 to 7.0.

[0090] In one embodiment, the daptomycin formulation prior to drying contains 1% w / V or less L-valine, the molar ratio of L-valine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is 4.5 to 7.0.

[0091] In one embodiment, the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.5. In one embodiment, the daptomycin formulation before drying contains 2.4% w / v or less of at least one branched aliphatic amino acid, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.5.

[0092] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 5.0 to 6.5, and the solid formulation of daptomycin has an improved reconstitution time, demonstrated as a 60% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0093] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 5.0 to 6.5, and the solid formulation of daptomycin has an improved reconstitution time, as demonstrated by an 80% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0094] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less of at least one branched aliphatic amino acid, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.5.

[0095] In one embodiment, the daptomycin formulation before drying contains no more than 2.4% w / V L-isoleucine, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.5.

[0096] In one embodiment, the daptomycin formulation prior to drying contains no more than 2.4% w / V L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is between 5.0 and 6.5.

[0097] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure before drying is 5.0 to 6.5.

[0098] In one embodiment, the daptomycin formulation before drying contains no more than 2.4% w / V L-valine, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.5. In one embodiment, the daptomycin formulation prior to drying contains no more than 2.4% w / V L-valine, the molar ratio of L-valine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is from 5.0 to 6.5.

[0099] In one embodiment, the daptomycin formulation prior to drying contains 1% w / V or less L-valine, the molar ratio of L-valine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.5.

[0100] In one embodiment, the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.5, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less. In one embodiment, the daptomycin formulation prior to drying includes excipients for reduced reconstitution time of 2.5% w / V or less, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.5, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less.

[0101] In one embodiment, the daptomycin formulation prior to drying includes excipients for reduced reconstitution time of 1% w / V or less, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.5, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less.

[0102] In one embodiment, the daptomycin formulation prior to drying includes excipients for reduced reconstitution time of 1% w / V or less, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.5, and the improved reconstitution time of the solid daptomycin formulation is 120 seconds or less.

[0103] In one embodiment, the daptomycin formulation prior to drying contains 1% w / V or less L-Ile, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.5, and the improved reconstitution time of the solid daptomycin formulation is 90 seconds or less.

[0104] In one embodiment, the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.4. In one embodiment, the daptomycin formulation before drying contains 2.4% w / v or less of at least one branched aliphatic amino acid, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.4.

[0105] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 5.0 to 6.4, and the solid formulation of daptomycin has an improved reconstitution time, as demonstrated by a 60% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0106] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 5.0 to 6.4, and the solid formulation of daptomycin has an improved reconstitution time, as demonstrated by an 80% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0107] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less of at least one branched aliphatic amino acid, and the target pH of the aqueous formulation according to the present disclosure before drying is from 5.0 to 6.4.

[0108] In one embodiment, the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.2. In one embodiment, the daptomycin formulation before drying contains 2.4% w / v or less of at least one branched aliphatic amino acid, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.2.

[0109] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 5.0 to 6.2, and the solid formulation of daptomycin has an improved reconstitution time, as demonstrated by an 80% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0110] In one embodiment, the daptomycin formulation before drying contains no more than 2.4% w / V L-isoleucine, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.2.

[0111] In one embodiment, the daptomycin formulation prior to drying contains no more than 2.4% w / V L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is from 5.0 to 6.2.

[0112] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure before drying is 5.0 to 6.2.

[0113] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less L-valine, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.2. In one embodiment, the daptomycin formulation prior to drying contains 1% w / V or less L-valine, the molar ratio of L-valine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.2.

[0114] In one embodiment, the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 6.2, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less. In one embodiment, the target pH of an aqueous formulation according to the present disclosure before drying is from 5.4 to 6.2, and the improved reconstitution time of the solid daptomycin formulation is 120 seconds or less.

[0115] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.2, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less.

[0116] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.4 to 6.2, and the improved reconstitution time of the solid daptomycin formulation is 120 seconds or less.

[0117] In one embodiment, the daptomycin formulation prior to drying comprises 1% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.2, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less.

[0118] In one embodiment, the daptomycin formulation prior to drying comprises 1% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.4 to 6.2, and the improved reconstitution time of the solid daptomycin formulation is 120 seconds or less.

[0119] In one embodiment, the daptomycin formulation prior to drying comprises 1% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.2, and the improved reconstitution time of the solid daptomycin formulation is 90 seconds or less.

[0120] In one embodiment, the daptomycin formulation prior to drying contains 1% w / V or less L-isoleucine, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.2, and the improved reconstitution time of the solid daptomycin formulation is 120 seconds or less.

[0121] In one embodiment, the daptomycin formulation prior to drying contains 1% w / V or less L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 6.2, and the improved reconstitution time of the solid daptomycin formulation is 120 seconds or less.

[0122] In one embodiment of the present disclosure, the target pH of a formulation according to the present disclosure before drying is from 5.0 to 7.0. In one embodiment of the present disclosure, the target pH of a formulation according to the present disclosure before drying is from 5.0 to 6.7.

[0123] In one embodiment, the daptomycin formulation before drying contains 2.4% w / v or less of at least one branched aliphatic amino acid, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 7.0.

[0124] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 5.0 to 7.0, and the solid formulation of daptomycin has an improved reconstitution time, as demonstrated by a 60% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0125] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 5.0 to 7.0, and the solid formulation of daptomycin has an improved reconstitution time, as demonstrated by an 80% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0126] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less of at least one branched aliphatic amino acid, and the target pH of the aqueous formulation according to the present disclosure before drying is from 5.0 to 7.0.

[0127] In one embodiment, the daptomycin formulation before drying contains 2.4% w / V or less L-isoleucine, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 7.0.

[0128] In one embodiment, the daptomycin formulation prior to drying contains no more than 2.4% w / V L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is between 5.0 and 7.0.

[0129] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure before drying is 5.0 to 7.

[0130] In one embodiment, the daptomycin formulation before drying contains no more than 2.4% w / V L-valine, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 7.0. In one embodiment, the daptomycin formulation prior to drying contains no more than 2.4% w / V L-valine, the molar ratio of L-valine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is between 5.0 and 7.0.

[0131] In one embodiment, the daptomycin formulation prior to drying contains 1% w / V or less L-valine, the molar ratio of L-valine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is 5.0 to 7.0.

[0132] In one embodiment, the target pH of an aqueous formulation according to the present disclosure before drying is from 5.0 to 7.0, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less. In one embodiment, the daptomycin formulation prior to drying includes excipients for reduced reconstitution time of 2.5% w / V or less, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 7.0, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less.

[0133] In one embodiment, the daptomycin formulation prior to drying includes excipients for reduced reconstitution time of 1% w / V or less, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 7.0, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less.

[0134] In one embodiment, the daptomycin formulation prior to drying includes excipients for reduced reconstitution time of 1% w / V or less, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.0 to 7.0, and the improved reconstitution time of the solid daptomycin formulation is 120 seconds or less.

[0135] In one embodiment of the present disclosure, the target pH of a formulation according to the present disclosure before drying is from 6 to 7. In one embodiment of the present disclosure, the target pH of a formulation according to the present disclosure before drying is from 5.8 to 6.5.

[0136] In one embodiment of the present disclosure, the target pH of a formulation according to the present disclosure before drying is from 5.8 to 6.4. In one embodiment, the daptomycin formulation before drying contains 2.4% w / V or less of at least one branched aliphatic amino acid, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.8 to 6.5.

[0137] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 5.8 to 6.5, and the solid formulation of daptomycin has an improved reconstitution time, as demonstrated by a 60% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0138] In one embodiment, the daptomycin formulation prior to drying comprises 2.4% w / V or less of at least one branched aliphatic amino acid, the target pH of the aqueous formulation according to the present disclosure prior to drying is from 5.8 to 6.5, and the solid formulation of daptomycin has an improved reconstitution time, as demonstrated by an 80% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0139] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less of at least one branched aliphatic amino acid, and the target pH of the aqueous formulation according to the present disclosure before drying is from 5.8 to 6.5.

[0140] In one embodiment, the daptomycin formulation before drying contains no more than 2.4% w / V L-isoleucine, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.8 to 6.5.

[0141] In one embodiment, the daptomycin formulation prior to drying contains no more than 2.4% w / V L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is 5.8 to 6.5.

[0142] In one embodiment, the daptomycin formulation before drying contains 1% w / V or less L-isoleucine, the molar ratio of L-isoleucine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure before drying is 5.8 to 6.5.

[0143] In one embodiment, the daptomycin formulation before drying contains no more than 2.4% w / V L-valine, and the target pH of an aqueous formulation according to the present disclosure before drying is from 5.8 to 6.5. In one embodiment, the daptomycin formulation prior to drying contains no more than 2.4% w / V L-valine, the molar ratio of L-valine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is 5.8 to 6.5.

[0144] In one embodiment, the daptomycin formulation prior to drying contains 1% w / V or less L-valine, the molar ratio of L-valine to daptomycin is 1:1, and the target pH of an aqueous formulation according to the present disclosure prior to drying is 5.8 to 6.5.

[0145] In one embodiment, the target pH of an aqueous formulation according to the present disclosure before drying is from 5.8 to 6.5, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less. In one embodiment, the daptomycin formulation prior to drying includes excipients for reduced reconstitution time of 2.5% w / V or less, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.8 to 6.5, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less.

[0146] In one embodiment, the daptomycin formulation prior to drying includes excipients for reduced reconstitution time of 1% w / V or less, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.8 to 6.5, and the improved reconstitution time of the solid daptomycin formulation is 150 seconds or less.

[0147] In one embodiment, the daptomycin formulation prior to drying includes excipients for reduced reconstitution time of 1% w / V or less, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.8 to 6.5, and the improved reconstitution time of the solid daptomycin formulation is 120 seconds or less.

[0148] In one embodiment, the daptomycin formulation prior to drying contains 1% w / V or less L-Ile, the target pH of the aqueous formulation according to the present disclosure prior to drying is 5.8 to 6.5, and the improved reconstitution time of the solid daptomycin formulation is 90 seconds or less.

[0149] All numbers used herein are modified by the term "about," which means that each number includes a small variation defined as 10% of that number. As used herein, the term "target pH" is defined as ±0.1 of a subject value or range.

[0150] "pH" is the conventional unit of measure of hydrogen ion activity in a solution at room temperature unless another temperature is specified. In one embodiment, the target pH of a formulation according to the present disclosure before drying is from 6.0 to 6.5.

[0151] In one embodiment, the target pH of a formulation according to the present disclosure before drying is 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0. In one embodiment, the target pH of a formulation according to the present disclosure before drying is 6.2.

[0152] As used herein, "aqueous composition" or "aqueous solution" refers to any solution in which water is the primary solvent (50% V / V or greater). Aqueous solutions include, but are not limited to, solutions containing 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% V / V water. Aqueous solutions can contain pharmaceutically acceptable organic solvents such as ethanol, glycerol, propylene glycol, polyethylene glycol (PEG200, PEG300, PEG400, PEG600, PEG4000, etc.). Aqueous solutions can contain up to 50% V / V of pharmaceutically acceptable organic solvents.

[0153] Commercially available daptomycin products (i.e., Cubist® RLD) are known to be stable under refrigerated conditions at 2-8 degrees Celsius. In one embodiment of the present disclosure, a solid daptomycin formulation containing a branched aliphatic amino acid as an excipient for reduced reconstitution time may have equivalent stability under refrigerated conditions to a commercially available dry daptomycin product (i.e., Cubist® RLD). In one embodiment, a solid daptomycin formulation containing a branched aliphatic amino acid as an excipient for reduced reconstitution time may have equivalent stability under refrigerated conditions to the same daptomycin formulation without the excipient for reduced reconstitution time.

[0154] Storage of daptomycin formulations of the present disclosure at temperatures above 2-8 degrees Celsius may require the addition of a "stabilizing excipient." As used herein, the phrase "stabilizing excipient" shall be understood to mean an excipient that can provide a stable daptomycin formulation at temperatures above refrigeration temperatures.

[0155] In one embodiment, the formulation may further comprise at least one excipient for stabilization. In one embodiment, the formulation may further comprise at least one excipient for stabilization of the solid formulation at room temperature conditions.

[0156] In one embodiment, the excipient for stabilization can be selected from a sugar, a sugar alcohol, an amino sugar, an organic solvent, a divalent cation or a cyclodextrin, or a pharmaceutically acceptable salt thereof or a derivative thereof.

[0157] In one embodiment, the formulation of the present disclosure comprises a stabilizing excipient selected from non-reducing sugars such as sucrose, trehalose, maltose, and the like. In one embodiment, the formulation of the present disclosure may include a divalent cation such as sodium, calcium, magnesium, or potassium. In one embodiment of the present disclosure, the formulation of the present disclosure may include calcium, which may be selected from calcium chloride (CaCl), calcium chloride dihydrate, calcium chloride hexahydrate, calcium citrate, Ca-α-D-heptagluconate, or calcium acetate.

[0158] In one embodiment of the disclosure, the calcium source is included in a molar ratio to daptomycin of 0.5:1 to 3:1, such as 0.5:1, 1:1, 2:1, or 3:1. In one embodiment, the solid daptomycin formulation of the present disclosure may include at least one stabilizing excipient selected from amino acids excluding branched aliphatic amino acids. In one embodiment, the at least one stabilizing excipient in the solid daptomycin formulation of the present disclosure may include alanine, arginine, asparagine, histidine, glycine, lysine, ornithine, phenylalanine, proline, threonine, tryptophan, tyrosine, or a pharmaceutically acceptable salt or derivative thereof.

[0159] In one embodiment, the solid daptomycin formulation of the present disclosure can include at least one stabilizing excipient selected from arginine or histidine. In one embodiment, the formulation comprises at least arginine, a pharmaceutically acceptable salt thereof, or a derivative thereof. In one embodiment, the formulation further comprises histidine, a pharmaceutically acceptable salt thereof, or a derivative thereof. In one embodiment, the formulation further comprises histidine hydrochloride.

[0160] In one embodiment, the daptomycin formulation further comprises arginine and histidine, their pharmaceutically acceptable salts, or their derivatives. In one embodiment, the at least one stabilizing excipient is included in a molar ratio to daptomycin of 1:1 to 5:1. In one embodiment, the at least one stabilizing excipient is included in a molar ratio to daptomycin of 1:1, 2:1, 3:1, 4:1, or 5:1.

[0161] In one embodiment, the at least one stabilizing excipient is included in a molar ratio to daptomycin of 3:1 to 5:1. In one embodiment, the daptomycin formulation further comprises arginine and histidine, their pharmaceutically acceptable salts, or derivatives thereof, wherein the molar ratio of daptomycin to excipients is Dapt:Arg:His from 1:1:1 to 1:5:5.

[0162] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from L-isoleucine, L-valine, or L-leucine, and at least one stabilizing excipient selected from arginine and histidine, their pharmaceutically acceptable salts, or derivatives thereof.

[0163] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from isoleucine and at least one stabilizing excipient selected from arginine and histidine, their pharmaceutically acceptable salts, or derivatives thereof.

[0164] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from leucine and at least one stabilizing excipient selected from arginine and histidine, their pharmaceutically acceptable salts, or derivatives thereof.

[0165] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from isoleucine and two stabilizing excipients, wherein the first stabilizing excipient is arginine and the second stabilizing excipient is histidine or a pharmaceutically acceptable salt or derivative thereof.

[0166] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients Dapt:Ile:Arg:His is from 1:0.5:1:1 to 1:3:5:5.

[0167] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients Dapt:Ile:Arg:His is 1:1:5:3.

[0168] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from valine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients Dapt:Val:Arg:His is from 1:1:1:1 to 1:3:5:5.

[0169] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from valine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients Dapt:Val:Arg:His is 1:1:5:3.

[0170] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from valine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients Dapt:Val:Arg:His is 1:3:5:3.

[0171] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients Dapt:Ile:Arg:His is 1:1:4:3.

[0172] In one embodiment, a solid formulation of daptomycin comprises an excipient for improving reconstitution time selected from isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients Dapt:Ile:Arg:His is 1:3:4:3.

[0173] In one embodiment, a solid formulation of daptomycin having an improved reconstitution time comprises an excipient for shortened reconstitution time selected from L-isoleucine, L-valine, or L-leucine and a stabilizing excipient, where the improved reconstitution time is demonstrated as a reduction in reconstitution time of 25% or more compared to the reconstitution time of an identical solid daptomycin formulation comprising a stabilizing excipient disclosed herein but not an excipient for improved reconstitution time selected from L-isoleucine, L-valine, or L-leucine.

[0174] In one embodiment, a solid formulation of daptomycin having an improved reconstitution time comprises a reconstitution time improving excipient selected from L-isoleucine and a stabilizing excipient selected from arginine and histidine, where the improved reconstitution time is demonstrated as a reduction in reconstitution time of 50% or more compared to the reconstitution time of an identical solid daptomycin formulation comprising a stabilizing excipient selected from arginine and histidine but not an improved reconstitution time excipient selected from L-isoleucine, L-valine, or L-leucine.

[0175] In one embodiment, a solid formulation of daptomycin having an improved reconstitution time comprises an excipient for improving reconstitution time selected from L-isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients Dapt:Ile:Arg:His is from 1:0.5:1:1 to 1:3:5:5, and wherein the improved reconstitution time is demonstrated as a reduction in reconstitution time of 75% or more compared to the reconstitution time of an identical solid daptomycin formulation without L-isoleucine.

[0176] In one embodiment, a solid formulation of daptomycin having an improved reconstitution time comprises a reconstitution time improving excipient selected from L-isoleucine and a stabilizing excipient selected from arginine and histidine, wherein the molar ratio of daptomycin to said excipients Dapt:Ile:Arg:His is 1:1:5:3, where improved reconstitution time is demonstrated as a reduction in reconstitution time of 75% or more compared to the reconstitution time of an identical solid daptomycin formulation that does not include L-isoleucine but comprises a stabilizing excipient selected from arginine and histidine in a molar ratio of daptomycin to said excipients Dapt:Arg:His of 1:5:3.

[0177] In one embodiment, a solid formulation of daptomycin having an improved reconstitution time comprises a reconstitution time improving excipient selected from L-isoleucine and a stabilizing excipient selected from arginine and histidine, wherein the molar ratio of daptomycin to said excipients is Dapt:Ile:Arg:His is 1:1:5:3, wherein the improved reconstitution time is demonstrated as a reduction in reconstitution time of 70% or more compared to the reconstitution time of a solid daptomycin formulation consisting of stabilizing excipients selected from arginine and histidine, wherein the molar ratio of daptomycin to said excipients is Dapt:Arg:His is 1:5:3.

[0178] In one embodiment, a 500 mg daptomycin solid formulation having an improved reconstitution time comprises a reconstitution time improving excipient selected from L-isoleucine and a stabilizing excipient selected from arginine and histidine, wherein the molar ratio of daptomycin to said excipients is 1:1:5:3, Dapt:Ile:Arg:His, where the improved reconstitution time is demonstrated as a reduction in reconstitution time of 70% or more compared to the reconstitution time of a solid daptomycin formulation consisting of stabilizing excipients selected from arginine and histidine, wherein the molar ratio of daptomycin to said excipients is 1:5:3, Dapt:Arg:His, where reconstitution of both formulations was performed with 10 mL of water for injection at controlled room temperature (i.e., 20-25 degrees Celsius).

[0179] In one embodiment, a solid formulation of daptomycin having an improved reconstitution time comprises a reconstitution time improving excipient selected from L-isoleucine and a stabilizing excipient selected from arginine and histidine, wherein the molar ratio of daptomycin to said excipients Dapt:Ile:Arg:His is 1:3:5:3, where improved reconstitution time is demonstrated as a reduction in reconstitution time of 75% or more compared to the reconstitution time of an identical solid daptomycin formulation that does not include L-isoleucine but comprises a stabilizing excipient selected from arginine and histidine in a molar ratio of daptomycin to said excipients Dapt:Arg:His of 1:5:3.

[0180] In one embodiment, a solid formulation of daptomycin having an improved reconstitution time comprises a reconstitution time improving excipient selected from L-isoleucine and a stabilizing excipient selected from arginine and histidine, wherein the molar ratio of daptomycin to said excipients is Dapt:Ile:Arg:His is 1:3:5:3, where improved reconstitution time is demonstrated as a reduction in reconstitution time of 70% or more compared to the reconstitution time of an identical solid daptomycin formulation consisting of a stabilizing excipient selected from arginine and histidine and a daptomycin to excipient molar ratio of Dapt:Arg:His of 1:5:3.

[0181] In one embodiment, a solid formulation of daptomycin having an improved reconstitution time comprises a reconstitution time improving excipient selected from L-isoleucine and a stabilizing excipient selected from arginine and histidine, wherein the molar ratio of daptomycin to said excipients Dapt:Ile:Arg:His is 1:1:4:3, where improved reconstitution time is demonstrated as a reduction in reconstitution time of 80% or more compared to the reconstitution time of an identical solid daptomycin formulation that does not include L-isoleucine but comprises a stabilizing excipient selected from arginine and histidine, and wherein the molar ratio of daptomycin to said excipients Dapt:Arg:His is 1:4:3.

[0182] Please note that unless otherwise specified, all results of comparisons of reconstitution times referred to herein are obtained using identical conditions, such as temperature conditions, reconstitution agents and amounts of reconstitution agents. In one embodiment, a solid formulation of daptomycin comprises isoleucine, arginine, and histidine, wherein the molar ratio of daptomycin to the excipients is 1:1:5:3, Dapt:Ile:Arg:His, and the reconstitution time for a 500 mg solid daptomycin formulation in 10 mL of water for injection at controlled room temperature (i.e., 20-25 degrees Celsius) is 50 seconds or less.

[0183] In one embodiment, a solid formulation of daptomycin comprises isoleucine, arginine, and histidine, wherein the molar ratio of daptomycin to the excipients is 1:1:5:3, Dapt:Ile:Arg:His, and the reconstitution time for a 500 mg solid daptomycin formulation in 10 mL of water for injection at controlled room temperature (i.e., 20-25 degrees Celsius) is 50 seconds or less.

[0184] In one embodiment, a solid formulation of daptomycin comprises isoleucine, arginine, and histidine, wherein the molar ratio of daptomycin to the excipients is 1:1:5:3, Dapt:Ile:Arg:His, and the reconstitution time of a 500 mg solid daptomycin formulation in 10 mL of water for injection at controlled room temperature (i.e., 20-25 degrees Celsius) is 45 seconds or less.

[0185] In one embodiment, a solid formulation of daptomycin comprises isoleucine, arginine, and histidine, wherein the molar ratio of daptomycin to the excipients is 1:1:5:3, Dapt:Ile:Arg:His, and the reconstitution time for a 500 mg solid daptomycin formulation in 10 mL of 0.9% sodium chloride at controlled room temperature (i.e., 20-25 degrees Celsius) is 45 seconds or less.

[0186] In one embodiment, a solid formulation of daptomycin comprises isoleucine, arginine, and histidine, wherein the molar ratio of daptomycin to the excipients is 1:1:5:3, Dapt:Ile:Arg:His, and the reconstitution time for a 350 mg solid daptomycin formulation in 7 mL of water for injection at controlled room temperature (i.e., 20-25 degrees Celsius) is 60 seconds or less.

[0187] In one embodiment, a solid formulation of daptomycin comprises isoleucine, arginine, and histidine, wherein the molar ratio of daptomycin to the excipients is 1:1:5:3, Dapt:Ile:Arg:His, and the reconstitution time of 3.5 g of the solid daptomycin formulation in 70 mL of water for injection at controlled room temperature (i.e., 20-25 degrees Celsius) is 90 seconds or less.

[0188] In one embodiment, a solid formulation of daptomycin comprises isoleucine, arginine, and histidine, wherein the molar ratio of daptomycin to the excipients is 1:1:4:3, Dapt:Ile:Arg:His, and the reconstitution time of a 500 mg solid daptomycin formulation in 10 mL of water for injection at controlled room temperature (i.e., 20-25 degrees Celsius) is 40 seconds or less.

[0189] In one embodiment, the daptomycin formulation before drying comprises 10% w / V daptomycin, 0.8% w / V L-isoleucine, 2.9% histidine, and 5.4% arginine and has a reconstitution time after drying of 45 seconds or less.

[0190] In one embodiment, the solid formulation of daptomycin can be stored under refrigerated conditions, such as at 2-8°C. In one embodiment, a solid formulation of daptomycin containing stabilizing excipients can achieve excellent stability without being affected by temperature or humidity, so that it can be stored for a long period of time, the formulation for injection can be easily prepared, and it will not be degraded by the effects of temperature or humidity during the manufacturing process.

[0191] In one embodiment, the formulations provided herein can be stored at room temperature (25°C), below room temperature, such as 20°C, 15°C, 10°C, and under refrigerated conditions, such as 2-8°C.

[0192] As used herein, "stable" is defined as either no more than a 10% increase in total impurity formation as determined by HPLC analysis, or no more than a 5% increase in the formation of any individual impurity as determined by HPLC analysis, under typical storage conditions after a given period of time.

[0193] For example, a stable or stabilized formulation may exhibit no more than a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% increase in total impurity formation after a given period of time.

[0194] In one embodiment of the present disclosure, a reconstituted formulation of daptomycin can be stable for at least 4 days at 2-8 degrees Celsius. In one embodiment of the present disclosure, a reconstituted formulation of daptomycin can be stable for at least 48 hours under room temperature conditions.

[0195] According to the present disclosure, the disclosed daptomycin solid formulations are stable over the course of typical storage conditions, including, for example, refrigerated conditions at 2-8°C, for periods of 7 days (1 week), 14 days (2 weeks), 30 days (1 month), 60 days (2 months), 150 days (5 months), 180 days (6 months), 12 months (1 year), and longer.

[0196] According to the present disclosure, the disclosed solid formulations of daptomycin containing stabilizing excipients are stable over the course of typical storage conditions, including 7 days (1 week), 14 days (2 weeks), 30 days (1 month), 60 days (2 months), 150 days (5 months), 180 days (6 months), 12 months (1 year), and longer, at temperatures of 25° C. (room temperature), and temperatures below room temperature.

[0197] In one embodiment, the solid formulation of the present disclosure can be stored at room temperature, for example, 25° C., for a predetermined period of time. In one embodiment, a suitable pH adjuster used before drying or during reconstitution is hydrochloric acid or sodium hydroxide.

[0198] Without being bound by the above description, other pH adjusting agents known and commonly used by those skilled in the art to which this disclosure pertains are also included herein. In one embodiment, the solid formulation of daptomycin can further comprise other excipients selected from antioxidants, surfactants, lipids, complexing agents, preservatives, bulking agents, buffers, diluents, vehicles, solubilizers, binders, etc. As used herein, "pharmaceutically acceptable" in terms of excipients means that they are useful in the preparation of pharmaceutical compositions that are generally non-toxic and not biologically or otherwise undesirable, and further do not result in unacceptable loss of the pharmacological activity of the drug, and are acceptable for use in human and / or animal therapy.

[0199] The solid formulations of the present disclosure can be reconstituted with known reconstitution solutions. As intended herein, a "reconstitution solution" is one that is pharmaceutically acceptable, i.e., safe and non-toxic for human administration and compatible with the preparation of diluted formulations.

[0200] The formulations described herein may be further diluted in accordance with the present disclosure to achieve lower therapeutically effective concentrations. Exemplary solutions applicable for both reconstitution and dilution include sterile water for injection, sterile saline, and lactated Ringer's injection.

[0201] For example, in a typical preparation of a diluted formulation, the appropriate amount of reconstituted formulation needed for the desired therapeutically effective dose can be aseptically collected and transferred to an infusion bag of an appropriate solution such as 0.225%, 0.45%, or 0.9% sodium chloride, or sterile water for injection or lactated Ringer's injection, and administered to a patient via an appropriate route of administration.

[0202] The reconstituted solid daptomycin formulation comprises a therapeutically effective amount of daptomycin, where the therapeutically effective amount is a concentration ranging from 0.5 mg / mL to 500 mg / mL, 20 mg / mL to 400 mg / mL, or 50 mg / mL to 300 mg / mL, e.g., 0.5 mg / mL, 1 mg / mL, 3 mg / mL, 5 mg / mL, 8 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 23 mg / mL, 25 mg / mL, 30 mg / mL, 33 mg / mL, 35 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, or 70 mg / mL. , 80mg / mL, 90mg / mL, 100mg / mL, 110mg / mL, 120mg / mL, 130mg / mL, 140mg / mL, 150mg / mL, 160mg / mL, 170mg / mL, 180mg / mL, 190m Concentrations include g / mL, 200mg / mL, 220mg / mL, 240mg / mL, 260mg / mL, 280mg / mL, 300mg / mL, 350mg / mL, 400mg / mL, 450mg / mL and 500mg / mL.

[0203] As used herein, the term "therapeutically effective amount" or "therapeutically effective concentration" of a daptomycin compound refers to the amount of reconstituted daptomycin administered to a patient sufficient to elicit a therapeutic response against one or more symptoms of the disease being treated.

[0204] The reconstitution solution of the present disclosure has a pH that can vary between 5.5 and 7. The solid formulations of daptomycin described herein can be administered, for example, by subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial injection, or intravenous infusion.

[0205] In one embodiment, the composition is prepared by the steps of mixing a daptomycin solution and at least one branched aliphatic amino acid, adjusting the pH of such solution to a pH of 4 to 9 with a suitable pH adjuster, and freeze-drying or spray-drying or fluid-bed drying such composition.

[0206] In one embodiment, the composition is prepared by combining a daptomycin solution and at least one branched aliphatic amino acid, adjusting the pH of such a solution, hi one embodiment, the pH is adjusted to between 5 and 6.5 with a suitable pH adjuster, and freeze-drying or spray-drying or fluid-bed drying such a composition.

[0207] In one embodiment, the composition is prepared by mixing a daptomycin solution and at least one branched aliphatic amino acid, adjusting the pH of such solution to a pH of 4.5 to 7 with a suitable pH adjuster, and freeze-drying or spray-drying or fluid-bed drying such composition.

[0208] In one embodiment, a solid formulation of daptomycin is prepared by lyophilizing an aqueous daptomycin solution containing at least one excipient selected from a branched aliphatic amino acid, wherein the liquid daptomycin solution has a target pH of 5.8 to 6.5.

[0209] In one embodiment, a solid formulation of daptomycin is prepared by lyophilizing an aqueous liquid daptomycin solution containing at least one excipient selected from a branched aliphatic amino acid, wherein the liquid daptomycin solution has a pH of 6.2.

[0210] The present disclosure further provides a method for improving the reconstitution time of a solid formulation of daptomycin, the method comprising the steps of combining a daptomycin solution and at least one branched aliphatic amino acid, and drying such composition.

[0211] The present disclosure further provides a method for improving the reconstitution time of a solid formulation of daptomycin, the method comprising the steps of mixing a daptomycin solution and L-isoleucine, and drying such composition.

[0212] In one embodiment, a method for reducing the reconstitution time of a solid formulation of daptomycin, the method comprising the steps of mixing a daptomycin solution and L-isoleucine, wherein the L-isoleucine concentration is 1% w / V or less, and drying such composition.

[0213] In one embodiment, a method for reducing the reconstitution time of a solid formulation of daptomycin, wherein the method comprises the steps of mixing a daptomycin solution and L-isoleucine, wherein the L-isoleucine has a concentration of 0.8% w / V, and drying such composition.

[0214] Also within the scope of this disclosure is the use of pharmaceutical formulations of daptomycin to treat diseases caused by Gram-positive bacteria, such as complicated skin and soft tissue infections (cSSTIs), bloodstream infections (bacteremia) due to Staphylococcus aureus, including those associated with right-sided infective endocarditis (RIE).

[0215] These uses include administering to a patient a therapeutically effective amount of a formulation according to the present disclosure or a preparation prepared from a pharmaceutical formulation of the present disclosure. For example, the present disclosure includes administering to a patient a therapeutically effective amount of a reconstituted solution and optionally further diluted solutions of solid pharmaceutically acceptable formulations according to the present disclosure.

[0216] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The following examples are provided for illustrative purposes only and should not be construed to limit the scope of the present disclosure.

[0217] method Compositions according to the present disclosure are prepared by providing a liquid solution of daptomycin and at least one excipient for reduced reconstitution time, adjusting the pH of such solution to the desired pH with a suitable pH adjuster, transferring such solution to vials to achieve the desired amount of daptomycin per vial, and lyophilizing.

[0218] After lyophilization, the initial time point levels of impurities were measured by HPLC, and then the vials were placed in stability chambers at different storage conditions, including 60°C, 25°C / 60% RH, and 40°C / 75% RH.

[0219] Reconstitution times were measured after lyophilization (initial), where the vials were reconstituted with 10.0 mL of WFI. To determine the impurity formation level and stability of daptomycin in formulations according to the present disclosure, vials were removed from the stability chamber at various time points, including 45 hours, 1 month, and 2 months, and analyzed by HPLC.

[0220] Analysis of the formulations of the present disclosure may be carried out using techniques known in the art, such as HPLC techniques, including HPLC as disclosed in WO 2011 / 063419.

[0221] [Table 1]

[0222] Example 1 Daptomycin (10.423 g, 97.7% daptomycin and 1.8% water when evaluated on an anhydrous basis) was added to a WFI solution containing reconstitution excipients. The molar ratio varied from 1:0.5 to 1:3 daptomycin:reconstitution excipients, including 1:0.5, 1:1, and 1:3 molar ratios. In some formulations, stabilizing excipients were also added.

[0223] The contents were then stirred using a magnetic stirrer. The pH was adjusted to 6.2 using 6 M HCl and / or 1 M NaOH solution. The solution was then transferred to a volumetric flask and WFI was added to bring the volume to 100 mL.

[0224] The solution was mixed to ensure homogeneity, filtered through a 0.2 μm filter, transferred to vials, and lyophilized. The reconstitution times shown in Table 1a refer to the time required to thaw 500 mg of lyophilized daptomycin in 10 mL of 0.9% sodium chloride at controlled room temperature (20-25°C). Comparative reconstitution times are shown for RLD (Cubicin®) versus the proprietary generic daptomycin product developed by Xeria versus various formulations of the present disclosure. The generic daptomycin product developed by Xeria does not contain excipients for shortening reconstitution according to the present disclosure and is stored refrigerated. The reconstitution times shown in Table 1a are the maximum reconstitution times measured for multiple samples of each formulation under identical conditions.

[0225] [Table 2]

[0226] From Table 1a, it is clear that the solid formulations containing branched aliphatic amino acids have reduced reconstitution times relative to the comparable reconstitution times of the commercially available daptomycin formulations. According to Table 1a, the reconstitution times of the tabulated daptomycin formulations are reduced by 82% to 96%.

[0227] The reconstitution times shown in Table 1b refer to the time required to thaw 500 mg of lyophilized daptomycin in 10 mL of injectable solution at controlled room temperature (20-25°C). Comparative reconstitution times are shown for daptomycin formulations with excipients for stability and with and without excipients to reduce reconstitution time. The reconstitution times shown in Table 1a are the maximum reconstitution times measured for multiple samples of each formulation under identical conditions.

[0228] [Table 3]

[0229] From Table 1b it is clear that the solid dosage forms containing Ile have reconstitution times that are reduced by 76% or even 82% compared to the same formulations without Ile. Example 2 Daptomycin (10.423 g, 97.7% daptomycin and 1.8% water when evaluated on an anhydrous basis) was added to a WFI solution containing reconstitution excipients at molar ratios ranging from 1:0.5 to 1:1.5, including 1:0.5, 1:1, and 1:1.5 daptomycin:reconstitution excipient molar ratios.

[0230] The contents were then stirred using a magnetic stirrer. The pH indicated in the table was adjusted using 6 M HCl solution. The solution was then transferred to a volumetric flask and WFI was added to bring the volume to 100 mL.

[0231] The solution was mixed to ensure homogeneity, filtered through a 0.2 μm filter, transferred to vials, and lyophilized. The reconstitution times shown in Tables 2a and 2b refer to the time required to thaw 500 mg of lyophilized daptomycin in 10 mL of injection solution (Table 2a) and 0.9% NaCl (Table 2b) at controlled room temperature (20-25°C). Comparative reconstitution times for various formulations of the present disclosure over a pH range of 5.0 to 5.8 are shown. The reconstitution times shown in Tables 2a and 2b are the maximum reconstitution times measured for multiple samples of each formulation under identical conditions.

[0232] [Table 4]

[0233] [Table 5]

[0234] Example 3 Daptomycin (10.423 g, 97.7% daptomycin and 1.8% water, based on anhydrous basis) was added to a WFI solution containing reconstitution excipients. Arginine and histidine were added as excipients for formulation stability at room temperature.

[0235] The contents were then stirred using a magnetic stirrer. The pH was adjusted using 6 M HCl and / or 1 M NaOH solution. The solution was then transferred to a volumetric flask and WFI was added to bring the volume to 100 mL.

[0236] The solution was mixed to ensure homogeneity, filtered through a 0.2 μm filter, transferred to vials, and lyophilized. The reconstitution times shown in Table 3a refer to the time required to thaw the weight of lyophilized daptomycin specified in Table 3a at controlled room temperature (20-25°C). The reconstitution times shown in Table 3a are the maximum reconstitution times measured on multiple samples of each formulation under identical conditions.

[0237] [Table 6]

[0238] [Table 7]

[0239] The reconstitution times shown in Table 3b refer to the time required to thaw 350 mg of lyophilized daptomycin solution in 7 mL of fluid for injection after a period of storage at the same temperature conditions, starting at controlled room temperature. The reconstitution times shown in Table 3b are the maximum reconstitution times measured for multiple samples of each formulation under the same conditions.

[0240] Example 4 - Stability of Daptomycin Solid Dosage Forms Under Refrigerated Conditions Solid dosage forms of daptomycin were prepared by adding daptomycin to a WFI solution containing reconstitution excipients. The molar ratios varied from 1:0.5 to 1:3 daptomycin:reconstitution excipients, including 1:0.5, 1:1, and 1:3.

[0241] The contents are stirred using a magnetic stirrer. The pH is adjusted to various pH values ​​between 5.0 and 6.5 using 6M HCl and / or 1M NaOH solutions. The solution is transferred to a volumetric flask and WFI is added to bring the volume to 100 mL.

[0242] The solution is mixed to ensure homogeneity, filtered through a 0.2 μm filter, transferred to vials, and lyophilized. The lyophilized formulation is then stored at 2-8°C and stability is determined at time points such as 1 month, 2 months, 3 months, 6 months, 12 months and beyond.

[0243] It is predicted that the formulation will be stable for 3 and 6 months at 2-8°C, and this can be extrapolated to show that the formulation is stable or stabilized for up to about 24 months. Example 5 The following numbered entries represent embodiments of liquid pharmaceutical formulations containing the active ingredient:

[0244] Item 1. A solid pharmaceutical formulation of daptomycin containing at least one branched aliphatic amino acid or a pharmaceutically acceptable salt or derivative thereof. Item 2. The solid pharmaceutical formulation of daptomycin according to Item 1, wherein at least one branched aliphatic amino acid is an excipient for improving reconstitution time, and the branched aliphatic amino acid comprises leucine, isoleucine, and valine.

[0245] Item 3. The solid pharmaceutical formulation of daptomycin according to items 1 and 2, wherein the formulation has an improved reconstitution time. Item 4. The solid formulation of daptomycin according to Item 2, wherein the at least one branched aliphatic amino acid is selected from L-leucine, L-isoleucine, and L-valine.

[0246] Item 5. The solid formulation of daptomycin according to Item 4, wherein the at least one branched aliphatic amino acid is L-isoleucine. Item 6. The solid formulation of daptomycin according to Item 4, wherein the at least one branched aliphatic amino acid is L-valine.

[0247] Item 7. The solid formulation of daptomycin according to Item 4, wherein the at least one branched aliphatic amino acid is L-leucine. Item 8. The solid formulation of daptomycin according to any one of Items 1 to 7, wherein the branched aliphatic amino acid is contained in the formulation before drying in an amount of 2.5% w / V or less.

[0248] Item 9. The solid formulation of daptomycin according to any one of Items 1 to 7, wherein the branched aliphatic amino acid is contained in the formulation before drying in an amount of 1% w / V or less. Item 10. The solid formulation of daptomycin according to Item 5, wherein the formulation before drying contains 10% w / v daptomycin and 0.8% w / v L-isoleucine.

[0249] Item 11. The solid formulation of daptomycin according to any one of Items 1 to 10, wherein the pH of the formulation before drying is 4.5 to 9. Item 12. The solid formulation of daptomycin according to any one of Items 1 to 10, wherein the pH of the formulation before drying is 4.5 to 7.0.

[0250] Item 13. The solid formulation of daptomycin according to any one of Items 1 to 10, wherein the pH of the formulation before drying is 5.0 to 6.2. Item 14. The solid formulation of daptomycin according to any one of Items 1 to 10, wherein the pH of the formulation before drying is 6.2.

[0251] Item 14. The solid formulation of daptomycin according to any one of Items 1 to 10, wherein the pH of the formulation before drying is 5.8 to 6.5. Item 16. The solid formulation of daptomycin according to any one of Items 1 to 10, wherein the pH of the formulation before drying is 5.0 to 6.5.

[0252] Item 17. The solid formulation of daptomycin according to any one of Items 1 to 16, wherein the at least one branched aliphatic amino acid is included in the solid formulation of daptomycin in a molar ratio to daptomycin of 0.5:1 to 5:1.

[0253] Item 18. The solid formulation of daptomycin according to any one of Items 1 to 16, wherein the at least one branched aliphatic amino acid is included in the solid formulation of daptomycin in a molar ratio to daptomycin of 1:1 to 3:1.

[0254] Item 19. The solid formulation of daptomycin according to any one of Items 1 to 16, wherein the at least one branched aliphatic amino acid is included in the solid formulation of daptomycin in a molar ratio to daptomycin of 1:1.

[0255] Item 20. The solid formulation of daptomycin according to any one of Items 1 to 19, wherein the reconstitution time of the formulation is 120 seconds or less. Item 21. The solid formulation of daptomycin according to any one of Items 1 to 19, wherein the pH of the formulation before drying is 5.0 to 6.2, and the reconstitution time of the formulation is 120 seconds or less.

[0256] Item 22. The solid formulation of daptomycin according to any one of items 1 to 19, wherein the reconstitution time for a 500 mg solid pharmaceutical daptomycin formulation in 10 mL of 0.9% sodium chloride at controlled room temperature is 120 seconds or less.

[0257] Item 23. The solid formulation of daptomycin according to any one of Items 1 to 19, wherein the pH of the formulation before drying is from 4.5 to 7.0 and the reconstitution time of a 500 mg solid pharmaceutical daptomycin formulation in 10 mL of injectable fluid at controlled room temperature is 120 seconds or less.

[0258] Item 24. The solid formulation of daptomycin according to any one of Items 1 to 19, wherein the pH of the formulation before drying is from 5.0 to 6.2, and the reconstitution time of a 500 mg solid pharmaceutical daptomycin formulation in 10 mL of injectable fluid at controlled room temperature is 120 seconds or less.

[0259] Item 25. The daptomycin solid formulation of any one of items 1 to 19, wherein the improved reconstitution time is demonstrated as a reconstitution time that is reduced by 60% to 96% compared to the reconstitution time of Cubicin® RLD.

[0260] Item 26. The daptomycin solid formulation of any one of items 1 to 19, wherein the improved reconstitution time is demonstrated as a reconstitution time that is reduced by 80% to 96% compared to the reconstitution time of Cubicin® RLD.

[0261] Item 27. The solid formulation of daptomycin according to any one of Items 1 to 26, wherein the formulation is stable at 2 to 8°C for a predetermined period of time. Item 28. The solid formulation of daptomycin according to any one of Items 1 to 19, comprising at least one stabilizing excipient.

[0262] Item 29. The solid formulation of daptomycin according to Item 28, wherein the formulation is stable for a predetermined period at room temperature, and the formulation contains at least one stabilizing excipient. Item 30. The solid formulation of daptomycin according to Item 27 or 29, wherein the predetermined period includes 7 days (1 week), 14 days (2 weeks), 30 days (1 month), 60 days (2 months), 150 days (5 months), 180 days (6 months), 12 months (1 year), and longer.

[0263] Item 31. The solid formulation of daptomycin according to Item 30, wherein the predetermined period is 6 months. Item 32. The solid formulation of daptomycin according to Item 29, wherein the at least one stabilizing excipient comprises alanine, arginine, asparagine, histidine, glycine, lysine, ornithine, phenylalanine, proline, threonine, tryptophan, tyrosine, or a pharmaceutically acceptable salt or derivative thereof.

[0264] Item 33. The solid formulation of daptomycin according to Item 32, wherein the at least one amino acid is selected from arginine and histidine, pharmaceutically acceptable salts thereof, or derivatives thereof.

[0265] Item 34. The solid formulation of daptomycin according to Items 32 and 32, wherein the formulation comprises two stabilizing excipients, the first stabilizing excipient being arginine and the second stabilizing excipient being histidine or a pharmaceutically acceptable salt or derivative thereof.

[0266] Item 35. The solid formulation of daptomycin according to any one of Items 28 to 34, wherein the stabilizing excipient is included in a molar ratio to daptomycin of 3:1 to 5:1. Item 36. The solid formulation of daptomycin according to any one of Items 32 to 34, comprising a branched aliphatic amino acid selected from isoleucine as an excipient for improving reconstitution time, and at least one stabilizing excipient selected from arginine and histidine, their pharmaceutically acceptable salts, or derivatives thereof.

[0267] Item 37. The solid formulation of daptomycin according to any one of Items 32 to 34, comprising an excipient for improving reconstitution time selected from leucine and two stabilizing excipients, wherein the first stabilizing excipient is arginine and the second stabilizing excipient is histidine or a pharmaceutically acceptable salt or derivative thereof.

[0268] Item 38. The solid formulation of daptomycin according to any one of Items 32 to 34, comprising an excipient for improving reconstitution time selected from valine and two stabilizing excipients, wherein the first stabilizing excipient is arginine and the second stabilizing excipient is histidine or a pharmaceutically acceptable salt or derivative thereof.

[0269] Item 39. The solid formulation of daptomycin according to Item 32 or 36, comprising an excipient for improving reconstitution time selected from isoleucine and two stabilizing excipients selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients Dapt:Ile:Arg:His is from 1:0.5:1:1 to 1:3:5:5.

[0270] Item 40. The solid formulation of daptomycin according to Item 32 or 36, comprising an excipient for improving reconstitution time selected from isoleucine and two stabilizing excipients selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients is Dapt:Ile:Arg:His is 1:1:5:3.

[0271] Item 41. The solid formulation of daptomycin according to Item 32 or 36, comprising an excipient for improving reconstitution time selected from isoleucine and two stabilizing excipients selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients is Dapt:Ile:Arg:His is 1:1:4:3.

[0272] Item 42. The daptomycin solid formulation of any one of Items 32 to 36, comprising an excipient for improving reconstitution time selected from L-isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to the excipients is Dapt:Ile:Arg:His is 1:1:5:3, and the reconstitution time of a 500 mg daptomycin solid formulation in 10 mL of injectable solution at controlled room temperature is 50 seconds or less.

[0273] Item 43. The daptomycin solid formulation of any one of Items 32 to 36, comprising an excipient for improving reconstitution time selected from L-isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to the excipients is Dapt:Ile:Arg:His is 1:1:5:3, and the reconstitution time of a 350 mg daptomycin solid formulation in 7 mL of injectable solution at controlled room temperature is 60 seconds or less.

[0274] Item 44. The daptomycin solid formulation of any one of Items 32 to 36, comprising an excipient for improving reconstitution time selected from L-isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to the excipients is Dapt:Ile:Arg:His is 1:1:5:3, and the reconstitution time of a 3500 mg daptomycin solid formulation in 70 mL of injectable fluid at controlled room temperature is 90 seconds or less.

[0275] Item 45. The daptomycin solid formulation of any one of Items 32 to 36, comprising an excipient for improving reconstitution time selected from L-isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to the excipients is Dapt:Ile:Arg:His is 1:1:4:3, and the reconstitution time of a 500 mg daptomycin solid formulation in 10 mL of injectable solution at controlled room temperature is 50 seconds or less.

[0276] Item 46. The solid formulation of daptomycin according to any one of Items 18 to 23, comprising an excipient for improving reconstitution time selected from L-isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to excipients Dapt:Ile:Arg:His is 1:1:5:3, and having an improved reconstitution time, wherein the improved reconstitution time is demonstrated as a reduction in reconstitution time of 75% or more compared to the reconstitution time of an identical solid daptomycin formulation comprising an excipient for stabilization selected from arginine and histidine in a molar ratio of daptomycin to excipients Dapt:Arg:His of 1:5:3 but excluding L-isoleucine.

[0277] Item 47. The solid formulation of daptomycin according to any one of Items 32 to 36, comprising an excipient for improving reconstitution time selected from L-isoleucine and an excipient for stabilization selected from arginine and histidine, wherein the molar ratio of daptomycin to the excipients Dapt:Ile:Arg:His is 1:1:5:3, and having an improved reconstitution time, wherein the improved reconstitution time is demonstrated as a reduction in reconstitution time of 70% or more compared to the reconstitution time of a solid daptomycin formulation consisting of an excipient for stabilization selected from arginine and histidine and wherein the molar ratio of daptomycin to the excipients Dapt:Ile:Arg:His is 1:5:3.

[0278] Item 48. The daptomycin solid formulation of any one of Items 1 to 4, wherein the solid formulation has an improved reconstitution time, the solid formulation comprising an excipient for shortened reconstitution time selected from L-isoleucine, L-valine, or L-leucine, and an excipient for stabilization, wherein the improved reconstitution time is demonstrated by a reduction in reconstitution time of 25% or more compared to the reconstitution time of an identical solid daptomycin formulation comprising the excipient for stabilization disclosed herein but not the excipient for improved reconstitution time selected from L-isoleucine, L-valine, or L-leucine.

[0279] Item 49. The solid formulation of daptomycin according to any one of Items 1 to 4, wherein the solid formulation contains at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, and L-leucine, and the daptomycin formulation before drying contains 2.5% w / v or less of the branched aliphatic amino acid, and the pH of the formulation before drying is 4.5 to 7.0.

[0280] Item 50. The solid formulation of daptomycin according to any one of Items 1 to 4, wherein the solid formulation contains at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, and L-leucine, and the daptomycin formulation before drying contains 2.4% w / v or less of the branched aliphatic amino acid, and the pH of the formulation before drying is 5.0 to 6.2.

[0281] Item 51. The daptomycin solid formulation according to any one of Items 1 to 4, wherein the daptomycin solid formulation comprises at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying comprises 2.4% w / v or less of the branched aliphatic amino acid, wherein the pH of the formulation before drying is 4.5 to 7.0, and wherein the daptomycin solid formulation has a reconstitution time of 180 seconds or less.

[0282] Item 52. The daptomycin solid formulation of any one of Items 1 to 4, wherein the daptomycin solid formulation comprises at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 2.4% w / v or less of the branched aliphatic amino acid, wherein the pH of the formulation before drying is 5.0 to 6.2, and wherein the daptomycin solid formulation has a reconstitution time of 150 seconds or less.

[0283] Item 53: The daptomycin solid formulation according to any one of Items 1 to 4, wherein the daptomycin solid formulation comprises at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying comprises 2.4% w / v or less of the branched aliphatic amino acid, wherein the pH of the formulation before drying is 5.4 to 6.2, and wherein the daptomycin solid formulation has a reconstitution time of 120 seconds or less.

[0284] Item 54. The solid formulation of daptomycin according to any one of Items 1 to 4, wherein the solid formulation of daptomycin contains L-isoleucine in an amount of 2.4% w / V or less before drying, the pH of the formulation before drying is 5.4 to 6.2, and the solid formulation of daptomycin has a reconstitution time of 120 seconds or less.

[0285] Item 55. The solid formulation of daptomycin according to any one of Items 1 to 4, wherein the solid formulation of daptomycin contains L-valine in an amount of 2.4% w / V or less before drying, the pH of the formulation before drying is 5.4 to 6.2, and the solid formulation of daptomycin has a reconstitution time of 120 seconds or less.

[0286] Item 56. The solid formulation of daptomycin according to any one of Items 1 to 4, wherein the solid formulation of daptomycin contains at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, and L-leucine, and the daptomycin formulation before drying contains 1% w / v or less of the branched aliphatic amino acid.

[0287] Item 57. The solid formulation of daptomycin according to any one of Items 1 to 4, wherein the solid formulation of daptomycin contains at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, and the daptomycin formulation before drying contains 2.4% w / v or less of the branched aliphatic amino acid.

[0288] Item 58. The solid formulation of daptomycin according to any one of Items 1 to 4, wherein the solid formulation of daptomycin contains at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, and the daptomycin formulation before drying contains 1% w / V or less of the branched aliphatic amino acid, and the pH of the formulation before drying is 4.5 to 7.0.

[0289] Item 59. A solid formulation of daptomycin comprising at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 1% w / v or less of the branched aliphatic amino acid, the pH of the formulation before drying is 4.5 to 7.0, and the daptomycin solid formulation has a reconstitution time of 180 seconds or less.

[0290] Item 60. A solid formulation of daptomycin comprising at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 1% w / v or less of the branched aliphatic amino acid, and the pH of the formulation before drying is 5.0 to 6.2.

[0291] Item 61. A solid formulation of daptomycin comprising at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 1% w / v or less of the branched aliphatic amino acid, the pH of the formulation before drying is 5.0 to 6.2, and the daptomycin solid formulation has a reconstitution time of 150 seconds or less.

[0292] Item 62. A solid formulation of daptomycin comprising at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 1% w / v or less of the branched aliphatic amino acid, the pH of the formulation before drying is 5.4 to 6.2, and the daptomycin solid formulation has a reconstitution time of 120 seconds or less.

[0293] Item 63. A solid dosage form of daptomycin containing L-isoleucine, wherein the daptomycin formulation before drying contains 1% w / v or less of L-isoleucine, the pH of the formulation before drying is 5.4 to 6.2, and the daptomycin solid dosage form has a reconstitution time of 120 seconds or less.

[0294] Item 64. A solid dosage form of daptomycin comprising L-valine, wherein the daptomycin formulation before drying contains 1% w / v or less of L-valine, and the pH of the formulation before drying is 5.4 to 6.2, and wherein the daptomycin solid dosage form has a reconstitution time of 120 seconds or less.

[0295] Item 65. A solid dosage form of daptomycin, wherein the formulation contains 2.4% w / v or less L-valine before drying, and the solid dosage form of daptomycin has an improved reconstitution time, demonstrated as a 60% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0296] Item 66. A solid formulation of daptomycin, wherein the formulation contains 2.4% w / v or less L-valine before drying, and the pH of the formulation before drying is from 4.5 to 7.0, and the solid formulation of daptomycin has an improved reconstitution time, demonstrated as a 60% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0297] Item 67. A solid dosage form of daptomycin, wherein the formulation contains 2.4% w / v or less L-valine before drying, and the pH of the formulation before drying is from 5.0 to 6.2, and the daptomycin solid dosage form has an improved reconstitution time, demonstrated as an 82% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0298] Item 68. A solid dosage form of daptomycin, wherein the formulation contains 2.4% w / v or less L-isoleucine before drying, and the solid dosage form of daptomycin has an improved reconstitution time, demonstrated as a 60% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0299] Item 69. A solid formulation of daptomycin, wherein the formulation contains 2.4% w / v or less L-isoleucine before drying, and the pH of the formulation before drying is from 5.0 to 7.0, and the solid formulation of daptomycin has an improved reconstitution time, demonstrated as a 60% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0300] Item 70. A solid formulation of daptomycin, wherein the formulation contains 2.4% w / v or less L-isoleucine before drying, and the pH of the formulation before drying is from 5.0 to 6.2, and the daptomycin solid formulation has an improved reconstitution time, demonstrated as a reconstitution time that is reduced by 82% or more compared to the reconstitution time of Cubicin® RLD.

[0301] Item 71. A solid dosage form of daptomycin containing isoleucine, arginine, and histidine, wherein the formulation contains no more than 2.4% w / v isoleucine before drying, and the molar ratio of daptomycin to excipients Dapt:Ile:Arg:His is from 1:0.5:1:1 to 1:3:5:5.

[0302] Item 71. A solid dosage form of daptomycin containing isoleucine, arginine, and histidine, wherein the formulation contains no more than 2.4% w / v isoleucine before drying, the pH of the formulation before drying is between 4.5 and 7.0, and the molar ratio of daptomycin to excipients is Dapt:Ile:Arg:His is between 1:0.5:1:1 and 1:3:5:5.

[0303] Item 72. The solid formulation of daptomycin according to any one of Items 1 to 19, wherein the pH of the formulation before drying is 5.0 to 6.5, and the reconstitution time of the formulation is 120 seconds or less. Item 73. The solid formulation of daptomycin according to any one of Items 1 to 4, wherein the solid formulation contains at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, and L-leucine, and the daptomycin formulation before drying contains 2.4% w / V or less of the branched aliphatic amino acid, and the pH of the formulation before drying is 5.0 to 6.5.

[0304] Item 74. The daptomycin solid formulation according to any one of Items 1 to 4, wherein the daptomycin solid formulation contains at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 2.4% w / v or less of the branched aliphatic amino acid, wherein the pH of the formulation before drying is 5.0 to 6.5, and wherein the daptomycin solid formulation has a reconstitution time of 150 seconds or less.

[0305] Item 75. A solid formulation of daptomycin comprising at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 1% w / v or less of the branched aliphatic amino acid, and the pH of the formulation before drying is 5.0 to 6.5.

[0306] Item 76. A solid formulation of daptomycin comprising at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 1% w / v or less of the branched aliphatic amino acid, the pH of the formulation before drying is 5.0 to 6.5, and the daptomycin solid formulation has a reconstitution time of 150 seconds or less.

[0307] Item 77. A solid dosage form of daptomycin, wherein the formulation contains 2.4% w / v or less L-valine before drying, and the pH of the formulation before drying is from 5.0 to 6.5, and the daptomycin solid dosage form has an improved reconstitution time, demonstrated as an 82% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0308] Item 78. A solid formulation of daptomycin, wherein the formulation contains 2.4% w / v or less L-isoleucine before drying, and the pH of the formulation before drying is from 5.0 to 6.5, and the daptomycin solid formulation has an improved reconstitution time, demonstrated as a reconstitution time that is reduced by 82% or more compared to the reconstitution time of Cubicin® RLD.

[0309] Item 79. A solid dosage form of daptomycin containing isoleucine, arginine, and histidine, wherein the formulation contains no more than 2.4% w / v isoleucine before drying, the pH of the formulation before drying is between 5.0 and 6.5, and the molar ratio of daptomycin to excipients is Dapt:Ile:Arg:His is between 1:0.5:1:1 and 1:3:5:5.

[0310] Item 80. The solid formulation of daptomycin according to any one of Items 1 to 19, wherein the pH of the formulation before drying is 5.8 to 6.5, and the reconstitution time of the formulation is 120 seconds or less. Item 81. The solid formulation of daptomycin according to any one of Items 1 to 4, wherein the solid formulation contains at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, and the daptomycin formulation before drying contains 2.4% w / V or less of the branched aliphatic amino acid, and the pH of the formulation before drying is 5.8 to 6.5.

[0311] Item 82. The daptomycin solid formulation of any one of Items 1 to 4, wherein the daptomycin solid formulation contains at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 2.4% w / v or less of the branched aliphatic amino acid, wherein the pH of the formulation before drying is 5.8 to 6.5, and wherein the daptomycin solid formulation has a reconstitution time of 150 seconds or less.

[0312] Item 83. A solid formulation of daptomycin comprising at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 1% w / v or less of the branched aliphatic amino acid, and the pH of the formulation before drying is 5.8 to 6.5.

[0313] Item 84. A solid formulation of daptomycin comprising at least one branched aliphatic amino acid selected from L-isoleucine, L-valine, or L-leucine, wherein the daptomycin formulation before drying contains 1% w / v or less of the branched aliphatic amino acid, the pH of the formulation before drying is 5.8 to 6.5, and the daptomycin solid formulation has a reconstitution time of 150 seconds or less.

[0314] Item 85. A solid dosage form of daptomycin, wherein the formulation contains 2.4% w / v or less L-valine before drying, and the pH of the formulation before drying is from 5.8 to 6.5, and the daptomycin solid dosage form has an improved reconstitution time, demonstrated as an 82% to 96% reduction in reconstitution time compared to the reconstitution time of Cubicin® RLD.

[0315] Item 86. A solid formulation of daptomycin, wherein the formulation contains 2.4% w / v or less L-isoleucine before drying, and the pH of the formulation before drying is from 5.8 to 6.5, and the daptomycin solid formulation has an improved reconstitution time, demonstrated as a reconstitution time that is reduced by 82% or more compared to the reconstitution time of Cubicin® RLD.

[0316] Item 87. A solid formulation of daptomycin comprising isoleucine, arginine, and histidine, wherein the formulation contains no more than 2.4% w / v isoleucine before drying, and the pH of the formulation before drying is from 5.8 to 6.5, and wherein the molar ratio of daptomycin to excipients Dapt:Ile:Arg:His is from 1:0.5:1:1 to 1:3:5:5.

[0317] Item 89. A method for producing a solid formulation of daptomycin according to any one of the preceding items, the method comprising providing a solution of daptomycin and at least one branched aliphatic amino acid, adjusting the pH of such solution to a pH of 4 to 9 with a suitable pH adjuster, and freeze-drying or spray-drying or fluid-bed drying such composition.

[0318] Item 90. A method for improving the reconstitution time of a solid dosage form of daptomycin by using at least one branched aliphatic amino acid in preparing the solid dosage form of daptomycin.

Claims

1. 1. A pharmaceutically acceptable solid formulation comprising daptomycin, arginine, histidine, and at least one branched aliphatic amino acid selected from the group consisting of leucine, isoleucine, valine, and pharmaceutically acceptable salts thereof, wherein the molar ratio of the at least one branched aliphatic amino acid to daptomycin in the solid formulation is from 0.5:1 to 5:

1.

2. 2. The solid formulation of claim 1, wherein the at least one branched aliphatic amino acid is selected from L-leucine, L-isoleucine, and L-valine.

3. 3. The solid formulation of claim 2, wherein the at least one branched aliphatic amino acid is L-isoleucine.

4. 3. The solid formulation of claim 2, wherein the at least one branched aliphatic amino acid is L-valine.

5. The solid formulation according to any one of claims 1 to 4, wherein the branched aliphatic amino acid is contained in the formulation before drying in an amount of 2.5% w / V or less.

6. 6. The solid formulation according to claim 5, wherein the branched aliphatic amino acid is contained in the formulation before drying in an amount of 1% w / v or less.

7. 4. The solid dosage form of claim 3, wherein the formulation before drying comprises 10% w / v daptomycin and 0.8% w / v L-isoleucine.

8. The solid formulation according to any one of claims 1 to 7, wherein the pH of the formulation before drying is from 4.5 to 9.

9. 9. The solid formulation of claim 8, wherein the pH of the formulation before drying is from 6 to 6.

5.

10. 5. The solid dosage form of claim 1, wherein the at least one branched aliphatic amino acid is present in the solid dosage form in a molar ratio to daptomycin of from 1:1 to 3:

1.

11. 2. The solid dosage form of claim 1, wherein histidine and arginine are each present in a molar ratio to daptomycin of from 3:1 to 5:

1.

12. 12. The solid formulation of claim 1, wherein the solid formulation comprises daptomycin, isoleucine, arginine, and histidine, and the molar ratio of daptomycin to isoleucine, arginine, and histidine (Dapt:Ile:Arg:His) is from 1:0.5:1:1 to 1:3:5:

5.

13. 13. The solid formulation of claim 12, wherein the solid formulation comprises daptomycin, isoleucine, arginine, and histidine, wherein the molar ratio of daptomycin to isoleucine, arginine, and histidine (Dapt:Ile:Arg:His) is 1:1:5:

3.

14. 14. A method for producing the solid dosage form according to any one of claims 1 to 13, the method comprising providing a solution of daptomycin, arginine, histidine, and at least one branched aliphatic amino acid selected from the group consisting of leucine, isoleucine, valine, and pharmaceutically acceptable salts thereof, wherein the at least one branched aliphatic amino acid is present in the formulation before drying in an amount of 2.5% w / v or less; adjusting the pH of such solution to a pH of 4 to 9 with a suitable pH adjuster; and freeze-drying or spray-drying or fluid-bed drying such composition.

15. 1. A method for improving the reconstitution time of a solid dosage form of daptomycin by combining a daptomycin solution and at least one branched aliphatic amino acid, and drying such dosage form.

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