Daptomycin-containing preparations and methods for producing daptomycin-containing preparations

Abstract

To provide a daptomycin-containing preparation that has excellent stability and requires a short time for re-dissolution.SOLUTION: A daptomycin-containing preparation contains daptomycin and sodium. The daptomycin-containing preparation is powder or powder aggregate. When the daptomycin-containing preparation is dissolved in water, sodium ions are contained by 3 mass% or more relative to 100 mass% of the daptomycin. The sodium ions may be contained by less than 7.79 mass% relative to 100 mass% of the daptomycin.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates to daptomycin-containing formulations, and in particular to lyophilized formulations thereof. [Background technology]

[0002] Daptomycin (N-(Decanoyl)-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-(3R)-3-methyl-L-glutamyl-3-(2-aminobenzoyl)-L-alanine1.13→3.4-lactone) exhibits bactericidal activity against aerobic gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), and is therefore used to treat infections caused by aerobic gram-positive bacteria resistant to other antibacterial agents. Daptomycin is provided, for example, by MSD K.K. as Cubicin (registered trademark) for intravenous injection, a freeze-dried injection.

[0003] On the other hand, freeze-dried injections require the addition of physiological saline before administration to patients to dissolve them, but existing freeze-dried daptomycin injections have the problem that it takes time to dissolve. It is also known that daptomycin has low thermal stability, and that the amount of related substances of daptomycin increases during storage of the preparation. To address these problems, for example, Patent Document 1 describes that freeze-drying with sucrose can provide a chemically stable daptomycin preparation that requires a short time for reconstitution. Patent Document 2 describes that a solution containing daptomycin and calcium chloride is stable for a long period of time when stored in a refrigerator. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2013-511557 [Patent Document 2] Special Publication No. 2013-511522 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a daptomycin-containing preparation that is highly stable and requires a short time for redissolution. [Means for solving the problem]

[0006] According to one embodiment of the present invention, there is provided a daptomycin-containing formulation comprising daptomycin and sodium, wherein the daptomycin-containing formulation is a powder or a powder agglomerate, and when the daptomycin-containing formulation is dissolved in water, the formulation contains 3% by mass or more of sodium ions relative to 100% by mass of the daptomycin.

[0007] The sodium ion may be contained in an amount of less than 7.79% by mass relative to 100% by mass of the daptomycin.

[0008] The sodium ions may be included as sodium hydroxide or sodium chloride.

[0009] The daptomycin may comprise 350 mg. Effect of the Invention

[0010] According to one embodiment of the present invention, a daptomycin-containing formulation is provided that is highly stable and requires a short time for reconstitution. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a flow diagram illustrating the manufacturing process of a daptomycin-containing formulation according to one embodiment of the present invention. [Diagram 2]FIG. 1 is a graph showing the relationship between the stability of daptomycin and sodium ions in a daptomycin-containing formulation according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] The daptomycin-containing formulation of the present invention is described in detail below. However, the daptomycin-containing formulation of the present invention is not to be construed as being limited to the description of the following embodiments and examples.

[0013] The daptomycin-containing formulation according to the present invention is an injection for intravenous administration. The daptomycin-containing formulation may be administered by intravenous drip infusion. In one embodiment, the daptomycin-containing formulation is a lyophilized formulation and is provided as a powder or a powder aggregate. In one embodiment, the daptomycin-containing formulation contains 350 mg of daptomycin as an effective amount per vial, but the content of daptomycin may be changed within a range in which a therapeutic effect is obtained.

[0014] The daptomycin-containing formulation of the present invention contains daptomycin and sodium. In one embodiment, when the daptomycin-containing formulation is dissolved in water, the daptomycin-containing formulation contains 3% by mass or more of sodium ions relative to 100% by mass of daptomycin. It is preferable that the daptomycin-containing formulation contains 4% by mass or more of sodium ions relative to 100% by mass of daptomycin. By containing 3% by mass or more of sodium ions relative to 100% by mass of daptomycin, the daptomycin-containing formulation of the present invention can significantly suppress the production of related substances. In addition, the daptomycin-containing formulation of the present invention requires a short time for redissolution.

[0015] The daptomycin-containing formulation preferably contains less than 7.79% by mass of sodium ions relative to 100% by mass of daptomycin. It is more preferable that the formulation contains less than 7.5% by mass of sodium ions relative to 100% by mass of daptomycin. By containing 3% by mass or more and less than 7.79% by mass of sodium ions relative to 100% by mass of daptomycin, the production of related substances can be significantly suppressed.

[0016] In one embodiment, the daptomycin-containing formulation can be dissolved in saline. For example, when the daptomycin-containing formulation is dissolved in 7 ml of saline, the formulation contains 3% by mass or more, preferably 4.05% by mass or more, of sodium ions relative to 100% by mass of daptomycin. Alternatively, the daptomycin-containing formulation contains less than 7.81% by mass, preferably less than 7.5% by mass, of sodium ions relative to 100% by mass of daptomycin.

[0017] If the daptomycin-containing formulation is provided as a powder or powder agglomerate, sodium ions may be included in the daptomycin-containing formulation as sodium hydroxide or sodium chloride. In one embodiment, the daptomycin-containing formulation is adjusted to a pH of 4.0 to 5.0.

[0018] The sodium ion concentration in a daptomycin-containing formulation can be measured by ion chromatography under the conditions in Table 1. The daptomycin-containing formulation can be dissolved in water (pure water), and the amount of sodium ions in the aqueous solution can be measured. [Table 1]

[0019] The daptomycin-containing formulation is dissolved in water (injection water) or physiological saline, or injection water and physiological saline, before administration. In one embodiment, when 350 mg of daptomycin is contained, daptomycin is dissolved in 7 ml of injection water or physiological saline, or injection water and physiological saline. At this time, the sodium hydroxide or sodium chloride contained in the daptomycin-containing formulation is ionized to generate sodium ions. At the time of dissolution, it is preferable that the osmotic pressure is 1 to 1.3 relative to physiological saline. From the viewpoint of the stability of the daptomycin-containing formulation during storage and the rapid dissolution of daptomycin, the sodium ion concentration of the daptomycin-containing formulation may be 7.79% by mass or more, but in order to make the osmotic pressure relative to physiological saline fall within the above range, the daptomycin-containing formulation is diluted with injection water within a range in which a therapeutic effect can be obtained.

[0020] [Manufacturing method of daptomycin-containing preparations] Fig. 1 is a flow diagram illustrating the manufacturing process of a daptomycin-containing formulation according to one embodiment of the present invention. Hydrochloric acid and sodium hydroxide are added to water (water for injection) to adjust the sodium ion content and prepare a solvent (step S101). Note that in one embodiment, sodium chloride may be added instead of hydrochloric acid and sodium hydroxide to adjust the sodium ion content. Also, in one embodiment, hydrochloric acid and sodium hydroxide may be combined with sodium chloride to adjust the sodium ion content.

[0021] Daptomycin is added to the solvent to dissolve the daptomycin (step S103). Sodium hydroxide is added to the daptomycin aqueous solution to adjust the pH to 4.0 to 5.0 (step S105). Water is added to the pH-adjusted daptomycin aqueous solution to a constant volume (step S107). The constant volume daptomycin aqueous solution is filtered (step S109). The filtered daptomycin aqueous solution is filled into vials (e.g., 10 ml vials) (step S111). The filled daptomycin aqueous solution is lyophilized to produce a daptomycin-containing formulation which is a powder or a powder aggregate (step S113). The vial containing the daptomycin-containing formulation is sealed and packed into a package as necessary. EXAMPLES

[0022] [Manufacturing of daptomycin-containing preparations] A specified amount of sodium chloride was added to 2 ml of water for injection to prepare an aqueous sodium chloride solution with an adjusted sodium ion content. 0.3675 g of daptomycin was added to the aqueous sodium chloride solution to dissolve daptomycin. An appropriate amount of sodium hydroxide was added to the aqueous daptomycin solution to adjust the pH to 4.6. Water for injection was added to the pH-adjusted aqueous daptomycin solution to obtain 3.5 ml of an aqueous daptomycin solution. The aqueous daptomycin solution was filtered through a filter (Merck, Millipore PVDF 0.22 μm) and filled into a 10 ml vial. The aqueous daptomycin solution in the vial was freeze-dried to produce a daptomycin-containing formulation. The vial containing the formulation containing daptomycin was sealed.

[0023] [Evaluation of the stability of daptomycin-containing formulations] The daptomycin-containing formulation was stored at 60°C and 60% RH for one week. After storage, the daptomycin-containing formulation was dissolved in 7 ml of water for injection, and the stability of the daptomycin-containing formulation was evaluated using the HPLC method shown in Table 2. Using the area percentage method, the sum of the peak areas of daptomycin and each component of daptomycin-derived related substances obtained on the chromatogram was set to 100, and the amount of daptomycin-derived related substances produced (%) was calculated from the peak area ratio. [Table 2]

[0024] Patent Document 1 mentions anhydrous daptomycin as a daptomycin-related substance that increases over time during storage of a formulation, and in the above analysis, a peak is detected at a relative retention time (RRT) of 1.30. For anhydrous daptomycin detected at a relative retention time (RRT) of 1.30, the increase was calculated from the values ​​before and after storage and plotted against the ratio of sodium ions to daptomycin. Figure 2 shows the relationship between the stability of daptomycin and sodium ions in a daptomycin-containing formulation according to one embodiment of the present invention. The respective values ​​are shown in Table 3. [Table 3]

[0025] 2, it was revealed that the production of related substances can be significantly suppressed by containing 3% by mass or more of sodium ions relative to 100% by mass of daptomycin. It was also revealed that the production of related substances can be significantly suppressed when sodium ions are contained in an amount of 3% by mass or more and less than 7.79% by mass relative to 100% by mass of daptomycin.

[0026] The time required for redissolution was measured when the daptomycin-containing preparations of Test Examples 1, 2, and 9 were dissolved in 7 ml of water for injection. The results in Table 2 show that the time required for redissolution was shortened by including 3% by mass or more of sodium ions relative to 100% by mass of daptomycin. [Table 4]

Claims

1. A solvent is prepared by adding hydrochloric acid and sodium hydroxide or sodium chloride to water; Daptomycin is added to the prepared solvent to dissolve the daptomycin, thereby preparing an aqueous daptomycin solution; Sodium hydroxide is added to the prepared daptomycin aqueous solution to adjust the pH to 4.0 to 5.0; A daptomycin-containing formulation produced by lyophilizing the aqueous daptomycin solution, 350 mg of daptomycin and sodium hydroxide or sodium chloride, the daptomycin-containing formulation is a powder or a powder agglomerate; A daptomycin-containing formulation, characterized in that when the daptomycin-containing formulation is dissolved in 7 ml of water, it contains sodium ions ionized from the sodium hydroxide or the sodium chloride in an amount of 3% by mass or more and less than 7.79% by mass relative to 100% by mass of the daptomycin.

2. A solvent is prepared by adding hydrochloric acid and sodium hydroxide or sodium chloride to water; Daptomycin is added to the prepared solvent to dissolve the daptomycin, thereby preparing an aqueous daptomycin solution; Sodium hydroxide is added to the prepared daptomycin aqueous solution to adjust the pH to 4.0 to 5.0; lyophilizing the aqueous daptomycin solution to produce a daptomycin-containing formulation that is a powder or an agglomerate of powder; The daptomycin-containing formulation comprises 350 mg of daptomycin and sodium hydroxide or sodium chloride, A method for producing a daptomycin-containing preparation, characterized in that when the daptomycin-containing preparation is dissolved in 7 ml of water, the preparation contains sodium ions ionized from the sodium hydroxide or the sodium chloride in an amount of 3% by mass or more and less than 7.79% by mass relative to 100% by mass of the daptomycin.

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