A stable aqueous solution of an ester peptide drug

Abstract

This invention pertains to the medical field, specifically relating to a stable aqueous solution of an ester peptide drug. The stable aqueous solution comprises an ester peptide drug and an amino acid derivative, wherein the amino acid derivative contains free thiol groups. The peptide ester drug aqueous solution formulation provided by this invention can significantly reduce the growth rate of impurities in aqueous solution at 2-8°C. Its stability at 2-8°C is at least 12 months.

Description

Technical Field

[0001] This invention belongs to the medical field, specifically relating to a stable aqueous solution of ester peptide drugs, aiming to solve the stability problem of ester peptide drugs, including daptomycin. Background Technology

[0002] Lipopeptides represent a class of potent anti-infective drugs that exhibit high antibacterial and antifungal activity against multidrug-resistant bacteria. A wide variety of lipopeptide drugs are currently available on the market, such as daptomycin, telavancin, caspofungin, micafungin, and anidulafungin, to combat invasive and often life-threatening infections.

[0003] Daptomycin's chemical name is: N-decanoyl-L-tryptophyl-D-asparaginyl-L-aspartyl-L-threonylglycyl-L-ornithyl-L-aspartyl-D-alanyl-L-aspartylglycyl-D-seryl-threo-3-methyl-L-glutamyl-3-anthraniloyl-L-alanineε1-lactone, and its molecular formula is: C 72 H 101 N 17 O 26 Its molecular weight is 1620.67, and its structural formula is as follows:

[0004]

[0005] Daptomycin (DAP) is a cyclic ester peptide compound. In 2003, the U.S. Food and Drug Administration (FDA) approved injectable daptomycin (brand name Cubicin) through a fast-track process for the treatment of secondary skin and skin structure infections caused by certain Gram-positive susceptible bacterial strains, such as abscesses, surgical site infections, and skin ulcers. Daptomycin works by disrupting the transport of amino acids across the cell membrane, thereby inhibiting the biosynthesis of peptidoglycan in the bacterial cell wall and altering the properties of the cell membrane. Additionally, it can kill bacteria by disrupting the bacterial cell membrane, causing its contents to leak out. Therefore, it may be difficult for bacteria to develop resistance to daptomycin.

[0006] Daptomycin is highly effective against Gram-positive bacteria and is used to treat the following infections:

[0007] 1. Complicated skin and soft tissue infections (CSSSI): Treatment of complicated skin and soft tissue infections caused by Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equina, and Enterococcus faecalis (only for vancomycin-sensitive strains).

[0008] 2. Staphylococcus aureus (including methicillin-sensitive and methicillin-resistant) bloodstream infection (bacteremia), and associated right-sided infective endocarditis.

[0009] According to existing literature, daptomycin is difficult to stabilize in solution, especially in aqueous solution, because it is readily hydrolyzed and degraded, and is known to degrade in slightly acidic solutions via aspartic transpeptidation at the asp-9 residue. Therefore, daptomycin is only marketed domestically and internationally as a lyophilized powder for intravenous injection. Lyophilized daptomycin powder exhibits rapid degradation upon reconstitution, and aqueous solutions also degrade during short-term storage; therefore, daptomycin is not suitable for long-term storage in aqueous solution. Currently, commercially available daptomycin formulated in reconstituted solution form (i.e., aqueous daptomycin) has a stability of 5 days under refrigeration, while its maximum stability at room temperature is 2 days. The main degradation products of daptomycin are daptomycin lactone hydrolysate, daptomycin β-isomer, and dehydrated daptomycin, with the following structural formulas:

[0010]

[0011]

[0012] For example, Kirsch disclosed the generation of dehydrated daptomycin and its β-isomer during the purification of daptomycin (Pharmaceutical Research, 6:387-393, 1989, Kirsch). Kirsch described a method for minimizing the levels of dehydrated daptomycin and its β-isomer by controlling pH and temperature conditions. However, Kirsch could not stabilize daptomycin and could not prevent the conversion of daptomycin to dehydrated daptomycin and its subsequent isomerization to the β-isomer. Kirsch also could not prevent the degradation of daptomycin into other degradation products unrelated to dehydrated daptomycin and its β-isomer. US Patent 6696412 discloses several additional impurities present in fermentation products from which daptomycin is derived, and provides a method for producing purified daptomycin with increased purity. These additional impurities include lactone hydrolysates of daptomycin. The disclosed daptomycin purification method may include forming daptomycin micelles, removing low molecular weight contaminants by filtration, then converting the micelle filtrate containing daptomycin into a non-micelle state, followed by anion exchange and reverse osmosis filtration to obtain high-purity daptomycin, and then lyophilizing it. The process is complex.

[0013] WO2014041425 discloses a lyophilized daptomycin formulation containing additives, wherein the excipients may be antioxidants, organic acids, or glucose derivatives. WO2013103801 discloses a powder formulation containing daptomycin and polyethylene glycol. WO20111063419 discloses a lyophilized daptomycin formulation with a shorter reconstitution time. Although these patent applications attempt to improve the stability of daptomycin, they all inevitably involve a reconstitution step and the risk of mismatch. Summary of the Invention

[0014] In order to solve the problems existing in the prior art, the present invention adopts the following technical solution:

[0015] A stable aqueous solution of an ester peptide drug, including an ester peptide drug and an amino acid derivative.

[0016] The ester peptide drugs are selected from daptomycin, Telavancin, Caspofungin, Micafungin, Anidulafungin, etc., with daptomycin being preferred.

[0017] The amino acid derivative contains a free sulfhydryl group or one of N-acetyl-glycine, N-acetyl-valine, N-acetyl-tyrosine, N-acetyl-alanine, N-acetyl-methionine, and N-methyl-cysteine.

[0018] Preferably, the amino acid derivative has the structure of Formula I:

[0019]

[0020] R1 is selected from hydrogen, C1-C3 alkyl, halogen; R2 and R3 are each independently selected from COR4, hydrogen, C1-C6 alkyl, and at least one of R2 and R3 is COR4, wherein R4 is selected from C1-C6 alkyl, aryl, alkylaryl, and the aryl or alkylaryl may be with 1-3 substituents selected from halogen, nitro, alkylacyl, C1-C6 straight-chain or branched alkyl.

[0021] For example, the alkyl groups of C1-C3 are selected from methyl, ethyl, propyl, and isopropyl.

[0022] For example, the halogen is selected from Cl, Br, and I.

[0023] For example, the C1-C6 alkyl groups are selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, and hexyl. The aryl groups are selected from benzene rings, pyridine rings, pyrimidine rings, pyrazine rings, pyridazine rings, furan rings, thiophene rings, pyrazole rings, imidazole rings, or triazole rings.

[0024] The alkylaryl group has the general formula (CH2)nAr, where n is 1-5, preferably 1-3, and Ar is selected from benzene ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, furan ring, thiophene ring, pyrazole ring, imidazole ring or triazole ring.

[0025] Preferably, R1 is selected from hydrogen, methyl, ethyl, and chlorine.

[0026] Preferably, R4 is selected from methyl, ethyl, and propyl.

[0027] Preferably, one of R2 and R3 is hydrogen.

[0028] Preferably, the amino acid derivative has the following structure:

[0029]

[0030] The definitions of R1, R2, and R4 are the same as those in the previous text.

[0031] Preferably, R1 is hydrogen, methyl, or halogen; R2 is hydrogen or methyl; and R4 is methyl, ethyl, propyl, or benzyl.

[0032] Preferably, the amino acid derivative is N-acetyl-cysteine.

[0033] Preferably, the N-acetylcysteine ​​can be a D-type, L-type, or a mixture of DL.

[0034] On the other hand, the present invention provides a stable aqueous solution of an ester peptide drug, comprising an ester peptide drug and an amino acid derivative, wherein the impurity growth rate of the aqueous solution of the ester peptide drug is within 0.01% w / w / day, preferably within 0.007% w / w / day. Preferably, the impurity growth rate is within 0.005% w / w / day.

[0035] In a preferred embodiment, the addition of N-acetylcysteine ​​can stabilize daptomycin and effectively reduce or inhibit the production of daptomycin lactone hydrolysate, β-isomer of daptomycin, and dehydrated daptomycin.

[0036]

[0037]

[0038] In stability tests, the daptomycin composition exhibits excellent stability, for example, at 2-8°C for at least 12 months, at least 18 months, at least 24 months, or at least 32 months.

[0039] Preferably, the peptide ester drug in the aqueous solution contains about 0.1-50% w / w; more preferably, it contains about 0.1-30% w / w; even more preferably, it contains about 0.1-20% w / w; and most preferably, it contains about 0.5-10% w / w.

[0040] Preferably, the amino acid derivative accounts for about 0.01-50% w / w; more preferably, the amino acid derivative accounts for about 0.01-10% w / w; more preferably, the amino acid derivative accounts for about 0.01-5% w / w; and even more preferably, the amino acid derivative accounts for about 0.01-2% w / w.

[0041] Wherein, "about" means within an acceptable error range for a specific value as determined by those skilled in the art, partly depending on how the value was measured or determined, i.e., limitations of the measurement system. In the context of a particular measurement, result, or embodiment, unless otherwise explicitly stated in the embodiments or elsewhere in the specification, "about" means within one standard deviation, or up to 5%, according to convention in the art. Furthermore, the numerical values ​​in this invention are instrument measurements and are subject to a certain degree of error; generally, ±10% is within a reasonable error range. Of course, the context in which the value is used must be considered; for example, in the case of component proportions, where the error variation after measurement does not exceed ±10%, the value can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0042] Preferably, the molar ratio of the peptide ester drug to the amino acid derivative is 1:(2-40); more preferably, the molar ratio of the peptide ester drug to the amino acid derivative is 1:(10-30); more preferably, the molar ratio of the peptide ester drug to the amino acid derivative is 1:(15-20); and most preferably, the molar ratio of the peptide ester drug to the amino acid derivative is 1:20.

[0043] More preferably, the aqueous solution of the peptide ester drug comprises a polyol.

[0044] Preferably, the polyol is selected from mannitol, sorbitol, sucrose, and trehalose.

[0045] More preferably, the aqueous solution of the ester peptide drug includes an organic solvent.

[0046] The organic solvent is selected from one or more of the following: dimethylacetamide, isopropanol, ethanol, benzyl alcohol, 2-methyl-1-propanol, tert-butanol, ethylene glycol, propylene glycol, glycerol, polysorbates such as polysorbate 20, polysorbate 40 and polysorbate 80, and polyethylene glycol (PEG) such as polyethylene glycol 200 (PEG 200), polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG400) and polyethylene glycol 600 (PEG 600).

[0047] Furthermore, for pharmaceutical purposes, those skilled in the art can add at least one other pharmaceutical excipient based on the technical solution of the present invention. The pharmaceutical excipient may be, for example, a carrier, antioxidant, surfactant, lipid, sugar, organic acid, complexing agent, preservative, stabilizer, solubilizer, surfactant, buffer, diluent, binder, etc.

[0048] The aqueous solutions of ester peptide drugs of the present invention can be packaged in glass vials, syringes, dropper bottles, tubes, applicators, unit dispensers, infusion bags, nebulizers, inhalation devices, or other drug containers. Optionally, the drug composition may be protected by filling with an inert gas such as nitrogen.

[0049] The aqueous solution of the ester peptide drug of the present invention can be used to prepare dosage forms such as injections, ophthalmic preparations, ear preparations, and nasal preparations.

[0050] This invention provides a method for preparing an aqueous solution of an ester peptide drug, comprising the following steps:

[0051] Step a: Weigh the prescribed amount of amino acid derivative into a beaker, add the prescribed amount of water, stir to dissolve, and obtain an amino acid derivative solution;

[0052] Step b: Weigh the prescribed amount of ester peptide drug and stir to dissolve it in the amino acid derivative solution obtained in step a above;

[0053] Furthermore, the preparation method includes the step of adding other pharmaceutical excipients.

[0054] This invention provides the use of the aqueous solution of the ester peptide drug in the preparation of medicaments for treating microbial infections, particularly those caused by Gram-positive organisms.

[0055] Finally, in one aspect, the present invention provides the use of the aqueous solution of the ester peptide drug in the preparation of a medicament for treating skin and soft tissue infections (cSSTI) and Staphylococcus aureus bloodstream infections (bacteremia).

[0056] It should also be noted that the aqueous solution formulation of ester peptide drugs provided by this invention can be used to prepare solid dosage forms, such as powders, granules, tablets, capsules, lyophilized powders, etc., without adding water.

[0057] The peptide ester drug aqueous solution formulation provided by this invention can significantly reduce the growth rate of impurities in aqueous solution at 8°C. The resulting aqueous solution can be used for the prevention and treatment of infections caused by susceptible strains, and its stability at 2-8°C is at least 12 months. Compared to lyophilized powder injections, the aqueous solution provided by this invention does not require a reconstitution step and can be used directly in clinical practice, reducing medication errors. Attached Figure Description

[0058] Figure 1 The HPLC chromatogram of formulation 7 at 40℃ / 24h is shown.

[0059] Figure 2 The HPLC chromatogram of Formulation 20 at 8℃ / 30 days is shown.

[0060] Figure 3 The HPLC chromatogram of formulation 21 at 8℃ / 60 days is shown.

[0061] Figure 4 The HPLC chromatogram of formulation 21 at 8℃ / 12 months is shown. Detailed Implementation

[0062] To better understand the technical solution of the present invention, the technical solution of the present invention will be further described below with reference to specific embodiments. The embodiments are only for the purpose of helping to understand the present invention and should not be regarded as specific limitations of the present invention.

[0063] The HPLC analysis conditions for the following examples are:

[0064] The liquid chromatograph is a Waters UPLC, the column is a Waters ACQUITY UPLC@BEH shield RP18, and the mobile phase is as follows:

[0065] Anhydrous sodium sulfate solution: Weigh 3.46g of anhydrous sodium sulfate, dissolve it in 1000ml of purified water, and adjust the pH to 3.4 with phosphoric acid.

[0066] Mobile phase A is a mixture of anhydrous sodium sulfate solution and acetonitrile in a ratio of 74:26.

[0067] Mobile phase B is a mixture of anhydrous sodium sulfate solution and acetonitrile in a 50:50 ratio.

[0068] Isocratic elution, mobile phase A:B = 66:34.

[0069] Take the sample to be tested, dilute it with 10% acetonitrile to 1 mg / ml, inject the sample for detection, column temperature 30℃, detector UV, injection volume 2 μL, detection wavelength 223 nm, flow rate 0.2 mL / min.

[0070] Example 1: Stability of daptomycin and different amino acids

[0071]

[0072] Preparation steps:

[0073] 1. Weigh the prescribed amount of amino acid compound into a beaker, add the prescribed amount of water, and stir to dissolve;

[0074] 2. Weigh the prescribed amount of daptomycin and stir to dissolve it in the amino acid compound solution obtained in step 1 above;

[0075] 3. Place at 40℃ for a certain period of time, then take samples to test for relevant substances. Calculate the percentage of impurity peak area using peak area normalization. The results are as follows.

[0076] General Miscellaneous Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 0 days 2.34 2.41 2.33 2.33 2.48 2.42 2.31 24h 7.48 7.77 10.50 7.84 7.33 7.55 6.30 growth 5.14 5.36 8.17 5.51 4.85 5.13 3.99

[0077] The results above show that the addition of cysteine ​​can slightly reduce the degradation of daptomycin in aqueous solution, reduce the growth of total impurities, and increase its stability, but the impurity growth rate is still very high.

[0078] Prescription 7, 40℃ / 24h HPLC chromatogram is shown below. Figure 1 The corresponding data is as follows:

[0079]

[0080]

[0081] Example 2: Stability of daptomycin and formulations with different organic solvents

[0082]

[0083] Preparation steps:

[0084] 1. Weigh the prescribed amount of organic solvent into a beaker, add it to 50 ml of water for injection, and stir to dissolve;

[0085] 2. Weigh the prescribed amount of daptomycin and stir to dissolve it in the solution obtained in step 1 above;

[0086] 3. Place at 40℃ for a certain period of time, then take samples to test for relevant substances. Calculate the percentage of impurity peak area using peak area normalization. The results are as follows.

[0087] General Miscellaneous Prescription 8 Prescription 9 Prescription 10 Prescription 11 Prescription 12 0 days 2.65 2.78 3.15 2.80 2.84 24h 8.03 7.84 7.33 7.55 7.21 growth 5.38 5.06 4.18 4.75 4.37

[0088] The results above show that, compared with daptomycin aqueous solution formulation 1, the addition of propylene glycol and glycerin slightly reduced the increase in impurities in daptomycin.

[0089] Experimental Example 3: Stability of daptomycin and amino acid derivatives

[0090]

[0091] Preparation steps:

[0092] 1. Weigh the prescribed amount of amino acid derivative into a beaker, add it to 50 ml of water for injection, and stir to dissolve;

[0093] 2. Weigh the prescribed amount of daptomycin and stir to dissolve it in the solution obtained in step 1 above;

[0094] 3. After placing the sample at 8℃ for a certain period of time, take samples to test for relevant substances. Calculate the percentage of impurity peak area using peak area normalization. The results are as follows.

[0095]

[0096] The results above show that, compared with daptomycin aqueous solution formulation 1, formulation 14 is the most stable and has the lowest degradation rate.

[0097] Experimental Example 4: Stability of Daptomycin Formulation

[0098]

[0099] Preparation steps:

[0100] 1. Weigh the prescribed amounts of N-acetyl-L-cysteine, mannitol, and glycerol into a beaker, add them to 50 ml of water for injection, and stir to dissolve.

[0101] 2. Weigh the prescribed amount of daptomycin and stir to dissolve it in the solution obtained in step 1 above;

[0102] 3. After placing the sample at 8℃ for a certain period of time, take samples to test for relevant substances. Calculate the percentage of impurity peak area using peak area normalization. The results are as follows.

[0103] General Miscellaneous Prescription 19 Prescription 20 Prescription 21 Prescription 22 0 days 2.33 2.14 2.25 2.15 30 days 3.56 2.45 2.39 2.75 growth 1.23 0.31 0.14 0.60 Rate / day 0.04 0.01 0.005 0.02

[0104] The results above show that, compared with daptomycin aqueous solution formulation 1, formulation 21 is the most stable and has the lowest degradation rate. The HPLC chromatogram of formulation 20 at 8℃ / 30 days is shown below. Figure 2 The corresponding data is as follows:

[0105] Peak Name RRT min Area% Area 1 Internal lipid hydrolyzate 16.700 0.045 8652 2 Daptomycin 22.536 97.55 18823618 3 β isomer 24.956 0.04 7633 4 Dehydrated daptomycin 26.873 1.20 230937

[0106] Example 5: Comparison of stability of different ester peptide drugs

[0107]

[0108] Preparation steps:

[0109] 1. Weigh the prescribed amounts of N-acetyl-L-cysteine, mannitol, and glycerol into a beaker, add them to 50 ml of water for injection, and stir to dissolve.

[0110] 2. Weigh the prescribed amount of ester peptide drug and stir to dissolve it in the solution obtained in step 1 above;

[0111] 3. After placing the sample at 8℃ for a certain period of time, take samples to test for relevant substances. Calculate the percentage of impurity peak area using peak area normalization. The results are as follows.

[0112] General Miscellaneous Prescription 23 Prescription 24 Prescription 25 Prescription 21 0 days 2.13 2.11 2.20 2.25 60 days 2.46 2.46 2.56 2.55 growth 0.33 0.35 0.36 0.31 Rate / day 0.005 0.006 0.006 0.005

[0113] The HPLC chromatogram of prescription 21, 8℃ / 60 days is shown below. Figure 3 The corresponding data is as follows:

[0114] Peak Name RRT min Area% Area 1 Internal lipid hydrolyzate 12.745 0.12 18675 2 Daptomycin 16.817 97.45 14957632 3 β isomer 18.617 0.03 5090 4 Dehydrated daptomycin 19.878 0.74 113375

[0115] Example 6: Comparison of stability of different concentrations of daptomycin

[0116]

[0117] Preparation steps:

[0118] 1. Weigh the prescribed amounts of N-acetyl-L-cysteine, mannitol, and glycerol into a beaker, add them to 50 ml of water for injection, and stir to dissolve.

[0119] 2. Weigh the prescribed amount of daptomycin and stir to dissolve it in the solution obtained in step 1 above;

[0120] 3. After placing the sample at 8℃ for a certain period of time, take samples to test for relevant substances. Calculate the percentage of impurity peak area using peak area normalization. The results are as follows.

[0121] General Miscellaneous Prescription 21 Prescription 26 Prescription 27 Prescription 28 0 days 2.25 2.31 2.12 2.27 60 days 2.55 2.63 2.55 2.68 growth 0.31 0.32 0.34 0.41 Rate / day 0.005 0.005 0.006 0.007

[0122] The experimental results above show that when the amount of daptomycin in the prescription increases to 30% w / w, the growth rate of impurities can still be controlled within the range of 0.007.

[0123] Example 7: Comparison of daptomycin stability at different times

[0124] The stability of the daptomycin composition of prescription 21 was investigated at 8°C for 2, 4, 6, 9, and 12 months. The percentage of impurity peak area was calculated by peak area normalization, and the results are as follows.

[0125] General Miscellaneous 2 months 4 months 6 months 9 months 12 months 0 days 2.25 2.25 2.25 2.25 2.25 Total growth 0.31 0.48 0.54 0.56 0.73 Rate / day 0.005 0.004 0.003 0.002 0.002

[0126] The experimental results above show that the impurity growth rate did not increase with prolonged storage time, but rather showed a decreasing trend, and the total impurity growth rate could be effectively controlled within the range of 0.7% w / w. The HPLC chromatogram of Formulation 21 at 8℃ / 12 months is shown below. Figure 4 The corresponding data is as follows:

[0127] Peak Name RRT min Area% Area 1 Internal lipid hydrolyzate 12.734 0.11 19051 2 Daptomycin 16.815 97.02 16285372 3 β isomer 18.599 0.03 5086 4 Dehydrated daptomycin 19.857 0.74 124064

[0128] Example 8: Comparison of the stability of daptomycin compositions in different amino acid derivatives

[0129] The amino acid derivative has the following general formula structure:

[0130]

[0131] The definitions of R1, R2, and R3 are the same as those in the previous text.

[0132]

[0133]

[0134] Preparation steps:

[0135] 1. Weigh the prescribed amounts of amino acid derivative, mannitol, and glycerol into a beaker, add them to 50 ml of water for injection, and stir to dissolve.

[0136] 2. Weigh the prescribed amount of daptomycin and stir to dissolve it in the solution obtained in step 1 above;

[0137] 3. After placing the sample at 8℃ for a certain period of time, take samples to test for relevant substances. Calculate the percentage of impurity peak area using peak area normalization. The results are as follows.

[0138] General Miscellaneous Prescription 21 Prescription 29 Prescription 30 Prescription 31 Prescription 32 0 days 2.25 2.05 2.18 2.31 2.19 60 days 2.56 2.48 2.71 2.67 2.68 growth 0.31 0.43 0.53 0.36 0.49 Rate / day 0.005 0.007 0.009 0.006 0.008

[0139] The experimental results above show that when using different amino acid derivatives with free thiol groups, the growth rate of impurities can still be controlled within the range of 0.009% w / w / day.

[0140] It should also be noted that the total impurity content of each formulation at day 0 differs in the various embodiments of the present invention because different starting materials were used.

Claims

1. A stable aqueous solution of an ester peptide drug, comprising the ester peptide drug and an amino acid derivative, wherein the amino acid derivative has the structure of Formula I: ， R1 is selected from hydrogen, C1-C3 alkyl, halogen; R2 is selected from hydrogen, C1-C6 alkyl; R3 is selected from COR4, R4 is selected from C1-C6 alkyl, alkylaryl, wherein the alkylaryl may have one substituent group, wherein the substituent group is selected from C1-C6 straight-chain or branched alkyl. The ester peptide drug in the aqueous solution contains 0.1-30% w / w of ester peptides; The molar ratio of the ester peptide drug to the amino acid derivative is 1:(10-20).

2. The aqueous solution of the ester peptide drug according to claim 1, wherein the ester peptide drug is selected from daptomycin, terbinafine, caspofungin, micafungin, and anidoxane.

3. The aqueous solution of the ester peptide drug according to claim 2, wherein the ester peptide drug is daptomycin.

4. The aqueous solution of the ester peptide drug according to claim 1, wherein the impurity growth rate of the aqueous solution of the ester peptide drug is within 0.01% w / w / day.

5. The aqueous solution of the ester peptide drug according to claim 4, wherein the impurity growth rate of the aqueous solution of the ester peptide drug is within 0.007% w / w / day.

6. The aqueous solution of the ester peptide drug according to claim 5, wherein the impurity growth rate of the aqueous solution of the ester peptide drug is within 0.005% w / w / day.

7. The aqueous solution of ester peptide drugs according to claim 1, wherein the proportion of ester peptide drugs in the aqueous solution is 0.1-20% w / w.

8. The aqueous solution of ester peptide drugs according to claim 7, wherein the proportion of ester peptide drugs in the aqueous solution is 0.5-10% w / w.

9. The aqueous solution of the ester peptide drug according to any one of claims 1-8, wherein the molar ratio of the ester peptide drug to the amino acid derivative is 1:(15-20).

10. The aqueous solution of the ester peptide drug according to claim 9, wherein the molar ratio of the ester peptide drug to the amino acid derivative is 1:

20.

11. The aqueous solution of the ester peptide drug according to claim 10, wherein the aqueous solution of the ester peptide drug comprises a polyol; the polyol is selected from mannitol, sorbitol, sucrose and trehalose.

12. The aqueous solution of the ester peptide drug according to claim 10, wherein the aqueous solution of the ester peptide drug comprises an organic solvent; the organic solvent is selected from at least one of dimethylacetamide, isopropanol, ethanol, benzyl alcohol, 2-methyl-1-propanol, tert-butanol, ethylene glycol, propylene glycol, glycerol, polysorbate 20, polysorbate 40, polysorbate 80, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600.

13. A method for preparing an aqueous solution of an ester peptide drug according to any one of claims 1-12, comprising the following steps: Step a: Weigh the prescribed amount of amino acid derivative into a beaker, add the prescribed amount of water, stir to dissolve, and obtain an amino acid derivative solution; Step b: Weigh the prescribed amount of ester peptide drug and stir to dissolve it in the amino acid derivative solution obtained in step a above; Furthermore, the preparation method includes the step of adding other pharmaceutical excipients.

14. The use of the aqueous solution of the ester peptide drug according to any one of claims 1-12 in the preparation of a medicament for treating microbial infections caused by Gram-positive organisms.

15. The application according to claim 14, wherein the microbial infection is a skin and soft tissue infection, or a Staphylococcus aureus bloodstream infection.

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