Highly stable daptomycin composition for injection, method of preparation thereof, and application thereof.

Abstract

The present invention provides a highly stable injectable daptomycin composition, its preparation method and application thereof, the injectable daptomycin composition comprising daptomycin and a pharma- ceutically acceptable carrier, the pharma-ceutically acceptable carrier comprising a divalent metal salt, a pH adjuster and an osmolality adjuster, wherein the molar ratio of daptomycin to divalent metal salt in the injectable daptomycin composition is 1:1.0-1:3.5. The injectable daptomycin composition of the present invention significantly improves the stability of the formulation, facilitates the storage and transportation of the formulation at room temperature, and ensures the safety of the drug, and the preparation method of the present invention has the advantages of environmental protection, suitability for industrialization and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and specifically relates to a highly stable daptomycin composition for injection, a preparation method thereof, and its application.

Background Art

[0002] Daptomycin (the structure is as shown in Formula I) is a cyclic acidic lipopeptide antibiotic that interferes with the transport of amino acids in the bacterial cell membrane, inhibits the biosynthesis of teichoic lipids in the peptidoglycan of the bacterial cell wall, and may change the physical and scientific properties of the cell membrane. By destroying the bacterial cell membrane, the intracellular soluble substances leak out, thereby exerting a rapid bactericidal activity in a concentration-dependent manner against Gram-positive bacteria (including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci, glycopeptide-susceptible Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, coagulase-negative Staphylococcus, etc.). It is mainly used for the treatment of complicated skin and soft tissue infections caused by Gram-positive bacteria, including the accompanying right-sided endocarditis caused by infections with methicillin-sensitive strains and methicillin-resistant strains, and sepsis caused by bloodstream infections with Staphylococcus aureus.

Chemical

[0003] Daptomycin and its formulation solutions have problems such as being easily decomposed and having poor stability. The commercially available original CUBICIN requires refrigerated storage (5 ± 3°C), which is inconvenient for storage and transportation and increases costs. To improve the stability problems of daptomycin and its formulation solutions, in some studies, protective agents (such as sucrose, sulfobutyl-β-cyclodextrin, etc.) and / or organic solvents such as t-butanol were added to the daptomycin solution. However, this increases the difficulty and cost of operation and leads to risks to the safety of pharmaceuticals. Therefore, there is an urgent need for a highly stable daptomycin formulation that is beneficial for the storage and transportation of the formulation and guarantees the efficacy and safety of the drug.

Summary of the Invention

[0004] The object of the present invention is to provide a highly stable daptomycin composition for injection, the daptomycin composition for injection comprising daptomycin and a pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier comprising a divalent metal salt, a pH adjuster, and an osmotic pressure adjuster, wherein the molar ratio of daptomycin to divalent metal salt in the daptomycin composition for injection is 1:1.0 to 1:3.5.

[0005] In a preferred technical solution of the present invention, the divalent metal salt is selected from one or a combination of calcium salts, magnesium salts, and zinc salts.

[0006] In a preferred technical solution of the present invention, the divalent metal salt is selected from one or a combination thereof from nitrates, hydrochlorides, hydrobroms, hydroiodides, sulfates, glucons, phosphates, hydrogen phosphates, and lactates.

[0007] In a preferred technical solution of the present invention, the divalent metal salt is selected from one or a combination thereof from calcium nitrate, calcium chloride, calcium hydrobromate, calcium hydroiodate, calcium gluconate, calcium hydrogen phosphate, calcium lactate, calcium acetate, calcium phosphate, magnesium nitrate, magnesium chloride, magnesium hydrobromate, magnesium hydroiodate, magnesium sulfate, magnesium gluconate, magnesium hydrogen phosphate, magnesium lactate, magnesium acetate, magnesium phosphate, zinc nitrate, zinc chloride, zinc hydrobromate, zinc hydroiodate, zinc sulfate, zinc gluconate, zinc hydrogen phosphate, zinc lactate, zinc acetate, and zinc phosphate.

[0008] In the preferred technical solution of the present invention, the molar ratio of daptomycin to divalent metal salt in the composition is 1:1.2 to 3.0, preferably 1:1.5 to 2.75, and more preferably 1:1.75 to 2.50.

[0009] In the preferred technical solution of the present invention, the molar ratio of daptomycin to hydrochloride in the composition is 1:1.2 to 3.0, preferably 1:1.5 to 2.75, and more preferably 1:1.75 to 2.50.

[0010] In the preferred technical solution of the present invention, the molar ratio of daptomycin to calcium chloride in the composition is 1:1.2 to 3.0, preferably 1:1.5 to 2.75, and more preferably 1:1.75 to 2.50.

[0011] In a preferred technical solution of the present invention, the pH adjusting agent is selected from one or a combination thereof from sodium hydroxide, calcium hydroxide, calcium lactate, sodium lactate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, citric acid, sodium citrate, sodium bicarbonate, and sodium carbonate.

[0012] In the preferred technical solution of the present invention, the pH of the composition is 3.5 to 6.0, preferably 4.0 to 5.5, and more preferably 4.5 to 5.0.

[0013] In a preferred technical solution of the present invention, the osmotic pressure regulator is selected from one or a combination thereof of sodium chloride, glucose, phosphate, and citrate.

[0014] In the preferred technical solution of the present invention, the molar ratio of daptomycin to osmotic regulator is 1:0 to 3.0, preferably 1:0.5 to 2.75, more preferably 1:1.0 to 2.5, and even more preferably 1:1.5 to 2.25.

[0015] In the preferred technical solution of the present invention, the molar ratio of daptomycin:divalent metal salt:osmotic pressure regulator in the composition is 1:1.0~3.5:0~3.0, preferably 1:1.2~3.0:0.5~2.75, more preferably 1:1.5~2.75:1.0~2.5, and even more preferably 1:1.75~2.50:1.5~2.25.

[0016] In the preferred technical solution of the present invention, the molar ratio of daptomycin:hydrochloride:osmotic regulator in the composition is 1:1.0~3.5:0~3.0, preferably 1:1.2~3.0:0.5~2.75, more preferably 1:1.5~2.75:1.0~2.5, and even more preferably 1:1.75~2.50:1.5~2.25.

[0017] In the preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:osmotic regulator in the composition is 1:1.0~3.5:0~3.0, preferably 1:1.2~3.0:0.5~2.75, more preferably 1:1.5~2.75:1.0~2.5, and even more preferably 1:1.75~2.50:1.5~2.25.

[0018] In a preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:sodium chloride in the composition is 1:1.2:2.74, and the pH of the composition is adjusted to 4.0 using sodium hydroxide.

[0019] In a preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:sodium chloride in the composition is 1:1.2:2.74, and the pH of the composition is adjusted to 5.0 using sodium hydroxide.

[0020] In a preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:sodium chloride in the composition is 1:1.2:2.74, and the pH of the composition is adjusted to 6.0 using sodium hydroxide.

[0021] In a preferred technical solution of the present invention, the molar ratio of daptomycin: calcium chloride: sodium chloride in the composition is 1:1.5:2.5, and sodium hydroxide is used to adjust the pH of the composition to 4.5.

[0022] In a preferred technical solution of the present invention, the molar ratio of daptomycin: calcium chloride: sodium chloride in the composition is 1:1.75:2.1, and sodium hydroxide is used to adjust the pH of the composition to 5.0.

[0023] In a preferred technical solution of the present invention, the molar ratio of daptomycin: calcium chloride: sodium chloride in the composition is 1:2.5:1.1, and sodium hydroxide is used to adjust the pH of the composition to 5.0.

[0024] In a preferred technical solution of the present invention, the molar ratio of daptomycin: calcium chloride in the composition is 1:3.5, and sodium hydroxide is used to adjust the pH of the composition to 5.0.

[0025] In a preferred technical solution of the present invention, the composition is selected from any one or a combination of freeze-dried powder or spray-dried powder.

[0026] In a preferred technical solution of the present invention, the total impurity content in the composition is ≤7.0%, the dehydrated daptomycin content is ≤4.0%, the β-isomer content is ≤1.5%, and the lactone hydrolysis product content is ≤1.5%.

[0027] In a preferred technical solution of the present invention, the total impurity content in the composition is ≤6.0%, the dehydrated daptomycin content is ≤3.5%, the β-isomer content is ≤1.0%, and the lactone hydrolysis product content is ≤1.0%.

[0028] In a preferred technical solution of the present invention, the total impurity content in the composition is ≤5.0%, the dehydrated daptomycin content is ≤3.0%, the β-isomer content is ≤0.8%, and the lactone hydrolysis product content is ≤0.8%.

[0029] In a preferred technical solution of the present invention, the total impurity content in the composition is ≤4.0%, the dehydrated daptomycin content is ≤2.0%, the β-isomer content is ≤0.6%, and the lactone hydrolysis product content is ≤0.6%.

[0030] In a preferred technical solution of the present invention, the total impurity content in the composition is ≤3.0%, the dehydrated daptomycin content is ≤1.0%, the β-isomer content is ≤0.5%, and the lactone hydrolysis product content is ≤0.5%.

[0031] In a preferred technical solution of the present invention, the water content of the composition is ≤5.0%, preferably ≤4.0%, more preferably ≤3.0%.

[0032] In a preferred technical solution of the present invention, the transparency of the solution after redissolving the composition is less than or close to the first turbidity standard solution.

[0033] In a preferred technical solution of the present invention, the solution absorbance A 450nm after redissolving the composition is ≤0.50, preferably ≤0.40, more preferably ≤0.30.

[0034] Another object of the present invention is to provide a method for preparing a highly stable daptomycin composition for injection, the daptomycin composition for injection comprising daptomycin and a pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier comprising a divalent metal salt and a pH adjuster, and an osmotic pressure adjuster, wherein the molar ratio of daptomycin to divalent metal salt in the daptomycin composition for injection is 1:1.0 to 1:3.5, the method comprising the steps of: dissolving the required amount of daptomycin and divalent metal salt in water for injection to prepare an aqueous solution; adding a pH adjuster to the prepared aqueous solution to adjust the pH of the aqueous solution to 3.5 to 6.0; optionally adding the required amount of an osmotic pressure adjuster to adjust to isotonicity; filtering to obtain a filtrate; and treating the filtrate by freeze-drying or spray-drying, or a combination thereof.

[0035] In a preferred technical solution of the present invention, the filtration is a filter membrane filtration, and the pore size of the filter membrane is preferably ≤0.45 μm, and more preferably any of 0.40 μm, 0.35 μm, 0.30 μm, 0.25 μm, or 0.22 μm.

[0036] In a preferred technical solution of the present invention, the divalent metal salt is selected from one or a combination of calcium salts, magnesium salts, and zinc salts.

[0037] In a preferred technical solution of the present invention, the divalent metal salt is selected from one or a combination thereof from nitrates, hydrochlorides, hydrobroms, hydroiodides, sulfates, glucons, phosphates, hydrogen phosphates, and lactates.

[0038] In a preferred technical solution of the present invention, the divalent metal salt is selected from one or a combination thereof from calcium nitrate, calcium chloride, calcium hydrobromide, calcium hydroiodide, calcium gluconate, calcium hydrogen phosphate, calcium lactate, calcium acetate, calcium phosphate, magnesium nitrate, magnesium chloride, magnesium hydrobromide, magnesium hydroiodide, magnesium sulfate, magnesium gluconate, magnesium hydrogen phosphate, magnesium lactate, magnesium acetate, magnesium phosphate, zinc nitrate, zinc chloride, zinc hydrobromide, zinc hydroiodide, zinc sulfate, zinc gluconate, zinc hydrogen phosphate, zinc lactate, zinc acetate, and zinc phosphate.

[0039] In the preferred technical solution of the present invention, the molar ratio of daptomycin to divalent metal salt in the composition is 1:1.2 to 3.0, preferably 1:1.5 to 2.75, and more preferably 1:1.75 to 2.50.

[0040] In the preferred technical solution of the present invention, the molar ratio of daptomycin to hydrochloride in the composition is 1:1.2 to 3.0, preferably 1:1.5 to 2.75, and more preferably 1:1.75 to 2.50.

[0041] In the preferred technical solution of the present invention, the molar ratio of daptomycin to calcium chloride in the composition is 1:1.2 to 3.0, preferably 1:1.5 to 2.75, and more preferably 1:1.75 to 2.50.

[0042] In a preferred technical solution of the present invention, the pH adjusting agent is selected from one or a combination thereof from sodium hydroxide, calcium hydroxide, calcium lactate, sodium lactate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, citric acid, sodium citrate, sodium bicarbonate, and sodium carbonate.

[0043] In the preferred technical solution of the present invention, the pH of the composition is 3.5 to 6.0, preferably 4.0 to 5.5, and more preferably 4.5 to 5.0.

[0044] In a preferred technical solution of the present invention, the osmotic pressure regulator is selected from one or a combination thereof of sodium chloride, glucose, phosphate, and citrate.

[0045] In the preferred technical solution of the present invention, the molar ratio of daptomycin to osmotic regulator is 1:0 to 3.0, preferably 1:0.5 to 2.75, more preferably 1:1.0 to 2.5, and even more preferably 1:1.5 to 2.25.

[0046] In the preferred technical solution of the present invention, the molar ratio of daptomycin:divalent metal salt:osmotic pressure regulator in the composition is 1:1.0~3.5:0~3.0, preferably 1:1.2~3.0:0.5~2.75, more preferably 1:1.5~2.75:1.0~2.5, and even more preferably 1:1.75~2.50:1.5~2.25.

[0047] In the preferred technical solution of the present invention, the molar ratio of daptomycin:hydrochloride:osmotic regulator in the composition is 1:1.0~3.5:0~3.0, preferably 1:1.2~3.0:0.5~2.75, more preferably 1:1.5~2.75:1.0~2.5, and even more preferably 1:1.75~2.50:1.5~2.25.

[0048] In the preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:osmotic regulator in the composition is 1:1.0~3.5:0~3.0, preferably 1:1.2~3.0:0.5~2.75, more preferably 1:1.5~2.75:1.0~2.5, and even more preferably 1:1.75~2.50:1.5~2.25.

[0049] In a preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:sodium chloride in the composition is 1:1.2:2.74, and the pH of the composition is adjusted to 4.0 using sodium hydroxide.

[0050] In a preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:sodium chloride in the composition is 1:1.2:2.74, and the pH of the composition is adjusted to 5.0 using sodium hydroxide.

[0051] In a preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:sodium chloride in the composition is 1:1.2:2.74, and the pH of the composition is adjusted to 6.0 using sodium hydroxide.

[0052] In a preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:sodium chloride in the composition is 1:1.5:2.5, and the pH of the composition is adjusted to 4.5 using sodium hydroxide.

[0053] In a preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:sodium chloride in the composition is 1:1.75:2.1, and the pH of the composition is adjusted to 5.0 using sodium hydroxide.

[0054] In a preferred technical solution of the present invention, the molar ratio of daptomycin:calcium chloride:sodium chloride in the composition is 1:2.5:1.1, and the pH of the composition is adjusted to 5.0 using sodium hydroxide.

[0055] In a preferred technical solution of the present invention, the molar ratio of daptomycin to calcium chloride in the composition is 1:3.5, and the pH of the composition is adjusted to 5.0 using sodium hydroxide.

[0056] In a preferred technical solution of the present invention, the composition is selected from either freeze-dried powder or spray-dried powder, or a combination thereof.

[0057] In a preferred technical solution of the present invention, the freeze-drying method is 1) After filling the vial with the filtrate, place it in a freeze-drying box and cool it to -20°C to -70°C to completely freeze the sample. 2) Heat to -10℃ to 5℃, maintain a vacuum of 0 to 0.25 mbar, and dry. 3) The process includes the step of heating to 5°C to 40°C and drying to obtain the product. In a preferred technical solution of the present invention, the spray drying method includes setting the air inlet temperature to 150-230°C, the air outlet temperature to 80-150°C, the process air flow rate to 25-45 kg / h, and the nozzle air flow rate to 3-5.5 kg / h, and after the parameters have stabilized, spray drying the prepared daptomycin aqueous solution.

[0058] In a preferred technical solution of the present invention, the air inlet temperature is 180 to 220°C, preferably 200 to 210°C.

[0059] In a preferred technical solution of the present invention, the air outlet temperature is 90 to 130°C, preferably 100 to 110°C.

[0060] In the preferred technical solution of the present invention, the process air flow rate is 30 to 43 kg / h, preferably 35 to 40 kg / h.

[0061] In a preferred technical solution of the present invention, the nozzle airflow rate is 3.5 to 5.0 kg / h, preferably 4.0 to 4.5 kg / h.

[0062] In the preferred technical solution of the present invention, the total impurity content in the composition is ≤7.0%, the dehydrated daptomycin content is ≤4.0%, the β-isomer content is ≤1.5%, and the lactone hydrolysate content is ≤1.5%.

[0063] In the preferred technical solution of the present invention, the total impurity content in the composition is ≤6.0%, the dehydrated daptomycin content is ≤3.5%, the β-isomer content is ≤1.0%, and the lactone hydrolysate content is ≤1.0%.

[0064] In the preferred technical solution of the present invention, the total impurity content in the composition is ≤5.0%, the dehydrated daptomycin content is ≤3.0%, the β-isomer content is ≤0.8%, and the lactone hydrolysate content is ≤0.8%.

[0065] In the preferred technical solution of the present invention, the total impurity content in the composition is ≤4.0%, the dehydrated daptomycin content is ≤2.0%, the β-isomer content is ≤0.6%, and the lactone hydrolysate content is ≤0.6%.

[0066] In the preferred technical solution of the present invention, the total impurity content in the composition is ≤3.0%, the dehydrated daptomycin content is ≤1.0%, the β-isomer content is ≤0.5%, and the lactone hydrolysate content is ≤0.5%.

[0067] In the preferred technical solution of the present invention, the water content of the composition is ≤5.0%, preferably ≤4.0%, and more preferably ≤3.0%.

[0068] In a preferred technical solution of the present invention, the clarity of the solution after redissolving the composition is less than or close to that of the first turbidity standard solution.

[0069] In a preferred technical solution of the present invention, the absorbance of the solution after redissolving the composition is A 450nm The value is ≤0.50, preferably ≤0.40, and more preferably ≤0.30.

[0070] Another object of the present invention is to provide the application of the highly stable injectable daptomycin composition of the present invention in the preparation of antimicrobial agents.

[0071] In a preferred technical solution of the present invention, the composition is selected from either freeze-dried powder or spray-dried powder.

[0072] In a preferred technical solution of the present invention, the composition is used to treat an infection caused by Gram-positive bacteria.

[0073] In a preferred technical solution of the present invention, the infection is selected from one or a combination thereof of skin and soft tissue infection, endocarditis, bacteremia, or complications thereof.

[0074] In the preferred technical solution of the present invention, the infection is selected from one or a combination thereof of complicated cutaneous soft tissue infections (cSSTIs), Staphylococcus aureus right endocarditis (RIE), bacteremia, and their complications.

[0075] In a preferred technical solution of the present invention, the composition further comprises other antimicrobial agents.

[0076] In the preferred technical solution of the present invention, the other antibacterial agent is selected from one or a combination thereof from among quinolone, penicillin, cephalosporin, β-lactam, aminoglycoside, macrolide, and lincomycin drugs.

[0077] In a preferred technical solution of the present invention, the quinolone drug is selected from one or a combination thereof from norfloxacin, enoxacin, ciprofloxacin, ofloxacin, levofloxacin, pefloxacin, and sparfloxacin.

[0078] In a preferred technical solution of the present invention, the penicillin-based drug is selected from one or a combination thereof of penicillin G, penicillin V, methicillin (Xinqing I), ampicillin, amoxicillin, ticarcillin, and piperacillin.

[0079] In the preferred technical solution of the present invention, the cephalosporin drug is selected from one or a combination thereof from cefazolin, cefradin, cephalexin, cefradin, cefadroxil, cefuroxime, cephamandol, cefoxitin, cefmetazole, cefuroxime axetil, cefacrol, cefotaxime, ceftazidime, ceftriaxone, cefoperazone, ceftizoxime, cefozidime, cefixime, cefpodoxime proxetil, cefteram pivoxil, cefetamet pivoxil, cefepime, and cefpirome.

[0080] In a preferred technical solution of the present invention, the β-lactam drug is selected from one or a combination of imipenem, cilastatin, and meropenem.

[0081] In a preferred technical solution of the present invention, the aminoglycoside drug is selected from one or a combination thereof of gentamicin, tobramycin, netylmycin, amikacin, streptomycin, and spectinomycin.

[0082] In a preferred technical solution of the present invention, the macrolide drug is selected from one or a combination thereof of erythromycin, clarithromycin, roxithromycin, azithromycin, josamycin, midecamycin, and spiramycin.

[0083] In a preferred technical solution of the present invention, the lincomycin-based drug is selected from either lincomycin or clindamycin, or a combination thereof.

[0084] The freeze dryer of this invention uses the Model Lyo1 (CIP) vacuum freeze dryer from Shanghai TOFFLON.

[0085] The spray dryer of this invention uses the SPX Model MS35 spray dryer.

[0086] Unless otherwise specified, when the present invention relates to a percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to a percentage between liquids and solids, the percentage is volume / weight percentage; when the present invention relates to a percentage between solids and liquids, the percentage is weight / volume percentage, and the remainder is weight / weight percentage.

[0087] Compared to the prior art, the present invention has the following beneficial effects. 1. The present invention scientifically screens the components and proportions of daptomycin compositions for injection, significantly improving the stability of the formulation, overcoming problems such as unsuitable clarity and excessive osmotic pressure caused by high concentrations of calcium ions, facilitating the storage and transport of the formulation at room temperature, and ensuring the safety of the drug. 2. The daptomycin composition for injection of the present invention has advantages such as having a simple composition, being free of protective agents and organic solvents, having good stability, using inexpensive and readily available auxiliary materials, being cost-effective, having controllable product quality, being environmentally friendly, and being suitable for industrialization. [Modes for carrying out the invention]

[0088] The present invention will be described in more detail below with reference to examples and experimental cases. These examples and experimental cases are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0089] Example 1 Preparation of ptomycin compositions for injection A method for preparing an injectable daptomycin composition includes the following steps: Weigh out 1,500 g of daptomycin and 51.4 g of calcium chloride, dissolve them in 2.5 L of sterile water for injection, add sodium hydroxide solution to adjust the pH to 4.5, add 45.1 g of sodium chloride, filter the resulting solution through a 0.22 μm filter membrane, and collect the filtrate. 2. The spray dryer's air inlet temperature was set to 200°C, the air outlet temperature to 110°C, the process air flow rate to 35 kg / h, and the nozzle air flow rate to 4.5 kg / h. The collected filtrate was spray-dried, and the collected spray-dried powder was dispensed into vials, capped, and sealed. A sample was taken, and the detected water content was 3.0%.

[0090] Example 2 Preparation of daptomycin compositions for injection A method for preparing an injectable daptomycin composition includes the following steps: Weigh 500g of daptomycin and 60g of calcium chloride, dissolve them in 1.5L of sterile water for injection, add sodium hydroxide solution to adjust the pH to 5.0, add 38g of sodium chloride, filter the resulting solution through a 0.22μm filter membrane, dispense the collected filtrate into vials, partially cap them, and place them in a freeze-drying box. Pre-freeze the sample solution at -40°C or below for approximately 4 hours. The temperature is then programmed to maintain a product temperature below 5°C, the vacuum is controlled to approximately 0.25mbar, and the vials are sublimated for approximately 20 hours. The temperature is then programmed to maintain a product temperature below 25°C for approximately 7 hours for analysis and drying. Nitrogen is then added, the stopper is pressed, the vacuum is broken, and the vials are removed from the box and capped. A sample is taken, and the detected water content is 2.0%.

[0091] Test Example 1 Stability study of daptomycin compositions for injection The injectable daptomycin compositions prepared in Example 1 and Example 2, the original commercially available formulation CUBICIN RF, and CUBICIN were left at 40°C for one month, and the related substances and their changes were detected. The results are shown in Table 1. [Table 1]

[0092] The results indicate that the stability of both the spray-dried and freeze-dried powders is superior to that of CUBICIN and CUBICIN RF.

[0093] Test Example 2. Examination of the redissolution stability of daptomycin composition for injection. The daptomycin compositions for injection and CUBICIN prepared in Examples 1 and 2 were added to sterile water for injection. This was then dissolved in a 50 mg / ml solution, and left to stand for 48 hours under conditions of 2-8°C to examine the changes in the relevant substances. The results are shown in Table 2. [Table 2]

[0094] The results show that the spray-dried powder of Example 1 and the freeze-dried powder of Example 2 exhibit superior stability compared to CUBICIN, ensuring drug safety for patients.

[0095] Test Example 3 Stability study of daptomycin calcium chloride solution 5.0 g of daptomycin and 1.2 g of calcium chloride were dissolved in 100 ml of sterile water for injection. This mixture was divided equally into three portions, and sodium hydroxide solution was added to adjust the pH to 4.0, 5.0, and 7.0. The mixtures were filtered, the collected filtrates were dispensed into vials, sealed, and left at 25°C for 24 hours. Changes in the relevant substances were examined, and the results are shown in Table 3. [Table 3]

[0096] The results indicate that as the pH value increases, the degree of change in daptomycin-related substances decreases, suggesting that higher pH levels result in greater stability.

[0097] Example 3 Preparation of daptomycin compositions for injection Weigh out 500g of daptomycin and 41g of calcium chloride, dissolve them in 2.5L of sterile water for injection, add sodium hydroxide solution to adjust the pH to 4.0, add 48g of sodium chloride, filter, and collect the filtrate. Set the air inlet temperature to 220°C, the air outlet temperature to 120°C, the process air flow rate to 30kg / h, and the nozzle air flow rate to 3.5kg / h, spray-dry the collected filtrate, dispense the collected spray-dried powder into vials, cap them, and seal them.

[0098] Examples 4-6. Preparation of daptomycin compositions for injection Following the method and formulation components of Example 3, the pH of the daptomycin solutions of Examples 4-6 was adjusted to 5.0, 6.0, and 7.0, respectively, using a sodium hydroxide solution, and then spray-dried to prepare spray-dried powder of daptomycin for injection.

[0099] Test Example 4. Stability study of daptomycin composition for injection. The spray-dried powders prepared in Examples 3-6 were left at 60°C for 10 days, and changes in the related substances were examined. The results are shown in Table 4. [Table 4]

[0100] The results show that as the pH value increases, the stability of the spray-dried powder decreases and the range of change in total impurities increases. The data indicate that daptomycin for injection is more stable at low pH when it exists as a solid powder.

[0101] Example 7 Preparation of daptomycin compositions for injection Weigh out 500g of daptomycin and 41g of calcium chloride, dissolve them in 2.5L of sterile water for injection, add sodium hydroxide solution to adjust the pH to 5.0, add 48g of sodium chloride, filter, and collect the filtrate. Set the air inlet temperature to 220°C, the air outlet temperature to 120°C, the process air flow rate to 30kg / h, and the nozzle air flow rate to 3.5kg / h, spray-dry the collected filtrate, dispense the collected spray-dried powder into vials, cap them, and seal them.

[0102] Example 8 Preparation of daptomycin compositions for injection Weigh out 500g of daptomycin and 41g of calcium chloride, dissolve them in 2.5L of sterile water for injection, add sodium hydroxide solution to adjust the pH to 7.0, add 48g of sodium chloride, filter, and collect the filtrate. Set the air inlet temperature to 220°C, the air outlet temperature to 120°C, the process air flow rate to 30kg / h, and the nozzle air flow rate to 3.5kg / h, spray dry the collected filtrate, dispense the collected spray-dried powder into vials, cap them, and seal them.

[0103] Test Example 5 Stability study of daptomycin composition for injection The spray-dried powders, CUBICIN RF, and CUBICIN prepared in Examples 7 and 8 were left at 40°C for 2 months, and the changes in impurities were examined. The results are shown in Table 5. [Table 5]

[0104] The results show that the stability of the spray-dried powder prepared under pH 5.0 conditions is superior to that of the spray-dried powder at pH 7.0, and is similar to that of CUBICIN RF, and superior to that of CUBICIN.

[0105] After daptomycin is prepared as a solid powder by spray drying, the stability of weakly acidic samples (pH 4.0-6.0) is superior to that of nearly neutral samples (pH 6.0-7.0).

[0106] Example 9 Preparation of daptomycin compositions for injection Take 50.0 g of daptomycin and 4.1 g of calcium chloride, dissolve them in 250 mL of sterile water for injection, add sodium hydroxide solution to adjust the pH to 5.0, add 4.8 g of sodium chloride, filter, collect the filtrate, dispense it into vials, partially stopper them, and place them in a freeze-drying box. Pre-freeze the sample solution at -50°C or below for about 4 hours. Increase the temperature using a program to control the product temperature to -5°C or below, control the vacuum to about 0.05 mbar, and sublimate dry for about 20 hours. Dry under conditions of a controlled temperature of 20°C or below for about 5 hours, fill with nitrogen, press the stopper, break the vacuum, remove from the box, and seal.

[0107] Examples 10-14 Preparation of daptomycin compositions for injection Table 6 shows the daptomycin compositions for injection and their components for Examples 10 to 14. Preparation by the method of Example 7: 50.0 g each of 5 parts of daptomycin was weighed out, and 6.0 g of calcium chloride and 3.8 g of sodium chloride, 8.6 g of calcium chloride and 2.0 g of sodium chloride, 12.0 g of calcium chloride, 13.7 g of calcium chloride, and 20.6 g of calcium chloride were weighed out. These were dissolved in 250 mL of sterile water for injection, sodium hydroxide solution was added to adjust the pH to 5.0, the mixture was filtered, and the collected filtrate was freeze-dried to prepare freeze-dried powder. [Table 6]

[0108] Test Example 6 Stability of formulations with various calcium chloride content levels. The freeze-dried powders prepared in Examples 9-12, the original commercially available formulation CUBICIN RF, and CUBICIN were left at 40°C for one month, and changes in the related substances were examined. The results are shown in Table 7. [Table 7]

[0109] The results indicate that the stability of the freeze-dried powder increases as the calcium ion ratio increases.

[0110] Test Example 7 Investigation of the transparency of daptomycin composition for injection after redissolution. The lyophilized powders prepared in Examples 9, 11, 12, 13, and 14 were taken and added to water for injection, dissolved in 50 mg / ml daptomycin solution, and compared with a turbidity standard solution according to the 2020 edition of the Chinese Pharmacopoeia. The results are shown in Table 8. [Table 8]

[0111] The results indicate that when the molar ratio of daptomycin to calcium ions is less than 1:2.5, the solution clarity is less than or close to that of the first turbidity standard solution. When the molar ratio of daptomycin to calcium ions is greater than 1:3.5, the solution clarity is less than that of the second turbidity standard solution and greater than that of the first turbidity standard solution, thus failing to meet the clarity standard.

[0112] Test Example 8 Osmotic pressure study of daptomycin compositions for injection Five parts of daptomycin were each weighed out to 500 mg, and dissolved in 10 ml of sterile water for injection with 41 mg of calcium chloride, 85.7 mg of calcium chloride, 120 mg of calcium chloride, 137 mg of calcium chloride, and 205.7 mg of calcium chloride, respectively. Sodium hydroxide solution was added to adjust the pH to 5.5, the mixture was filtered, the filtrate was collected, and this was dispensed into vials. After partially capping, the vials were placed in a freeze-drying box. The sample solutions were pre-frozen at -30°C or below for approximately 4 hours. The temperature was then increased by program so that the product temperature was controlled to -5°C or below, the vacuum was controlled to approximately 0.05 mbar, and sublimation drying was performed for approximately 20 hours. The temperature was then controlled by program and the product was dried at a temperature of 15°C for approximately 5 hours. Nitrogen was then added, the stopper was pressed, the vacuum was broken, and the vials were removed from the box and capped. Daptomycin was dissolved in sterile water for injection to a concentration of 50 mg / ml, and the osmotic pressure was measured according to the freezing point reduction method described in "0632" of the 2020 edition of the Chinese Pharmacopoeia (Part IV). The results are shown in Table 9. [Table 9]

[0113] The results show that when the molar ratio of daptomycin to calcium ions is 1:3.5, the molar concentration of the osmotic pressure of the solution is approximately 300 mosm, which is close to the osmotic pressure of human plasma, indicating that it is an isotonic solution.

[0114] The above description of specific embodiments of the present invention is not intended to limit the invention, and those skilled in the art can make various modifications or alterations in accordance with the invention, as long as they do not depart from the spirit of the invention, all of which will fall within the scope of protection of the claims of the present invention.

Claims

1. A highly stable injectable daptomycin composition for treating infections caused by Gram-positive bacteria, The daptomycin composition for injection comprises daptomycin and a pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier comprising calcium chloride, a pH adjuster, and an osmotic pressure adjuster, wherein the pH adjuster is sodium hydroxide and the osmotic pressure adjuster is sodium chloride, and the molar ratio of daptomycin:calcium chloride:sodium chloride in the daptomycin composition for injection is 1:1.5:2.5, and the pH of the daptomycin composition for injection is adjusted to 4.5 using sodium hydroxide before freeze-drying or spray-drying. Daptomycin composition for injection.

2. The aforementioned daptomycin composition for injection is characterized by being a freeze-dried powder or a spray-dried powder. The daptomycin composition for injection according to claim 1.

3. A method for preparing a highly stable daptomycin composition for injection according to any one of claims 1 to 2, The daptomycin composition for injection comprises daptomycin and a pharmaceutically acceptable carrier, the pharmaceutically acceptable carrier comprising calcium chloride, a pH adjuster, and an osmotic pressure adjuster, the pH adjuster being sodium hydroxide, and the osmotic pressure adjuster being sodium chloride, wherein the molar ratio of daptomycin:calcium chloride:sodium chloride in the daptomycin composition for injection is 1:1.5:2.5, and the preparation method is as follows: The method is characterized by comprising the steps of: dissolving the required amount of daptomycin and calcium chloride in water for injection to prepare an aqueous solution; adding sodium hydroxide to the prepared aqueous solution to adjust the pH of the aqueous solution to 4.5; adding the required amount of sodium chloride to adjust the solution to isotonicity; filtering to obtain a filtrate; and treating the filtrate by freeze-drying, spray-drying, or a combination thereof to obtain a daptomycin composition for injection. Preparation method.

4. Treating the filtrate by freeze-drying is 1) After filling the vial with the filtrate, place it in a freeze-drying box and cool it to -20°C to -70°C to completely freeze the filtrate. 2) Heating to -10°C to 5°C, maintaining a vacuum of 0 to 0.25 mbar, and drying, 3) The step of heating to 5°C to 40°C and drying to obtain a daptomycin composition containing freeze-dried powder is also included. The preparation method according to claim 3.

5. The process of treating the filtrate by spray drying is characterized by including the step of setting the air inlet temperature to 150 to 230°C and the air outlet temperature to 80 to 150°C, and after the parameters have stabilized, spray drying the prepared daptomycin aqueous solution to obtain a daptomycin composition containing spray-dried powder. The preparation method according to claim 3.

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