Application of propylene glycol aqueous solution in inhibiting degradation of dalbavancin hydrochloride, dalbavancin injection preparation, preparation method and application

Abstract

The present invention discloses the use of an aqueous solution of propylene glycol for inhibiting the degradation of dalbavancin hydrochloride, a dalbavancin injection preparation, a preparation method, and applications. The present invention applies an aqueous solution of propylene glycol to the dalbavancin injection preparation. The resulting dalbavancin injection preparation significantly reduces production costs compared to lyophilized preparations, further improving drug safety and ease of use. This not only brings significant economic benefits to manufacturers, but also provides more safe, effective, and cost-effective products to patients, generating immeasurable social benefits.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to a Chinese patent application filed with the Patent Office of China on July 26, 2024, with application number CN2024110170360 and entitled “Application of an aqueous solution of propylene glycol in inhibiting the degradation of dalbavancin hydrochloride, dalbavancin injection preparation, preparation method and application”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to the technical field of pharmaceutical preparations, and in particular to the use of an aqueous solution of propylene glycol in inhibiting the degradation of dalbavancin hydrochloride, a dalbavancin injection preparation, a preparation method and an application thereof. Background Art

[0004] Currently, only the original research product of dalbavancin is available in the US market. Its dosage form is lyophilized powder with a specification of 500mg / bottle. On May 23, 2014, the US Food and Drug Administration (FDA) approved the injection of dalbavancin owned by ABBVIE INC, with the trade name It is approved for the treatment of adult and pediatric patients with acute bacterial skin and skin appendage infections (ABSSSI) caused by susceptible strains of specified Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus allolactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, and Streptococcus constellatus), and Enterococcus faecalis (vancomycin-susceptible strains).

[0005] It is a sterile, preservative-free, white to off-white to pale yellow lyophilized solid. Each vial contains dalbavancin hydrochloride, equivalent to 500 mg of dalbavancin free base, and the excipients: 129 mg of lactose and 129 mg of mannitol. Sodium hydroxide or hydrochloric acid may be added during the manufacturing process to adjust the pH. The route of administration is intravenous injection. According to the product instructions, the product needs to be reconstituted and further diluted before intravenous injection, that is, each bottle of product must first be reconstituted with 25mL of sterile water for injection or 5% glucose injection. To avoid foaming, alternately gently rotate and flip the vial until its contents are completely dissolved, do not shake. The reconstituted vial contains 20mg / mL of dalbavancin as a clear, colorless to yellow solution, which is then further diluted with 5% glucose injection only to a final concentration of 1mg / mL to 5mg / mL. The reconstituted solution and the diluted solution can be refrigerated at 2-8°C or stored at controlled room temperature, and the product should not exceed 48 hours from reconstitution to dilution to administration.

[0006] As a lyophilized preparation, the production cost is relatively high, and it needs to be reconstituted and diluted before use, which greatly reduces the convenience of administration. Before clinical use, 25 mL of diluent needs to be added for reconstitution to form a 20 mg / mL solution, which is then further diluted for clinical use. Therefore, large 50 mL vials are used for packaging, which increases the storage and transportation costs of the drug. Summary of the Invention

[0007] The present invention provides an application of a propylene glycol aqueous solution in inhibiting the degradation of dalbavancin hydrochloride, a dalbavancin injection preparation, a preparation method and an application thereof, which can overcome the existing The problem of freeze-dried preparations needing to be reconstituted before use is conducive to improving the convenience of drug administration.

[0008] In a first aspect, the present invention provides a use of an aqueous solution of propylene glycol in inhibiting the degradation of dalbavancin hydrochloride.

[0009] In a second aspect, the present invention provides a dalbavancin injection preparation, comprising an aqueous solution of dalbavancin hydrochloride and propylene glycol, wherein the aqueous solution of propylene glycol can be used to inhibit the degradation of dalbavancin hydrochloride, and the concentration of dalbavancin hydrochloride is 20 mg / mL-120 mg / mL calculated as dalbavancin free base.

[0010] In a third aspect, the present invention provides a method for preparing the dalbavancin injection preparation according to any one of the aforementioned embodiments, comprising mixing an aqueous solution of propylene glycol with dalbavancin hydrochloride to obtain a clear mixed solution, and adjusting the pH of the mixed solution with a pH regulator to obtain a dalbavancin injection product solution.

[0011] In a fourth aspect, the present invention provides a use of the dalbavancin injection formulation according to any one of the aforementioned embodiments in the preparation of a medicament for treating bacterial infection.

[0012] The present invention has the following beneficial effects:

[0013] Compared with lyophilized preparations, the dalbavancin injection preparation of the present invention can significantly reduce production costs and further improve drug safety and ease of use. It can not only bring huge economic benefits to manufacturers, but also provide more safe, effective and cost-effective products to patients. The social benefits it generates are also immeasurable. DETAILED DESCRIPTION

[0014] To make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are used. Where the manufacturer of the reagents or instruments is not specified, all are conventional products that can be purchased commercially.

[0015] Dalbavancin hydrochloride API is a heat-sensitive and hygroscopic material. While relatively stable under acidic conditions, it readily degrades under alkaline and high-temperature conditions to form major degradation impurities. To prevent the formation of impurities, dalbavancin hydrochloride must be stored at -20±5°C. Research indicates that the major degradation impurities of dalbavancin hydrochloride are compounds represented by the following formulas: I, III, and IV.

[0016]

[0017]

[0018] Since dalbavancin hydrochloride is easily degraded in aqueous solution, it leads to high levels of impurities. This product is prepared as a lyophilized powder. Before clinical use, it must be reconstituted with sterile water for injection or 5% glucose injection, and then diluted with 5% glucose injection alone to a final concentration of 1 mg / mL to 5 mg / mL. The lyophilized preparation requires reconstitution and dilution before use. To ensure product quality, the reconstituted and diluted solution has a very short storage time, which greatly reduces the convenience of administration.

[0019] In order to solve the above-mentioned technical problems, such as improving the convenience of administration, storage and transportation, the present invention provides the use of an aqueous solution of propylene glycol in inhibiting the degradation of dalbavancin hydrochloride, a method for using the aqueous solution of propylene glycol, a dalbavancin injection preparation, a preparation method, an application and a method of using the same.

[0020] The present invention can overcome the existing The problem of freeze-dried preparations needing to be reconstituted before use is conducive to improving the convenience of administration, storage and transportation.

[0021] An embodiment of the present invention provides use of an aqueous solution of propylene glycol in inhibiting the degradation of dalbavancin hydrochloride.

[0022] An embodiment of the present invention provides a method of using an aqueous solution of propylene glycol, comprising using the aqueous solution of propylene glycol to inhibit the degradation of dalbavancin hydrochloride.

[0023] In this embodiment of the present invention, a propylene glycol aqueous solution is used to inhibit the degradation of dalbavancin hydrochloride, improving its stability and facilitating the preparation of dalbavancin injection. Compared to lyophilized formulations, aqueous injection products can eliminate the need for reconstitution, improving the convenience of administration. Furthermore, the production process is simpler, the production cycle is shorter, and expensive equipment such as lyophilizers is not required, significantly reducing production costs. This significant reduction in production costs directly impacts the selling price of the finished product, which will benefit more patients.

[0024] In one or more embodiments, in the aqueous solution of propylene glycol, the volume ratio of propylene glycol to water for injection is 2:8-6:4, preferably 4:6-6:4, and more preferably 5.5:4.5-4.5:5.5.

[0025] In one or more embodiments, in the aqueous solution of propylene glycol, the volume ratio of propylene glycol to water for injection is preferably 4:6.

[0026] In the aqueous solution of propylene glycol, if the proportion of propylene glycol is too large or too small, it is not conducive to improving the stability of dalbavancin hydrochloride, and will lead to an increase in the total impurity content after storage.

[0027] An embodiment of the present invention further provides a dalbavancin injection preparation, comprising an aqueous solution of dalbavancin hydrochloride and propylene glycol, wherein the aqueous solution of propylene glycol can inhibit the degradation of dalbavancin hydrochloride, wherein the concentration of dalbavancin hydrochloride is 20 mg / mL-120 mg / mL calculated as dalbavancin free base, and the pH of the dalbavancin injection preparation is 3.5-5.5.

[0028] The dalbavancin injection preparation provided by the embodiments of the present invention has the following advantages compared to existing lyophilized preparations:

[0029] 1. Simpler production process and lower production costs. The production process for water injection products is simpler, the production cycle is shorter, and expensive equipment such as freeze dryers is not required, significantly reducing production costs. This significant reduction in production costs directly affects the selling price of the finished product. Low-priced, high-quality products will bring benefits to a wide range of patients.

[0030] 2. More convenient administration. Lyophilized preparations require reconstitution before use, which reduces the convenience of administration. However, aqueous injection preparations do not require reconstitution before administration, reducing administration procedures and improving administration convenience. It also reduces the risk of microbial contamination introduced by manual handling during clinical application of lyophilized preparations.

[0031] 3. Enhanced product safety. The successful development of aqueous injection formulations will reduce the use of lyophilized excipients. Furthermore, the dalbavancin injection formulations of the present invention do not require the addition of additional stabilizers, thereby reducing the type and amount of excipients in the formulation, further improving drug safety.

[0032] 4. Good product stability. The dalbavancin injection preparation according to the embodiment of the present invention has high stability. Although the proposed storage conditions are low-temperature storage at 2-8°C, it also shows excellent stability under high-temperature conditions (40°C). After being placed at 40°C for 10 days, the impurity level of the dalbavancin injection preparation according to the embodiment of the present invention is lower than the impurity level of the original formulation at the end of its validity period under long-term conditions (original formulation: validity period until: 2023.01.01, detection time: 2022.04.04, impurity content: impurity I: 3.29%, impurity III: 1.03%, impurity IV: 0.20%, total impurities: 7.80%). The present invention reduces the impurity level and safety risks of the product and improves the effectiveness of the product.

[0033] 5. More convenient transportation and storage. The original preparation needs to be reconstituted with 25 mL of diluent before clinical use to form a 20 mg / mL solution, which is then further diluted for clinical use. Therefore, it is packaged in 50 mL vials. The present invention can prepare high-concentration or low-concentration dalbavancin injection preparations as needed. The concentration of dalbavancin in the injection preparation can reach up to 120 mg / mL. In this case, only 5 mL vials are needed for packaging, which can greatly reduce transportation costs and storage space.

[0034] In summary, the dalbavancin injection formulation of the present invention can significantly reduce production costs and further improve drug safety and ease of use. It can not only bring huge economic benefits to manufacturers, but also provide more safe, effective, and cost-effective products to patients. The social benefits it generates are also immeasurable.

[0035] The API used in the present invention is the hydrochloride form of dalbavancin, i.e., dalbavancin hydrochloride. Dalbavancin hydrochloride is composed of five closely related active homologues (including A0, A1, B0, B1, and B2), of which B0 is the main component of dalbavancin. The homologues have the same core structure, as shown in Formula II:

[0036]

[0037] The only difference between A0, A1, B0, B1 and B2 is whether there is an additional methyl group (R2) on the fatty acid side chain and / or the terminal amino group of the N-aminoglucuronic acid portion (R1). The molecular formulas of A0, A1, B0, B1 and B2 and the molecular weights of the anhydrous free bases corresponding to A0, A1, B0, B1 and B2 are shown in Table 1:

[0038] Table 1

[0039] Dalbavancin <![CDATA[R1]]> <![CDATA[R2]]> Molecular formula Molecular weight <![CDATA[A0]]> <![CDATA[CH(CH3)2]]> H <![CDATA[C 87 H 98 N 10 O 28 Cl2·1.6HCl]]> 1802.7 <![CDATA[A1]]> <![CDATA[CH2CH2CH3]]> H <![CDATA[C 87 H 98 N 10 O 28 Cl2·1.6HCl]]> 1802.7 <![CDATA[B0]]> <![CDATA[CH2CH(CH3)2]]> H <![CDATA[C 88 H 100 N 10 O 28 Cl2·1.6HCl]]> 1816.7 <![CDATA[B1]]> <![CDATA[CH2CH2CH2CH3]]> H <![CDATA[C 88 H 100 N 10 O 28 Cl2·1.6HCl]]> 1816.7 <![CDATA[B2]]> <![CDATA[CH2CH(CH3)2]]> <![CDATA[CH3]]> <![CDATA[C 89 H 102 N 10 O 28 Cl2·1.6HCl]]> 1830.7

[0040] Dalbavancin hydrochloride is a white to tan powder that is freely soluble in water, dimethyl sulfoxide, and dimethylformamide, very slightly soluble in methanol, and insoluble in chloroform, n-butanol, and n-octanol.

[0041] In one or more embodiments of the present invention, the concentration of dalbavancin in the injection preparation can be 20 mg / mL-120 mg / mL, specifically 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, or any value between 20 mg / mL and 120 mg / mL, calculated as dalbavancin free base.

[0042] In one or more embodiments, the concentration of dalbavancin hydrochloride can be 20 mg / mL to 60 mg / mL, preferably 40 mg / mL to 60 mg / mL, calculated as dalbavancin free base. In one or more embodiments, the concentration of dalbavancin hydrochloride can be 60 mg / mL to 120 mg / mL, preferably 60 mg / mL to 90 mg / mL, and more preferably 80 mg / mL to 85 mg / mL, calculated as dalbavancin free base. In one or more embodiments, the concentration of dalbavancin hydrochloride can be 45 mg / mL to 55 mg / mL, calculated as dalbavancin free base. Excessively high dalbavancin concentrations can exceed its solubility in the solvent system, resulting in solid precipitation. Excessively low concentrations can result in excessively large injection volumes while ensuring effective administration, potentially increasing the amount of propylene glycol used in the formulation and thereby increasing the osmotic pressure of the formulation, affecting the safety of administration.

[0043] In one or more embodiments of the present invention, the pH of the dalbavancin injection formulation is 3.5-5.5, specifically 3.5, 3.7, 3.9, 4.1, 4.3, 4.5, 4.7, 4.9, 5.1, 5.3, 5.5 or any value between 3.5 and 5.5.

[0044] In one or more embodiments, the pH of the dalbavancin injection preparation is 4.0-5.0, preferably 4.4-4.6, and more preferably 4.45-4.55. Dalbavancin hydrochloride has better stability under this pH condition, which is beneficial for reducing the content of impurities in the injection preparation.

[0045] The dalbavancin injection formulation according to the embodiment of the present invention satisfies at least one of the following conditions after being stored at 40° C. for 10 days:

[0046] 1) The total impurity content is less than 5.0%;

[0047] 2) The increase in the impurity content of Formula I is ≤2.5%, wherein the structure of the compound represented by Formula I is as follows:

[0048]

[0049]

[0050] 3) The content of the main drug (calculated as dalbavancin free base) is reduced by ≤5.0%, wherein the main drug is dalbavancin hydrochloride, including the compound represented by Formula II:

[0051]

[0052] The main drugs include A0, A1, B0, B1 and B2, wherein the molecular formulas of A0, A1, B0, B1 and B2 and the molecular weights of the corresponding anhydrous free bases are shown in Table 1 above.

[0053] In some embodiments, after the dalbavancin injection preparation is placed at 40° C. for 10 days, the total impurity content is less than 5.0%, and the increase in the content of the impurity represented by Formula I is ≤2.5%.

[0054] An embodiment of the present invention further provides a method for preparing the dalbavancin injection preparation according to any one of the aforementioned embodiments, comprising mixing an aqueous solution of propylene glycol with dalbavancin hydrochloride to obtain a clear mixed solution, and adjusting the pH of the mixed solution with a pH regulator to obtain the dalbavancin injection product.

[0055] In a specific operation, approximately 40% of the batch of water for injection is first added to a dispensing tank, the solution temperature is maintained at 15° C. to 30° C., propylene glycol is added in the batch amount, and the mixture is stirred evenly. Dalbavancin hydrochloride in the batch amount is added and stirred until the dalbavancin hydrochloride is dissolved to obtain a clear solution. The pH of the solution is then adjusted to 3.5 to 5.5 using a pH adjuster, which is at least one of hydrochloric acid and sodium hydroxide. The remaining required amount of water for injection is then added to the volume. The dalbavancin injection product is then sterile-filtered and filled into transparent vials. The vials are then fully stoppered and capped with aluminum caps to obtain the finished product.

[0056] In an embodiment of the present invention, hydrochloric acid and sodium hydroxide can be used to adjust the pH of the mixed solution, and only chloride ions and sodium ions are introduced to improve the safety of the injection preparation.

[0057] An embodiment of the present invention further provides a use of the dalbavancin injection preparation according to any one of the aforementioned embodiments in preparing a medicament for treating bacterial infection.

[0058] An embodiment of the present invention further provides a method for using the dalbavancin injection preparation according to any one of the aforementioned embodiments, comprising using the dalbavancin injection preparation to prepare a medicament for treating bacterial infection.

[0059] In one or more embodiments, the bacterial infection comprises acute bacterial skin and skin appendage infections (ABSSSI) caused by specified susceptible strains of Gram-positive microorganisms, wherein the specified susceptible strains of Gram-positive microorganisms include Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus allolactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus) and Enterococcus faecalis (vancomycin-susceptible strains).

[0060] In one or more embodiments, the medicament can be used to treat adult and pediatric patients with acute bacterial skin and skin appendage infections (ABSSSI) caused by susceptible strains of designated Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus allolactiae, Streptococcus anginosus group (including Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus), and Enterococcus faecalis (vancomycin-susceptible strains).

[0061] The features and properties of the present invention are further described in detail below in conjunction with the examples. In the following examples and comparative examples, unless otherwise specified, the contents refer to mass fractions.

[0062] Example 1: Effect of pH on the stability of dalbavancin injection formulations

[0063] This embodiment provides a method for preparing a dalbavancin injection preparation, which specifically comprises:

[0064] Add about 400 mL of water for injection to the dispensing tank, maintain the solution temperature at 25°C, add the batch amount of propylene glycol, stir evenly, then add the batch amount (theoretical requirement: 50 g, calculated as dalbavancin free base) of dalbavancin hydrochloride, and stir until dissolved and clear.

[0065] The pH of the drug solutions of Preparations 1 to 7 were adjusted to the preset values ​​of 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, and 5.9, respectively, using a pH adjuster (sodium hydroxide and / or hydrochloric acid); and the volume of the drug solution was then adjusted to 1000 mL with water for injection.

[0066] The drug solution was sterile-filtered through a sterilizing filter and approximately 10.6 mL was filled into a 10 mL transparent vial. A 20 mm rubber stopper was installed and the aluminum cap was crimped to obtain the finished formulation (propylene glycol: water for injection volume ratio of 1:1). The impurity content of the finished formulation was tested after preparation and after 10 days at 40°C. The stability of each formulation is shown in Table 2.

[0067] Table 2

[0068]

[0069]

[0070] Remark:

[0071] The contents in Tables 2, 5, 7, 9, 10, and 11 refer to the ratios of the measured dalbavancin hydrochloride concentration (calculated as dalbavancin free base) to the preset dalbavancin hydrochloride concentration (calculated as dalbavancin free base), wherein the preset dalbavancin hydrochloride concentration (calculated as dalbavancin free base) in Table 2 is 50 mg / ml.

[0072] 1. After sample preparation, it was stored at 2-8°C. After storage at 2-8°C, the sample turned into a milky white gel-like solid. This may be due to the low temperature and high pH, ​​which caused the solubility of the API to decrease and precipitate. Therefore, other test items were not performed.

[0073] After being removed from the stability chamber, the sample was stored at 2-8°C. After storage at 2-8°C, the sample transformed into a milky white gel-like solid. This may be due to the low temperature and high pH, ​​which together reduced the solubility of the API and caused precipitation. Therefore, no other tests were performed.

[0074] According to Table 2, it can be seen that when the pH of the solvent is 3.5-5.5, the stability of the preparation can be improved, and when the pH of the solvent is 4.45-4.55, the effect is most obvious.

[0075] The chromatographic conditions for impurity detection are shown in Table 3:

[0076] Table 3

[0077]

[0078] Instrument: Waters ultra-high performance liquid chromatograph.

[0079] Gradient elution is shown in Table 4:

[0080] Table 4

[0081] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 95 5 10 95 5 45 5 95 109 5 95 110 95 5 120 95 5

[0082] Mobile phase:

[0083] Buffer solution: Dissolve 2.87 g of ammonium dihydrogen phosphate in 1000 mL of water, adjust the pH to 6.0 with aqueous ammonia, and filter through a 0.22 μm filter membrane.

[0084] Mobile phase A: Buffer and acetonitrile were mixed in a ratio of 80:20 (V / V) and degassed by ultrasonication.

[0085] Mobile phase B: Buffer and acetonitrile were mixed in a ratio of 66:34 (V / V) and degassed by ultrasonication.

[0086] In the chromatogram obtained after the test, except for the five peaks corresponding to dalbavancin hydrochloride A0, A1, B0, B1 and B2, the others were recorded as impurities.

[0087] Example 2: Effect of solvent composition on the stability of dalbavancin injection formulations

[0088] This example provides a method for preparing a dalbavancin injection formulation. This method differs from Example 1 primarily in the ratio of propylene glycol to water for injection in the solvent. The impurity content of the finished formulations was tested after preparation and after 10 days at 40°C. The stability of each formulation is shown in Table 5.

[0089] Table 5

[0090]

[0091]

[0092] Note: The preset concentration of dalbavancin hydrochloride in preparations 8-10 (calculated as dalbavancin free base) is 50 mg / ml; the preset concentration of dalbavancin hydrochloride in preparations 11-13 (calculated as dalbavancin free base) is 20 mg / ml.

[0093] It can be seen from Table 5 that when the volume fraction of propylene glycol in the solvent is 30%-60%, the stability of the preparation can be improved, and when the volume fraction of propylene glycol in the solvent is 50%, the effect is most obvious.

[0094] It should be noted that the volume of hydrochloric acid and sodium hydroxide used to adjust the pH of the mixture is less than 1% of the volume of the dalbavancin injection preparation, so the effect of the pH adjuster on the volume ratio of propylene glycol to water for injection in the injection preparation can be ignored.

[0095] Comparative Example 1: Effect of Solvent Type on the Stability of Dalbavancin Injection Formulation

[0096] This comparative example provides a method for preparing a dalbavancin injection preparation. The main difference from Example 1 is that the solvent type is different. The solvents used in each preparation are shown in Table 6. The impurity content of the finished preparations was tested after preparation and after storage at 40°C for 10 days. The stability of each preparation is shown in Table 7.

[0097] Table 6

[0098] preparation Preparation materials Volume ratio of solution solvent pH of the drug solution Preparation 14 API Anhydrous ethanol: water for injection = 1:1 4.6±0.1 Preparation 11 API Propylene glycol: water for injection = 1:1 4.6±0.1 Preparation 15 API Polyethylene glycol 300: water for injection = 1:1 4.6±0.1 Preparation 16 API Polyethylene glycol 400: water for injection = 1:1 4.6±0.1 Preparation 17 API N,N-dimethylacetamide: water for injection = 1:1 4.6±0.1

[0099] Table 7

[0100]

[0101] Note: The default concentration of dalbavancin hydrochloride in formulations 14-17 (calculated as dalbavancin free base) is 20 mg / ml.

[0102] It can be seen from Tables 6 and 7 that when the solvent is an aqueous solution of propylene glycol, the stability of the preparation is better, while other solvents have no obvious effect on improving the stability of the preparation, and some even have the effect of reducing the stability of the preparation.

[0103] Comparative Example 2: Effect of Stabilizers on the Stability of Dalbavancin Injection Formulations

[0104] This comparative example provides a method for preparing a dalbavancin injection preparation. The main difference from Example 1 is that water for injection is used as the solvent, and a stabilizer is added to the preparation. The composition and amount of the stabilizer are shown in Table 8. The impurity content of the finished preparation was tested after preparation and after storage at 40°C for 10 days. The stability of each preparation is shown in Table 9.

[0105] Table 8

[0106]

[0107] Table 9

[0108]

[0109] It can be seen from Tables 8 and 9 that adding stabilizers (lactose, mannitol, or glucose) to the formulation does not significantly improve the stability of the product and may even reduce the stability of the product.

[0110] Example 3: Effect of API Concentration on the Stability of Dalbavancin Injection Formulations

[0111] This example provides a method for preparing a dalbavancin injection preparation. The main difference from Example 1 is that the concentration of the API (active pharmaceutical ingredient) in the preparation is higher than that in Example 1. The method specifically comprises:

[0112] Add about 400 mL of water for injection to the preparation tank, maintain the solution temperature at 25°C, add the batch amount of propylene glycol, stir evenly, then add the batch amount (theoretical requirement: 83.3 g, calculated as dalbavancin free base) of dalbavancin hydrochloride, and stir until dissolved and clear.

[0113] The pH of the solution was adjusted to a preset value of 4.5 ± 0.1 using a pH regulator (sodium hydroxide), and then the volume of the solution was fixed to 1000 mL using water for injection.

[0114] The drug solution was sterile filtered through a sterilizing filter, and approximately 6.4 mL of the drug solution was filled into a 6 mL transparent vial. A 13 mm rubber stopper was installed and the aluminum cap was crimped to obtain the finished formulation (propylene glycol:water for injection, volume ratio:4:6), i.e., Formulation 22. The impurity content of the finished formulation was tested after preparation and after 10 days at 40°C. The stability is shown in Table 10 below.

[0115] Table 10

[0116]

[0117] Note: The preset concentration of dalbavancin hydrochloride in Formulation 22 (calculated as dalbavancin free base) is 83.3 mg / ml.

[0118] From the above results, it can be seen that after preparation 22 was placed at 40°C for 10 days, its total impurity content was less than 5.0%; the increase in the content of impurity I was ≤2.5%, and the decrease in the content of the main drug was ≤5.0%, indicating that the preparation had good stability.

[0119] In addition, to investigate the compatibility stability of the present invention's formulation during clinical use, the compatibility stability of Formulation 22 was studied. The compatibility stability test method involved first diluting Formulation 22 with water for injection to a 20 mg / mL dalbavancin hydrochloride solution (calculated as dalbavancin free base). The solution was then diluted with 5% glucose injection alone to final concentrations of 1 mg / mL and 5 mg / mL, respectively. The stability of the resulting 1 mg / mL and 5 mg / mL solutions was investigated at 25°C. The results are shown in Table 11 below:

[0120] Table 11

[0121]

[0122] The above test results show that the diluted solution prepared from the preparation 22 obtained in the present invention has a stability of at least 14 days at 25°C, which means that it has good compatibility stability during clinical use.

[0123] The foregoing description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be within the scope of protection of the present invention.

Claims

1. Use of an aqueous solution of propylene glycol in preparing a preparation for inhibiting the degradation of dalbavancin hydrochloride, characterized in that: In the aqueous solution of propylene glycol, the volume ratio of propylene glycol to water for injection is 2:8-6:4; and the pH value of the preparation is 3.5-5.

5.

2. Use of the aqueous solution of propylene glycol according to claim 1 in preparing a preparation for inhibiting the degradation of dalbavancin hydrochloride, characterized in that: In the aqueous solution of propylene glycol, the volume ratio of propylene glycol to water for injection is 4:6-6:

4.

3. Use of the aqueous solution of propylene glycol according to claim 1 in preparing a preparation for inhibiting the degradation of dalbavancin hydrochloride, characterized in that: In the aqueous solution of propylene glycol, the volume ratio of propylene glycol to water for injection is 5.5:4.5-4.5:5.

5.

4. Use of the aqueous solution of propylene glycol according to claim 1 in preparing a preparation for inhibiting the degradation of dalbavancin hydrochloride, characterized in that: In the aqueous solution of propylene glycol, the volume ratio of propylene glycol to water for injection is 4:

6.

5. A dalbavancin injection preparation, characterized in that: The invention relates to an aqueous solution comprising dalbavancin hydrochloride and propylene glycol, wherein the aqueous solution of propylene glycol can be used to inhibit the degradation of dalbavancin hydrochloride, the concentration of dalbavancin hydrochloride is 20 mg / mL-120 mg / mL calculated as dalbavancin free base, and the pH of the dalbavancin injection preparation is 3.5-5.5; and in the aqueous solution of propylene glycol, the volume ratio of propylene glycol to water for injection is 2:8-6:

4.

6. The dalbavancin injection preparation according to claim 5, characterized in that The concentration of dalbavancin hydrochloride is 20 mg / mL to 60 mg / mL as dalbavancin free base; Alternatively, the concentration of dalbavancin hydrochloride is 60 mg / mL to 90 mg / mL as dalbavancin free base.

7. The dalbavancin injection preparation according to claim 6, characterized in that The concentration of dalbavancin hydrochloride is 80 mg / mL to 85 mg / mL as dalbavancin free base.

8. The dalbavancin injection preparation according to claim 5, characterized in that The pH of the dalbavancin injection preparation is 4.4-4.

6.

9. The dalbavancin injection preparation according to claim 5, characterized in that: The pH of the dalbavancin injection preparation is 4.45-4.

55.

10. The dalbavancin injection preparation according to claim 5, characterized in that: After the dalbavancin injection preparation was placed at 40°C for 10 days: Total impurity content is less than 5.0%; and / or, the increase in the impurity content of Formula I is ≤2.5%, wherein the compound structure of Formula I is as follows: Formula I; And / or, the content of the main drug is reduced by ≤5.0%, wherein the main drug is dalbavancin hydrochloride, including the compound represented by Formula II: Formula II The main drugs include A0, A1, B0, B1 and B2, wherein the molecular formulas of A0, A1, B0, B1 and B2 and the molecular weights of the corresponding anhydrous free bases are shown in Table 1: Table 1 11. A method for preparing the dalbavancin injection preparation according to any one of claims 5 to 10, characterized in that: The method comprises mixing an aqueous solution of propylene glycol with dalbavancin hydrochloride to obtain a clear mixed solution, and adjusting the pH of the mixed solution with a pH regulator to obtain a dalbavancin injection product solution; The method also includes sterilizing and filtering the in-process drug solution of the dalbavancin injection, filling, stoppering and capping to obtain the packaged dalbavancin injection preparation.

12. The method for preparing the dalbavancin injection preparation according to claim 11, characterized in that: The pH adjuster is at least one selected from the group consisting of hydrochloric acid and sodium hydroxide; And / or, the mixing and the adjustment of the pH of the mixed solution are both performed at 15°C-30°C.

13. The method for preparing the dalbavancin injection preparation according to claim 11, characterized in that: The step of mixing the aqueous solution of propylene glycol with dalbavancin hydrochloride to obtain a clear mixed solution comprises: adding approximately 40% of a batch of water for injection into a dispensing tank, maintaining the solution temperature at 15° C. to 30° C., adding a batch amount of propylene glycol, and stirring uniformly; adding a batch amount of dalbavancin hydrochloride, and stirring until the dalbavancin hydrochloride is dissolved to obtain a clear solution; And / or, the step of adjusting the pH of the mixed solution with a pH regulator to obtain the dalbavancin injection product comprises: adjusting the pH of the solution to 3.5-5.5 with a pH regulator, and then adding the remaining required amount of water for injection to make up the volume.

14. Use of the dalbavancin injection preparation according to any one of claims 5 to 10 in the preparation of a medicament for treating bacterial infection.

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