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

Abstract

The invention discloses application of an aqueous solution of propylene glycol in inhibition of degradation of dalbavancin hydrochloride, a dalbavancin injection preparation, a preparation method and application. The aqueous solution of propylene glycol is applied to the dalbavancin injection preparation, and compared with a freeze-dried preparation, the obtained dalbavancin injection preparation has the advantages that the production cost can be remarkably reduced, the medicine safety and the use convenience are further improved, huge economic benefits can be brought to production enterprises, and the application prospect is wide. More safe, effective and high-price products can be provided for the majority of patients, and the generated social benefits are immeasurable as well.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the priority of the Chinese patent application filed with the China Patent Office on July 26, 2024, with application number CN2024110170360 and titled “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 by reference into this application. Technical Field

[0003] The present invention relates to the technical field of pharmaceutical preparations, and in particular to application 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 product of dalbavancin has been launched in the US market. Its product dosage form is freeze-dried powder with a specification of 500 mg / bottle. On May 23, 2014, the US Food and Drug Administration (FDA) approved the dalbavancin for injection 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, 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 bottle of the product includes dalbavancin hydrochloride, equivalent to 500 mg of dalbavancin free base, and excipients: 129 mg lactose and 129 mg mannitol. During the production process, sodium hydroxide or hydrochloric acid may be added 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 be reconstituted with 25mL of sterile water for injection or 5% glucose injection. To avoid foaming, alternately rotate and flip the vial slightly until its contents are completely dissolved, do not shake. The reconstituted vial contains 20mg / mL of dalbavancin as a clear, colorless to yellow solution, and then continues to be 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 drug 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, a large 50 mL vial is 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 an aqueous solution of propylene glycol 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 clarified mixed solution, and adjusting the pH of the mixed solution with a pH adjuster to obtain a dalbavancin injection product solution.

[0011] In a fourth aspect, the present invention provides a use of the dalbavancin injection preparation described in 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 the lyophilized preparation, the dalbavancin injection preparation of the present invention can significantly reduce the production cost and further improve the safety and convenience of the drug. It can not only bring huge economic benefits to the production enterprises, but also provide more safe, effective and cost-effective products for the patients. The social benefits generated are also immeasurable. DETAILED DESCRIPTION

[0014] In order to make the purpose, technical scheme and advantages of the embodiments of the present invention clearer, the technical scheme in the embodiments of the present invention will be described clearly and completely below. If the specific conditions are not specified in the embodiments, they are carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0015] The raw material of dalbavancin hydrochloride is a heat-sensitive material, hygroscopic, relatively stable under acidic conditions, and easily degraded to form major degradation impurities under alkaline and high temperature conditions. To inhibit the generation of impurities, dalbavancin hydrochloride is required to be stored at -20±5°C. According to research, the main degradation impurities of dalbavancin hydrochloride are compounds of the following formulas I, III and IV.

[0016]

[0017]

[0018] Since dalbavancin hydrochloride is prone to degradation 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 only to a final concentration of 1 mg / mL to 5 mg / mL. Lyophilized preparations need to be reconstituted and diluted before use, and in order not to affect the quality of the product, the storage time of the reconstituted and diluted solution is very short, which greatly reduces the convenience of administration.

[0019] In order to solve the above 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 of using an 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 an application 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 the embodiment of the present invention, the aqueous solution of propylene glycol is used to inhibit the degradation of dalbavancin hydrochloride, improve the stability of dalbavancin, and facilitate the preparation of dalbavancin injection. Compared with freeze-dried preparations, water injection products can omit the reconstitution operation on the one hand, which is conducive to improving the convenience of drug administration; on the other hand, the production process is simpler, the production cycle is shorter, and no expensive equipment such as freeze dryers are required, so its production cost will be greatly reduced. The substantial reduction in production costs directly affects the selling price of the finished product, which will also 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, which 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 embodiment of the present invention has the following advantages compared with the existing lyophilized preparations:

[0029] 1. The production process is simpler and the production cost is lower. The production process of water injection products is simpler, the production cycle is shorter, and no expensive equipment such as freeze dryers is required, so its production cost will be greatly reduced. The significant reduction in production costs will directly affect the selling price of the finished product. Low-priced, high-quality products will bring good news to the majority of patients.

[0030] 2. More convenient administration. Freeze-dried preparations need to be reconstituted before use, which reduces the convenience of administration. However, water injection preparations do not need to be reconstituted before administration, which reduces the administration operation, improves the convenience of administration, and reduces the risk of microbial contamination introduced by manual operation during the clinical application of freeze-dried preparations.

[0031] 3. Higher product safety. The successful development of water injection preparations will reduce the use of lyophilized excipients. In addition, in the dalbavancin injection preparations of the embodiments of the present invention, no additional stabilizer is required, thereby reducing the type or amount of excipients in the preparation, so that the safety of the drug can be further improved.

[0032] 4. Good product stability. The dalbavancin injection preparation according to the embodiment of the present invention has high stability. Although the proposed storage condition is low-temperature storage at 2-8°C, it also shows excellent stability under high temperature conditions (40°C). After the dalbavancin injection preparation according to the embodiment of the present invention was placed at 40°C for 10 days, the impurity level was lower than the impurity level of the original preparation at the end of the near-effective period under long-term conditions (original preparation: expiration date: 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, and then further diluted for clinical use, so 50 mL vials are used for packaging; the present invention can prepare high-concentration dalbavancin injection preparations or low-concentration dalbavancin injection preparations as needed, and the concentration of dalbavancin in the injection preparation can reach up to 120 mg / mL. At this time, only 5 mL vials are needed for packaging, which can greatly reduce transportation costs and storage space.

[0034] In summary, 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 production companies, but also provide more safe, effective and cost-effective products for patients. The social benefits it generates are also immeasurable.

[0035] The raw material 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), wherein B0 is the main component of dalbavancin. The homologues have the same core structure, and the structural formula is as shown in Formula II:

[0036]

[0037] The 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 part (R1) structure. The molecular formula of A0, A1, B0, B1 and B2 and the molecular weight of the anhydrous free base 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, 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-60 mg / mL, preferably 40 mg / mL-60 mg / mL, based on dalbavancin free base. In one or more embodiments, the concentration of dalbavancin hydrochloride can be 60 mg / mL-120 mg / mL, preferably 60 mg / mL-90 mg / mL, and more preferably 80 mg / mL-85 mg / mL, based on dalbavancin free base. In one or more embodiments, the concentration of dalbavancin hydrochloride can be 45 mg / mL-55 mg / mL based on dalbavancin free base. If the concentration of dalbavancin is too high, it will exceed its solubility in the solvent system, and solids will precipitate; if the concentration is too low, the administration volume of the injection solution is too large on the basis of ensuring the administration effect, which may cause an increase in the amount of propylene glycol in the preparation, thereby increasing the osmotic pressure of the preparation and affecting the safety of administration.

[0043] In one or more embodiments of the present invention, the pH of the dalbavancin injection preparation 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 to reduce the content of impurities in the injection preparation.

[0045] The dalbavancin injection preparation according to the embodiment of the present invention satisfies at least one of the following conditions after being placed 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 compound structure of 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 impurity content represented by Formula I is ≤2.5%.

[0054] An embodiment of the present invention also provides a method for preparing the dalbavancin injection preparation described in 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 adjuster to obtain the dalbavancin injection product solution.

[0055] In the specific operation, firstly, about 40% of the batch of water for injection is added to the liquid preparation tank, the solution temperature is maintained at 15°C-30°C, and the batch amount of propylene glycol is added and stirred evenly. The batch amount of dalbavancin hydrochloride is added and stirred until the dalbavancin hydrochloride is dissolved to obtain a clear solution, and then the pH of the liquid is adjusted to 3.5-5.5 with a pH adjuster, and the pH adjuster is at least one of hydrochloric acid and sodium hydroxide, and then the remaining required amount of water for injection is added to make up the volume, and then the dalbavancin injection liquid in the product is sterilized and filtered, and the liquid is filled into a transparent vial, and the rubber stopper is fully plugged, and the aluminum cap is rolled to obtain the finished preparation.

[0056] In the 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 also provides a use of the dalbavancin injection preparation described in any one of the aforementioned embodiments in the preparation of a medicament for treating bacterial infection.

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

[0059] In one or more embodiments, the bacterial infection includes 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-sensitive and methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus allolactiae, the anginosus Streptococcus 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 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: 50 g, based on 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 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 then the drug solutions were fixed to 1000 mL using water for injection.

[0066] The drug solution was sterilized and filtered through a sterilizing filter, and about 10.6 mL of the drug solution was filled into a 10 mL transparent vial, and the 20 mm rubber stopper was fully plugged, and the aluminum cap was rolled to obtain the finished preparation (the volume ratio of propylene glycol to water for injection was 1:1). The impurity content of the finished preparation was tested after preparation and after being placed at 40°C for 10 days, and the stability of each preparation was obtained as 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 ratio of the measured concentration of dalbavancin hydrochloride (calculated as dalbavancin free base) to the preset concentration of dalbavancin hydrochloride (calculated as dalbavancin free base), wherein the preset concentration of dalbavancin hydrochloride (calculated as dalbavancin free base) in Table 2 is 50 mg / ml.

[0072] 1 After the sample was prepared, 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 raw material to decrease and precipitate. Therefore, no other items were tested.

[0073] 2 After the samples were taken out of the stability box, they were stored at 2-8°C. After being stored at 2-8°C, the samples turned into milky white gel-like solids. This may be due to the low temperature and high pH, ​​which caused the solubility of the API to decrease and precipitate. Therefore, no other tests were performed.

[0074] It can be seen from Table 2 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: 2.87 g of ammonium dihydrogen phosphate was dissolved in 1000 mL of water, the pH was adjusted to 6.0 with aqueous ammonia, and filtered 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 detection, 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 preparation, which differs from Example 1 mainly in that the ratio of propylene glycol to water for injection in the solvent is different. The impurity content of the finished preparation was tested after preparation and after being placed at 40° C. for 10 days, and the stability of each preparation 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 mixed solution 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 and water for injection in the injection preparation can be ignored.

[0095] Comparative Example 1: Effect of solvent type on the stability of dalbavancin injection preparation

[0096] This comparative example provides a method for preparing a dalbavancin injection preparation, which is different from Example 1 mainly in that the types of solvents are 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 being placed 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 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 preset concentration of dalbavancin hydrochloride in Preparations 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, and 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 stabilizer on the stability of dalbavancin injection preparation

[0104] This comparative example provides a method for preparing a dalbavancin injection preparation, which is different from Example 1 mainly in that water for injection is used as a solvent, a stabilizer is further added to the preparation, the composition and amount of the stabilizer are shown in Table 8, and the impurity content of the finished preparation is tested after preparation and after being placed at 40° C. for 10 days, and 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 or mannitol or glucose) to the preparation 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 embodiment provides a method for preparing a dalbavancin injection preparation, which is mainly different from Example 1 in that the concentration of 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, based on dalbavancin free base) of dalbavancin hydrochloride, and stir until dissolved and clear.

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

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

[0115] Table 10

[0116]

[0117] Note: The preset concentration of dalbavancin hydrochloride in Preparation 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, in order to investigate the compatibility stability of the preparation of the present invention during clinical use, the compatibility stability of preparation 22 was studied. The compatibility stability test method includes: first diluting preparation 22 with water for injection to a solution with a concentration of 20 mg / mL of dalbavancin hydrochloride (calculated as dalbavancin free base), and then diluting it with only 5% glucose injection to solutions with final concentrations of 1 mg / mL and 5 mg / mL, respectively, and investigating the stability of the obtained 1 mg / mL and 5 mg / mL solutions at 25°C. The results are shown in Table 11 below:

[0120] Table 11

[0121]

[0122] From the above test results, it can be seen 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, that is, it has good compatibility stability during clinical use.

[0123] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. Use of an aqueous solution of propylene glycol in inhibiting the degradation of dalbavancin hydrochloride.

2. Use of the aqueous solution of propylene glycol according to claim 1 in 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, preferably 4:6-6:4, and more preferably 5.5:4.5-4.5:5.5 or 4:

6.

3. 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, and the concentration of dalbavancin hydrochloride is 20 mg / mL-120 mg / mL calculated as dalbavancin free base.

4. The dalbavancin injection preparation according to claim 3, 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, preferably 80 mg / mL to 85 mg / mL, calculated as dalbavancin free base.

5. The dalbavancin injection preparation according to claim 3, characterized in that: The pH of the dalbavancin injection preparation is 3.5-5.5, preferably 4.4-4.6, and more preferably 4.45-4.

55.

6. The dalbavancin injection preparation according to claim 3, 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: And / or, the content of the main drug decreases by ≤5.0%, wherein the main drug is dalbavancin hydrochloride, including the compound shown in formula II: The main drug includes A0, A1, B0, B1 and B2, wherein the molecular formula of A0, A1, B0, B1 and B2 and the molecular weight of the corresponding anhydrous free base are shown in Table 1: Table 1 7. A method for preparing the dalbavancin injection preparation according to any one of claims 3 to 6, 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 semi-finished drug solution of dalbavancin injection; The method also includes sterilizing and filtering the in-process drug solution of the dalbavancin injection, filling, plugging and capping to obtain the packaged dalbavancin injection preparation.

8. The method for preparing the dalbavancin injection preparation according to claim 7, characterized in that: The pH adjuster is at least one selected from the group consisting of hydrochloric acid and sodium hydroxide; And / or, mixing and adjusting the pH of the mixed solution are both performed at 15°C-30°C.

9. The method for preparing the dalbavancin injection preparation according to claim 7, characterized in that: The step of mixing the aqueous solution of propylene glycol with dalbavancin hydrochloride to obtain a clear mixed solution comprises: adding about 40% of the batch of water for injection into a liquid preparation tank, maintaining the solution temperature at 15° C. to 30° C., adding the batch amount of propylene glycol, and stirring evenly; adding the 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 a semi-finished drug solution of dalbavancin injection comprises: adjusting the pH of the drug 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.

10. Use of the dalbavancin injection preparation according to any one of claims 3 to 6 in the preparation of a medicament for treating bacterial infection; Preferably, the bacterial infection comprises an acute bacterial skin and skin appendage infection caused by a designated susceptible strain of Gram-positive microorganism.

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