Argatroban injection and prefilled syringe

Abstract

The present application provides an argatroban injection containing an acidic component such as boric acid or lactic acid and a solubilizer such as PEG300 or polysorbate 40 and a corresponding prefilled syringe. The injection of the present application has good thermal stability, light stability and safety.

Description

Technical Field

[0001] The present application belongs to the field of cardiovascular and cerebrovascular disease treatment and pharmaceutical technology. Specifically, the present application provides an argatroban injection and a corresponding prefilled syringe. Background Art

[0002] Argatroban is an antithrombotic drug developed by Mitsubishi Chemical Research Institute in Japan. It is a low molecular weight direct inhibitor of thrombin that can reversibly bind to the active site of thrombin. It is currently widely used in the clinic to treat patients in the acute phase of ischemic cerebral infarction, with a dosage of 60 mg per day for 2 days and 20 mg per day for the next 5 days.

[0003] Argatroban is an arginine derivative that is poorly soluble in water and sensitive to light and heat. Since it is an emergency drug, increasing the concentration and reducing the infusion volume is also beneficial to actual clinical operations. Therefore, the main research direction of argatroban preparations is to increase drug concentration and stability. Currently, there are records of the use of organic acids, sorbitol, PEG, cyclodextrin, etc. in the known argatroban preparations at home and abroad, which can achieve preparation stability at a concentration of 5 mg / mL argatroban.

[0004] In our research, we found that the stability of argatroban injection under light is poor, although brown bottles, outer packaging, EDTA chelating agents and other methods have been used to solve this problem. However, on the one hand, EDTA chelating agents are common in patients with acute ischemic cerebral infarction due to side effects such as allergies, decreased blood sugar, blood pressure and blood calcium ions, and are not suitable for use in patients in the acute stage of ischemic cerebral infarction; on the other hand, too many packaging requirements are likely to cause inconvenience in actual clinical use (for example, after unpacking and using a small number of preparations, the remaining part is often not strictly preserved), and because of the safety issues of polypropylene light shielding agents, it is not suitable for preparation into the most convenient pre-filled syringe. Summary of the invention

[0005] To solve the above problems, the applicant tried a large number of new excipient combinations and found that the use of acids with certain chelating effects, such as boric acid or lactic acid, and solubilizers such as polysorbate 40 in a specific ratio can chelate metal ions while promoting dissolution, thereby improving the photostability of the preparation and avoiding potential problems such as allergies, blood sugar, blood pressure, and blood calcium ions caused by EDTA; it provides a good basis for the preparation of higher concentration, practical argatroban injections, especially prefilled syringes.

[0006] In one aspect, the present application provides an argatroban injection, which comprises argatroban, a solubilizer and an acidic component.

[0007] Furthermore, the concentration of argatroban in the argatroban injection is above 3 mg / mL.

[0008] Furthermore, the solubilizing agent is PEG300 or polysorbate 40.

[0009] Furthermore, the solubilizing agent content is 5%-20% w / v.

[0010] Furthermore, the acidic component is boric acid or lactic acid.

[0011] Furthermore, the acidic component content is 0.05%-0.25% w / v.

[0012] Furthermore, the mass ratio of the solubilizer to the acidic component is 10-50:1.

[0013] Furthermore, the pH of the argatroban injection is 5.6-6.5, preferably pH 6.

[0014] Further, the argatroban injection comprises argatroban 5 mg / mL, boric acid 0.25% w / v, polysorbate 40 10% w / v, and pH 6; or the argatroban injection comprises argatroban 5 mg / mL, lactic acid 0.1% w / v, polysorbate 40 12% w / v, and pH 6.

[0015] On the other hand, the present application provides a prefilled syringe comprising the above-mentioned argatroban injection.

[0016] On the other hand, the present application provides the use of the above-mentioned injection or prefilled syringe in the preparation of a medicine or a medicine kit for treating ischemic cerebral infarction.

[0017] The content of argatroban in the present application is calculated as argatroban. Those skilled in the art can convert the amount of argatroban corresponding to the hydrates, salts, prodrugs, etc. of different raw materials using conventional chemical knowledge.

[0018] The various excipients in this application are not limited to specific manufacturers or places of origin, as long as their quality meets the requirements of the corresponding injection excipients.

[0019] In addition to acute ischemic cerebral infarction, the injection of the present application can also be used for other uses of argatroban known in research, and the specific clinical dosage and usage regimen can be determined by clinical physicians based on their judgment and regimen.

[0020] The prefilled syringe can be made of materials known in the art, such as polypropylene, glass, etc.; the specifications can be determined according to the disease to be treated, the available treatment options and the concentration of argatroban in the injection, including but not limited to 1mL, 2mL, 5mL, 10mL, 20mL, etc. The sterilization, filling, sealing and packaging methods and devices of prefilled syringes known in the art can be used for the prefilled syringes of the present application.

[0021] The medicine kit may contain a plurality of medicines required for treating the same disease. DETAILED DESCRIPTION

[0022] The argatroban API and standard products in this application were purchased from Hubei Weideli.

[0023] The excipients in this application, such as anhydrous ethanol, lactic acid, citric acid, boric acid, PEG300, polysorbate 40, etc., were purchased from regular manufacturers such as Xi'an Tianzheng or produced by ourselves.

[0024] HPLC instrument: Shimadzu LC-2060D; ShimNex HE cyano-bonded silica column (250 mm × 4.0 mm, 5 μm); mobile phase: methanol, 10% tetrabutylammonium hydroxide, phosphoric acid, water (700:20:0.5:200); 257 nm UV detection; flow rate: 1 mL / min, column temperature: 40 degrees Celsius.

[0025] The analytical reagents used in the examples are all conventional domestically produced types.

[0026] Example 1 Formulation and preparation of injection

[0027] To solve the above problems, the applicant tried to find a more suitable combination of acidic components and solubilizers to solve the problems of high alcohol content and stability, especially light stability. The applicant tried a large number of formulations. Table 1 below shows some representative formulations and their storage properties. A large number of formulations used in formulation design, especially orthogonal experimental formulations, are not fully shown:

[0028] Argatroban Anhydrous ethanol lactic acid Citric acid Boric acid PEG300 Polysorbate 40 Recipe 1 5g 10g N / A N / A 2.5g N / A 100g Recipe 2 5g 10g N / A N / A 2.5g N / A 150g Recipe 3 5g 10g N / A N / A 1.5g N / A 100g Recipe 4 5g 10g N / A N / A 2.5g 100g N / A Recipe 5 5g 10g N / A N / A 4g N / A 110g Recipe 6 5g 10g 1g N / A N / A N / A 120g Recipe 7 5g 10g 1g N / A N / A 100g N / A Recipe 8 5g 10g 0.5g N / A N / A N / A 100g Recipe 9 5g 10g N / A 4g N / A N / A 150g

[0029] * Table 1 shows the dosage per 1000 mL of injection solution, the remainder is water for injection and NaOH and / or HCl for adjusting pH; N / A: None.

[0030] Preparation method:

[0031] Stir and dissolve the required amount of PEG300 or polysorbate 40 in 200 mL of water for injection for later use; stir and dissolve the required amount of lactic acid, citric acid or boric acid in 700 mL of water for injection, add the required amount of argatroban and then add the above PEG300 or polysorbate 40 solution, continue stirring and dissolving; adjust the pH value to 6.0; add water for injection to make up to 1000 mL and filter (0.22 micron).

[0032] Example 2 Study on the stability of injection

[0033] The following controls were used in the stability studies:

[0034] Reference substance 1: commercially available argatroban injection (Nobostai, Mitsubishi Tanabe, 2 mL / piece, each containing 10 mg argatroban);

[0035] Reference substance 2: commercially available argatroban injection (Dabei, Tianjin Pharmaceutical Research Institute, 20 mL / piece, each containing 10 mg of argatroban);

[0036] Reference substance 3: prepared according to Example 1 of the prior art CN113476398A: 5 g of argatroban, 200 g of anhydrous ethanol, 150 g of PEG300, and diluted to 1000 mL with water for injection.

[0037] All reference substances and formulations 1-9 were refilled into 2 mL colorless ampoules for the following stability tests.

[0038] The initial states of formulations 1-9 and controls 1-3 are shown in Table 2:

[0039] Basic status pH Argatroban content, % Total impurity content, % Recipe 1 Colorless and clear, no visible foreign matter 6.03 99.8 0.005 Recipe 2 Colorless and clear, no visible foreign matter 6.10 99.9 0.006 Recipe 3 Colorless and clear, no visible foreign matter 6.05 100.2 0.004 Recipe 4 Colorless and clear, no visible foreign matter 5.97 100.1 0.005 Recipe 5 Colorless and clear, no visible foreign matter 6.02 99.7 0.007 Recipe 6 Colorless and clear, no visible foreign matter 6.02 99.5 0.005 Recipe 7 Colorless and clear, no visible foreign matter 5.98 100.3 0.006 Recipe 8 Colorless and clear, no visible foreign matter 6.07 100.0 0.007 Recipe 9 Colorless and clear, no visible foreign matter 6.04 100.2 0.002 Reference 1 Colorless and clear, no visible foreign matter 5.92 99.9 0.003 Reference 2 Colorless and clear, no visible foreign matter 6.12 99.9 0.004 Reference 3 Colorless and clear, no visible foreign matter 5.95 100.1 0.008

[0040] 2-1 Temperature stability

[0041] The accelerated stability test was conducted at 50±2 degrees Celsius and 70±5% for 20 days. The results are shown in Table 3:

[0042] Basic status pH Argatroban content, % Total impurity content, % Recipe 1 Colorless and clear, no visible foreign matter 6.05 99.5 0.022 Recipe 2 Colorless and clear, no visible foreign matter 6.11 99.6 0.017 Recipe 3 Colorless and clear, no visible foreign matter 6.03 99.7 0.032 Recipe 4 Colorless and clear, no visible foreign matter 5.99 99.8 0.028 Recipe 5 Colorless and clear, no visible foreign matter 6.01 99.3 0.027 Recipe 6 Colorless and clear, no visible foreign matter 6.02 99.3 0.015 Recipe 7 Colorless and clear, no visible foreign matter 5.95 99.7 0.036 Recipe 8 Colorless and clear, no visible foreign matter 6.09 99.5 0.024 Recipe 9 Colorless and clear, no visible foreign matter 6.03 99.9 0.019 Reference 1 Colorless and clear, no visible foreign matter 5.97 99.6 0.020 Reference 2 Colorless and clear, no visible foreign matter 6.03 99.8 0.016 Reference 3 Colorless and clear, no visible foreign matter 6.02 99.4 0.028

[0043] The results showed that under high temperature and high humidity conditions, the pH of the product remained basically unchanged, and the content and amount of argatroban slightly deteriorated, but were all within the acceptable normal range. The above formulas and reference products all had good temperature stability.

[0044] 2-2 Light stability

[0045] Using 10000Lx±1000Lx illumination and 30±2 degrees Celsius, a 20-day accelerated stability test was conducted. The results are shown in Table 4:

[0046] Basic status pH Argatroban content, % Total impurity content, % Recipe 1 Colorless and clear, no visible foreign matter 6.06 99.4 0.039 Recipe 2 Colorless and clear, no visible foreign matter 6.07 99.2 0.238 Recipe 3 Colorless and clear, no visible foreign matter 6.09 98.7 0.198 Recipe 4 Colorless and clear, no visible foreign matter 6.05 99.1 0.212 Recipe 5 Colorless and clear, no visible foreign matter 6.10 99.2 0.291 Recipe 6 Colorless and clear, no visible foreign matter 6.02 99.3 0.082 Recipe 7 Colorless and clear, no visible foreign matter 5.93 98.4 0.253 Recipe 8 Colorless and clear, no visible foreign matter 5.99 98.9 0.194 Recipe 9 Colorless and clear, no visible foreign matter 6.07 99.0 0.319 Reference 1 Colorless and clear, no visible foreign matter 5.74 99.6 0.390 Reference 2 Colorless and clear, no visible foreign matter 5.54 99.8 0.125 Reference 3 Colorless and clear, no visible foreign matter 5.67 99.4 0.474

[0047] It can be seen from the table above that the three reference substances, especially the high concentration (5 mg / mL) reference substances 1 and 3, have poor light stability, the pH value in the accelerated test has significantly decreased, and the impurity content has significantly increased. The formulas provided in this application, especially formulas 1 and 6, have obvious advantages in terms of impurity content; such stable injections are more suitable for preparing prefilled syringes.

[0048] Example 3 Preparation of prefilled syringe

[0049] The injection of formula 1 was used to prepare a 2 mL colorless prefilled syringe (polypropylene syringe, piston, high pressure steam sterilization). The unpackaged prefilled syringe was placed in the office environment for 3 months (enough to cover the common clinical storage time after opening), and all indicators remained good. If further protection such as blisters and packaging boxes is added, the shelf life can be further extended.

[0050] Obviously, the above embodiments of the present invention are only examples for clearly explaining the present invention, and are not intended to limit the implementation methods of the present invention. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. However, these obvious changes or modifications derived from the spirit of the present invention are still within the scope of protection of the present invention.

Claims

1. An argatroban injection, characterized in that: Each 1000 mL of the argatroban injection consists of 5 g of argatroban, 10 g of anhydrous ethanol, 2.5 g of boric acid, 100 g of polysorbate 40, and the remainder of water for injection and NaOH and / or HCl for adjusting the pH. The pH of the argatroban injection is 6.

2. An argatroban injection, characterized in that: Each 1000 mL of the argatroban injection consists of 5 g of argatroban, 10 g of anhydrous ethanol, 1 g of lactic acid, 120 g of polysorbate 40, and the remainder of water for injection and NaOH and / or HCl for adjusting the pH. The pH of the argatroban injection is 6.

3. A prefilled syringe, characterized in that: The prefilled syringe contains the argatroban injection according to claim 1 or 2.

4. Use of the argatroban injection according to claim 1 or 2 or the prefilled syringe according to claim 3 in the preparation of a medicament for treating ischemic cerebral infarction.