A nalmefene hydrochloride injection and its preparation method

Abstract

The present invention relates to the field of pharmaceutical technology and provides a nalmefene hydrochloride injection and a preparation method thereof. Each 1,000 injections comprise the following components in parts by weight: 2.0 g of nalmefene hydrochloride, 18 g of an osmotic pressure regulator, and 0.05 to 0.1 g of meglumine, with water for injection added to 2,000 mL. The preparation method comprises the following steps: S1. adding the prescribed amount of the osmotic pressure regulator and meglumine to 90% of the total amount of water for injection, stirring until dissolved, and adjusting the pH to 3.5 to 4.0 with a hydrochloric acid solution; S2. adding the prescribed amount of nalmefene hydrochloride to the solution in step S1, stirring until dissolved, and adjusting the pH to 3.5 to 3.8; S3. adding water for injection to the full amount, stirring thoroughly, filtering, sealing in an ampoule, sterilizing, inspecting for leaks with a light source, and packaging. By adding a small amount of meglumine, the amount of dinalmefene impurities produced by oxidation of nalmefene hydrochloride injection during long-term storage can be reduced, the adverse reactions that may be caused by the use of a large amount of meglumine can be reduced, and the content of dinalmefene impurities can be maintained at a low level, thereby improving the safety of the injection.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical technology, and in particular to a nalmefene hydrochloride injection and a preparation method thereof. Background Art

[0002] Nalmefene hydrochloride (chemical name: 4,5α-epoxy-6-methylenemorphinan-17-cyclopropylmethyl-3,14-diol hydrochloride) is an opioid receptor antagonist and an analog of 6-methylene-naltrexone. Its chemical structure is as follows:

[0003]

[0004] Nalmefene hydrochloride is a water-soluble derivative of NTX. Its chemical structure with a methylene group at the 6th position offers advantages such as long duration of action, multiple routes of administration, high bioavailability, minimal side effects, strong physiological activity, and improved penetration of biological membranes. It can be used to prevent or reverse the effects of opioids, including respiratory depression, sedation, and hyponatremia. Currently available nalmefene hydrochloride is available in injectable form. Nalmefene hydrochloride contains a phenolic hydroxyl group, which is easily oxidized in aqueous solution upon exposure to light, ultraviolet light, or high temperatures to form the nalmefene hydrochloride dimer, dicalmefene. Even upon long-term storage at room temperature, auto-oxidation to dicalmefene can occur, causing discoloration and deterioration of the injectable solution, seriously impacting drug safety. Therefore, the National Drug Standard YBH07072010 explicitly stipulates that the content of the degradation impurity dicalmefene hydrochloride in nalmefene hydrochloride injection must not exceed 1.0%, and the total content of all impurities other than dicalmefene must not exceed 1.0%. According to studies, for a small number of patients, nalmefene hydrochloride sometimes causes transient symptoms such as chest tightness, shortness of breath, chills, myalgia, irritability, abdominal cramps and joint pain, which may be related to the dinalmefene impurity in it.

[0005] CN109200017B discloses a nalmefene hydrochloride injection pharmaceutical composition and its preparation method. By adding meglumine as an antioxidant to the injection, the content of nalmefene impurities can be effectively controlled, significantly improving product quality and safety. However, the inclusion of a large amount of meglumine, while applicable to the production of the injection, inevitably produces some side effects, thereby reducing product safety. Summary of the Invention

[0006] In view of this, the present invention aims to provide a nalmefene hydrochloride injection and a preparation method thereof, so as to solve the problem in the prior art that excessive amounts of antioxidants are added to prevent nalmefene hydrochloride injection from oxidation during long-term storage, thereby affecting the safety of the product.

[0007] To achieve the above object, the technical solution of the present invention is achieved as follows:

[0008] On the one hand, the present invention provides a nalmefene hydrochloride injection, wherein each 1000 injections comprise the following components in parts by weight: 2.0 g of nalmefene hydrochloride (calculated as nalmefene), 18 g of an osmotic pressure regulator, 0.05-0.1 g of meglumine, and water for injection is added to 2000 mL.

[0009] Furthermore, the osmotic pressure regulator is sodium chloride.

[0010] On the other hand, the present invention also provides a method for preparing the nalmefene hydrochloride injection as described above, comprising the following steps:

[0011] S1. Add the prescribed amount of osmotic pressure regulator and meglumine to 90% of the total amount of water for injection and stir until dissolved. Adjust the pH to 3.5-4.0 with hydrochloric acid solution.

[0012] S2. The prescribed amount of nalmefene hydrochloride is added to the solution of step S1 and stirred until dissolved, and the pH is adjusted to 3.5~3.8;

[0013] S3. Add water for injection to the full volume, stir well, filter, seal in an ampoule, sterilize, inspect for leaks with a light, and package.

[0014] Furthermore, in step S3, the drug solution obtained after stirring is filtered through 0.45 μm and 0.22 μm cartridge filters in sequence into a buffer tank, and then canned into an ampoule.

[0015] Furthermore, in step S3, the nalmefene hydrochloride injection is sterilized in a water bath at 121° C. for 15 min.

[0016] Furthermore, in step S1, the amount of water for injection added is controlled to be 70-80% of the total amount of the prescription.

[0017] Furthermore, the preparation method of the nalmefene hydrochloride injection comprises the following steps:

[0018] S1. Add the prescribed amount of osmotic pressure regulator and meglumine to 70-80% of the total amount of water for injection and stir until dissolved. Adjust the pH to 3.5-4.0 with hydrochloric acid solution.

[0019] S2. The prescribed amount of nalmefene hydrochloride was added to the solution of step S1 and stirred until dissolved. After adding half of the remaining water for injection and stirring, the pH value was adjusted to 3.5 to 3.8;

[0020] S3. Add water for injection to the full volume, stir well, filter, seal in an ampoule, sterilize, inspect for leaks with a light, and package.

[0021] Compared with the prior art, the nalmefene hydrochloride injection and the preparation method thereof of the present invention have the following advantages: by adding a small amount of meglumine, the amount of dinalmefene impurities produced by oxidation of the nalmefene hydrochloride injection during long-term storage can be reduced, the adverse reactions that may be caused by the use of a large amount of meglumine can be reduced, and the content of dinalmefene impurities can be maintained at a low level, thereby improving the safety of the injection. DETAILED DESCRIPTION

[0022] The present invention will be further described below in conjunction with specific embodiments. It should be noted that the data in the following experimental examples are obtained by the inventor through a large number of experiments. Due to space limitations, only a portion thereof is shown in the specification, and those skilled in the art can understand and implement the present invention under these data. These embodiments are merely intended to illustrate the present invention and are not intended to limit the scope of the present invention. It should also be understood that, after having read the contents of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these changes or modifications also fall within the scope protected by this application.

[0023] The nalmefene hydrochloride injection of the present invention comprises the following components in parts by weight per 1000 injections: 2.0 g of nalmefene hydrochloride (calculated as nalmefene), 18 g of an osmotic pressure regulator, 0.05-0.1 g of meglumine, and water for injection is added to 2000 mL.

[0024] The preparation method of the nalmefene hydrochloride injection comprises the following steps:

[0025] S1. Add the prescribed amount of osmotic pressure regulator and meglumine to the total amount of water for injection and stir until dissolved. Adjust the pH to 3.5-4.0 with hydrochloric acid solution.

[0026] S2. The prescribed amount of nalmefene hydrochloride is added to the solution of step S1 and stirred until dissolved, and the pH is adjusted to 3.5~3.8;

[0027] S3. Add water for injection to the full volume, stir well, filter, seal in an ampoule, sterilize, inspect for leaks with a light, and package.

[0028] Specifically, in step S3, the liquid medicine obtained after stirring is filtered through 0.45μm and 0.22μm cartridge filters in turn into a buffer tank, and then canned into ampoules. During filling, the filling range and residual oxygen in the headspace are controlled, and nitrogen is filled for 5s after filling. Nalmefene hydrochloride injection is sterilized in a water bath at 121°C for 15 minutes. After sterilization, the light inspection speed is controlled. All products are leak-tested using a high-voltage discharge method, and the leak detection parameters are: leak detection voltage 18KV, bottle head leakage voltage upper limit 1.44V, bottle neck leakage voltage upper limit 1.68V, bottle body leakage voltage upper limit 1.05V, bottle bottom leakage voltage upper limit 1.05V. When the detection value exceeds the set leakage voltage upper limit, the sample is judged to be leaking, and the equipment automatically rejects it. Products that pass the light inspection and leak detection are labeled and coded. Blister, box, and carton. In the specific embodiment, the filtration, canning, sterilization, light inspection and packaging processes are not described in detail.

[0029] Example 1

[0030] The prescription of nalmefene hydrochloride injection (1000 vials) is:

[0031] Nalmefene hydrochloride 2.216g

[0032] 18g sodium chloride

[0033] Meglumine 0.05g

[0034] 2000mL of water for injection.

[0035] Add 18g of sodium chloride and 0.05g of meglumine to 1800mL of water for injection and stir until dissolved. Adjust the pH to 3.8 with 0.1mol / L hydrochloric acid. Then, add 2.216g of nalmefene hydrochloride and stir until dissolved. Adjust the pH to 3.6 with 0.1mol / L hydrochloric acid. Add water for injection to the total volume, stir thoroughly, filter, and seal in an ampoule. Sterilize, inspect for leaks, and package.

[0036] Example 2

[0037] The prescription of nalmefene hydrochloride injection (1000 vials) is:

[0038] Nalmefene hydrochloride 2.216g

[0039] 18g sodium chloride

[0040] Meglumine 0.1g

[0041] 2000mL of water for injection.

[0042] Add 18g of sodium chloride and 0.1g of meglumine to 1800mL of water for injection and stir until dissolved. Adjust the pH to 4.0 with 0.1mol / L hydrochloric acid. Then, add 2.216g of nalmefene hydrochloride and stir until dissolved. Adjust the pH to 3.5 with 0.1mol / L hydrochloric acid. Add water for injection to the total volume, stir thoroughly, filter, and seal in an ampoule. Sterilize, inspect for leaks, and package.

[0043] The present invention changes the order of feeding, and sodium chloride and meglumine are first added to a portion of water for injection, and the pH value of the solution is adjusted to acidic by hydrochloric acid, so that the nalmefene hydrochloride added subsequently is in an acidic environment when feeding, which is conducive to ensuring the stability of the injection system. At the same time, the prior art is mostly that nalmefene hydrochloride, sodium chloride, and hydrochloric acid are added to water for injection at the same time. The heat released by hydrochloric acid can increase the temperature of the system, causing nalmefene hydrochloride to be easily oxidized. The present application first adds hydrochloric acid and adjusts the pH value of the solution to acidic before adding nalmefene hydrochloride, avoiding direct contact between the two, thereby improving the stability of nalmefene hydrochloride. By changing the order of feeding, the possibility of oxidation during long-term storage of the injection is further reduced in the presence of a limited amount of meglumine. At the same time, meglumine is mixed with nalmefene hydrochloride after forming a solution, which is conducive to full contact between the two, so that meglumine can better play a role.

[0044] Compared to CN109200017B, although the present invention reduces the dosage of meglumine to 0.05-0.1 g, thereby introducing fewer excipients, the present inventors have attempted to further improve the preparation method of nalmefene hydrochloride to further reduce the dosage of meglumine and better optimize the composition of the formulation.

[0045] Specifically, the inventors discovered that during step S2, when nalmefene hydrochloride is added to the solution of step S1, stirring is required for a long time until it dissolves. The inventors unexpectedly discovered that by controlling the amount of water for injection added in step S1, the dissolution time of nalmefene hydrochloride can be shortened, thereby reducing the risk of prolonged exposure and oxidation of the drug solution due to prolonged preparation time, when sodium chloride and meglumine are added.

[0046] The present inventors studied the effects of different water for injection dosages on the time required to prepare nalmefene hydrochloride. The specific results are shown in Table 1. It should be noted that the relevant experiments were single-factor experiments. That is, while maintaining the same dosages of sodium chloride, meglumine, and nalmefene hydrochloride, as well as the pH value and stirring rate, only the amount of water for injection was varied to examine the effects of the changes in water for injection dosage.

[0047] Table 1

[0048]

[0049] As shown in Table 1, controlling the amount of water for injection added in step S1 to 70-95% of the total amount of the prescription facilitates rapid dissolution of nalmefene hydrochloride, thereby reducing the preparation time of the injection solution and reducing oxidation caused by prolonged exposure of the injection solution. Consequently, the amount of meglumine added can be reduced. Therefore, the amount of meglumine used is further adjusted to 0.01-0.05 g.

[0050] Accordingly, when the dosage of meglumine is 0.01-0.05 g, the preparation method of nalmefene hydrochloride injection comprises the following steps:

[0051] S1. Add the prescribed amount of osmotic pressure regulator and meglumine to 70-95% of the total amount of water for injection and stir until dissolved. Adjust the pH to 3.5-4.0 with hydrochloric acid solution.

[0052] S2. The prescribed amount of nalmefene hydrochloride was added to the solution of step S1 and stirred until dissolved. After adding half of the remaining water for injection and stirring, the pH value was adjusted to 3.5 to 3.8;

[0053] S3. Add water for injection to the full amount, stir well, filter, seal in an ampoule, sterilize, inspect for leaks with a light, and package.

[0054] Specifically, the water for injection of half the remaining water for injection is added in step S2 in order to use less water for injection to constant volume in step S3. If a part of the water for injection is not added in step S2, but all the remaining water for injection are directly added in step S3, the water yield in step S3 will be excessive, which may affect the pH value adjusted in step S2. In addition, although it is also necessary to adjust the pH in step S2, the time of step S2 will not be increased too much. This process can be expanded to large-scale production by determining the amount of the buffer solution that needs to be added in a pilot test. The process of adjusting the pH in step S2 will not cause a longer exposure time when configuring nalmefene hydrochloride.

[0055] Example 3

[0056] The prescription of nalmefene hydrochloride injection (1000 vials) is:

[0057] Nalmefene hydrochloride 2.216g

[0058] 18g sodium chloride

[0059] Meglumine 0.05g

[0060] 2000mL of water for injection.

[0061] Add 18g of sodium chloride and 0.05g of meglumine to 1400mL of water for injection and stir until dissolved. Adjust the pH to 3.8 with 0.1mol / L hydrochloric acid. Then, add 2.216g of nalmefene hydrochloride and stir until dissolved. Add 300ml of water for injection and stir thoroughly. Adjust the pH to 3.6 with 0.1mol / L hydrochloric acid. Add water for injection to the full volume, stir thoroughly, filter, and seal in an ampoule. Stir, inspect for leaks, and package.

[0062] Example 4

[0063] The prescription of nalmefene hydrochloride injection (1000 vials) is:

[0064] Nalmefene hydrochloride 2.216g

[0065] 18g sodium chloride

[0066] Meglumine 0.01g

[0067] 2000mL of water for injection.

[0068] Add 18g of sodium chloride and 0.01g of meglumine to 1600mL of water for injection and stir until dissolved. Adjust the pH to 4.0 with 0.1mol / L hydrochloric acid. Then, add 2.216g of nalmefene hydrochloride and stir until dissolved. Add 200ml of water for injection and stir thoroughly. Adjust the pH to 3.8 with 0.1mol / L hydrochloric acid. Add water for injection to the full volume, stir thoroughly, filter, and seal in an ampoule. Sterilize, inspect for leaks, and package.

[0069] Example 5

[0070] The prescription of nalmefene hydrochloride injection (1000 vials) is:

[0071] Nalmefene hydrochloride 2.216g

[0072] 18g sodium chloride

[0073] Meglumine 0.03g

[0074] 2000mL of water for injection.

[0075] Add 18g of sodium chloride and 0.01g of meglumine to 1600mL of water for injection and stir until dissolved. Adjust the pH to 4.0 with 0.1mol / L hydrochloric acid. Then add 2.216g of nalmefene hydrochloride and stir until dissolved. Add 200ml of water for injection and stir thoroughly. Adjust the pH to 3.8 with glacial acetic acid. Add water for injection to the full volume, stir thoroughly, filter, and seal in an ampoule. Sterilize, inspect for leaks, and package.

[0076] Comparative Example 1

[0077] Comparative Example 1 adopts the prescription and preparation method of Example 10 in CN109200017B.

[0078] Comparative study on stability of accelerated tests

[0079] Accelerated stability tests were performed on the nalmefene hydrochloride injections prepared in Examples 1-5 and Comparative Example 1. The accelerated test conditions were as follows: each sample was packaged according to commercial packaging and stored at 60°C ± 2°C and a relative humidity of 75% ± 5% for 12 months. Samples were collected at the end of the 0th, 3rd, 9th, and 12th month to determine the nalmefene impurity content (%). The results are shown in Table 2.

[0080] Table 2

[0081]

[0082] As shown in Table 2, the injections of Examples 1 to 5 prepared using the components and preparation method of the nalmefene hydrochloride injection of the present invention have good stability, and the nalmefene impurities are well controlled. After a long period of accelerated testing, the nalmefene impurity content does not increase significantly. In particular, after 12 months, the nalmefene impurity content in Comparative Example 1 is increased to 0.18%, but the nalmefene impurity content in Examples 1 to 5 is only 0.09 to 0.11%. Compared with Comparative Example 1, Examples 1 to 5 can improve the storage stability of the injection under the condition of less meglumine dosage, avoiding excessive oxidation to produce impurities. In Examples 3 to 5, by changing the amount of water added in step S1, the dissolution time of nalmefene hydrochloride can be shortened, thereby reducing oxidation caused by excessive exposure time. Accordingly, Examples 3 to 5 can further reduce the amount of meglumine added. Due to the reduction in the amount of added excipients, the adverse reactions of the nalmefene hydrochloride injection are reduced, and the safety of use is improved.

[0083] Strong light exposure test

[0084] The nalmefene hydrochloride injections prepared in Examples 1 to 5 and Comparative Example 1 were irradiated in an adjustable light box with an illumination of 4500 lx±500 lx, and samples were taken for testing on day 0, day 10, and day 30, respectively. The results are shown in Table 3.

[0085] Table 3

[0086]

[0087] As shown in Table 2, the nalmefene hydrochloride injections prepared in Examples 1 to 5 and Comparative Example 1 all have good appearance under illumination conditions. However, after 30 days of illumination, the pH of Comparative Example 1 increased from 3.18 to 3.51. It is speculated that the possible reason is that hydrochloric acid is used directly to adjust the pH after adding nalmefene hydrochloride, and the drug is directly in contact with strong acid, which is not conducive to the long-term stability of pH. Examples 1 to 4 have undergone two pH adjustments. When the pH is adjusted for the first time, nalmefene hydrochloride is placed in an acidic solution environment, but the second pH adjustment is also directly with hydrochloric acid. After 30 days of illumination, the pH will change to a certain extent. In Example 5, glacial acetic acid is used for adjustment when the pH is adjusted for the second time. After 30 days of illumination, the pH changes from 3.82 to 3.85, with no obvious change. Therefore, when adjusting the pH for the second time, glacial acetic acid can be used instead of hydrochloric acid, and long-term storage will not cause a large change in pH, which is beneficial to the stability of nalmefene hydrochloride and remains in a relatively stable pH environment. At the same time, a stable pH environment is also beneficial to the stability of the injection product and reduces the generation of impurities.

[0088] Although the present invention is disclosed as above, the present invention is not limited thereto. Any person skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be based on the scope defined by the claims.

Claims

1. A nalmefene hydrochloride injection, characterized in that: Each 1000 vials of injection contains the following components by weight: 2.0 g of nalmefene hydrochloride, 18 g of osmotic pressure regulator, 0.05-0.1 g of meglumine, and water for injection is added to 2000 mL. The preparation method of the nalmefene hydrochloride injection comprises the following steps: S1. Add the prescribed amount of osmotic pressure regulator and meglumine to 70-95% of the total amount of water for injection and stir until dissolved. Adjust the pH to 3.5-4.0 with hydrochloric acid solution. S2. The prescribed amount of nalmefene hydrochloride was added to the solution of step S1 and stirred until dissolved. After adding half of the remaining water for injection and stirring, the pH value was adjusted to 3.5 to 3.8; S3. Add water for injection to the full amount, stir well, filter, seal in an ampoule, sterilize, inspect for leaks with a light, and package.

2. The nalmefene hydrochloride injection according to claim 1, characterized in that The osmotic pressure regulator is sodium chloride.

3. The nalmefene hydrochloride injection according to claim 1, characterized in that In step S3, the drug solution obtained after stirring is filtered through 0.45 μm and 0.22 μm cartridge filters in sequence into a buffer tank, and then canned into an ampoule.

4. The nalmefene hydrochloride injection according to claim 1, characterized in that In step S3, the nalmefene hydrochloride injection is sterilized in a water bath at 121° C. for 15 min.

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