A kind of nalbuphine hydrochloride injection and preparation method thereof

Abstract

The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a nalbuphine hydrochloride injection and a preparation method thereof. The nalbuphine hydrochloride injection comprises: nalbuphine hydrochloride, sodium chloride, a buffer mixture, water for injection, or further comprises a complexing agent. The present invention solves the problem of the easy generation of nalbuphine impurities in the prior art by changing the prescription components and contents, significantly improves the stability of the preparation, and reduces the risks that may be caused by various potential side effects. At the same time, the preparation process is optimized, the process time is greatly shortened, and the exposure time of the product is reduced.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a nalbuphine hydrochloride injection and a preparation method thereof. Background Art

[0002] Nalbuphine is a semisynthetic opioid agonist-antagonist analgesic, chemically similar to the opioid oxymorphone and the opioid antagonist naloxone. Nalbuphine exhibits both agonist effects on opioid κ receptors and antagonist effects on μ receptors. Nalbuphine can be administered via a variety of routes, including intravenous, intramuscular, subcutaneous, and spinal administration, and is effective in controlling severe and profound pain caused by cardiac, pulmonary, abdominal, bone disease and obstetric surgery, severe burns, and advanced cancer. Nalbuphine takes effect within 2 to 3 minutes after intravenous administration and within 15 minutes after intramuscular or subcutaneous injection.

[0003] Nalbuphine hydrochloride is a white or off-white crystalline powder that is easily soluble in water. According to prior art, nalbuphine hydrochloride injection (trade name: Nubain) is stable in a slightly acidic environment, but when the pH rises above 6, dinalbuphine impurities are formed. The formation of this impurity is also affected by light and heavy metal ions, which causes nalbuphine hydrochloride injection to lose stability during the shelf life of the drug.

[0004] Patent RU 2254852 (published on June 27, 2005) discloses a nalbuphine injection solution containing 0.8-2.2 wt.% nalbuphine hydrochloride, 0.5-3.5 wt.% buffer mixture, 0.001-0.2 wt.% complexing agent, 0.15-0.25 wt.% stabilizer and water for injection. The patent reduces the production of the impurity binalbuphine by adding the complexing agent EDTA, but there may be side effects associated with intravenous injection of EDTA for more than 5 days, such as hypokalemia, worsening of kidney and liver diseases. In addition, this drug may cause adverse reactions in patients with diabetes, hypokalemia, heart rhythm disorders and cardiovascular diseases. The patent specification of RU 2254852 does not contain information about the safety of the proposed drug.

[0005] Patent RU 2483731 (published on June 10, 2013) discloses a nalbuphine hydrochloride injection with significant analgesic effect, which contains nalbuphine hydrochloride 1.0-2.0 wt.%, citric acid 1.26 wt.%, sodium citrate 0.94 wt.%, sodium chloride 0.1 wt.%, sodium pyrosulfite 0.1 wt.%, and water for injection. The antioxidant sodium pyrosulfite is added to the injection to improve the stability of the drug, but it will not be suitable for asthma patients who are sensitive to sulfur-containing components.

[0006] Based on the problems existing in the prior art, there is still a need for a nalbuphine hydrochloride injection with good stability and fewer side effects to reduce the generation of bisnalbuphine impurities, improve the stability of the preparation, and be suitable for a variety of patient populations. Summary of the invention

[0007] The present invention provides a nalbuphine hydrochloride injection and a preparation method thereof, which solves the technical problem of easy generation of nalbuphine impurities in the prior art, significantly improves the stability of the preparation, and reduces the risks that may be caused by various potential side effects.

[0008] The first aspect of the present invention provides a nalbuphine hydrochloride injection, wherein each unit of the injection contains the following components: 5-20 mg nalbuphine hydrochloride, 1.5-7.5 mg sodium chloride, a buffer mixture, and water for injection.

[0009] The pH value of the injection solution is about 3.0-4.0.

[0010] In some embodiments, each unit of nalbuphine hydrochloride injection contains: 10-20 mg nalbuphine hydrochloride, 2-7 mg sodium chloride, buffer mixture, and water for injection.

[0011] In some embodiments, each unit of nalbuphine hydrochloride injection contains: 10 mg nalbuphine hydrochloride, 4-7.5 mg sodium chloride, buffer mixture, and water for injection.

[0012] The buffer mixture comprises citric acid and sodium citrate. In some embodiments, the mass ratio of citric acid to sodium citrate is 1:0.55-0.9; preferably, the mass ratio of citric acid to sodium citrate is 1:0.65-0.75. In some embodiments, the mass ratio of citric acid to sodium citrate is 1:0.50, 1:0.60, 1:0.65, 1:0.70, 1:0.80, 1:0.85.

[0013] In some embodiments, each unit of nalbuphine hydrochloride injection contains the following components: 10-20 mg nalbuphine hydrochloride, 1.5-7.5 mg sodium chloride, citric acid, sodium citrate, and water for injection. Further, in some embodiments, each unit of nalbuphine hydrochloride injection contains the following components: 10-20 mg nalbuphine hydrochloride, 2-7 mg sodium chloride, citric acid, sodium citrate, and water for injection; wherein the mass ratio of citric acid to sodium citrate is 1:0.55-0.9, and the preferred mass ratio is 1:0.65-0.75.

[0014] In some embodiments, the mass ratio of nalbuphine hydrochloride: citric acid + sodium citrate is about 1:0.35-0.75; preferably, the mass ratio is about 1:0.45-0.55.

[0015] In some embodiments, each unit of nalbuphine hydrochloride injection contains the following components: 10 mg nalbuphine hydrochloride, 4-7.5 mg sodium chloride, citric acid, sodium citrate, and water for injection; wherein the mass ratio of citric acid to sodium citrate is 1:0.55-0.9, and the preferred mass ratio is 1:0.65-0.7; the mass ratio of nalbuphine hydrochloride to citric acid + sodium citrate in the buffer mixture is about 1:0.35-0.75, and the preferred mass ratio is about 1:0.45-0.55.

[0016] In some embodiments, the nalbuphine hydrochloride injection further contains a chelating agent, and the mass ratio of the chelating agent to citric acid + sodium citrate in the buffer stabilizer is 1:0.005-0.015, preferably 1:0.01-0.012.

[0017] Preferably, the complexing agent is sodium calcium edetate.

[0018] In some embodiments, each unit of nalbuphine hydrochloride injection contains the following components: 10-20 mg nalbuphine hydrochloride, 1.5-7.5 mg sodium chloride, citric acid, sodium citrate, sodium calcium edetate, and water for injection.

[0019] Furthermore, in some embodiments, each unit of nalbuphine hydrochloride injection contains the following components: 10-20 mg nalbuphine hydrochloride, 2-7 mg sodium chloride, citric acid, sodium citrate, sodium edetate calcium, and water for injection; wherein the mass ratio of citric acid: sodium citrate is 1:0.55-0.9, and the preferred mass ratio is 1:0.65-0.75; the mass ratio of (citric acid + sodium citrate): sodium edetate calcium is 1:0.005-0.015, and the preferred mass ratio is 1:0.01-0.012.

[0020] In some embodiments, each unit of nalbuphine hydrochloride injection contains the following components: 10 mg nalbuphine hydrochloride, 4-7.5 mg sodium chloride, citric acid, sodium citrate, sodium edetate calcium, and water for injection; wherein the mass ratio of citric acid: sodium citrate is 1:0.55-0.9, and the preferred mass ratio is 1:0.65-0.75; the mass ratio of nalbuphine hydrochloride to citric acid + sodium citrate in the buffer mixture is about 1:0.35-0.75, and the preferred mass ratio is about 1:0.45-0.555; the mass ratio of (citric acid + sodium citrate): sodium edetate calcium is about 1:0.005-0.015, and the preferred mass ratio is 1:0.01-0.012.

[0021] The second aspect of the present invention provides a method for preparing the above-mentioned nalbuphine hydrochloride injection, comprising the following steps:

[0022] Step a: Add water for injection into the liquid preparation tank, adjust the water temperature, and fill with nitrogen;

[0023] Step b: adding the prescribed amount of auxiliary materials to the liquid preparation tank, stirring until the auxiliary materials are completely dissolved, and then continuing to add the prescribed amount of nalbuphine hydrochloride, stirring until the raw materials are completely dissolved; lowering the temperature of the liquid medicine, filtering and sterilizing;

[0024] Step c: After the ampoule is cleaned, sterilized and dried, it is filled and filled with nitrogen before and after filling;

[0025] Step d: Sterilization and packaging.

[0026] In some embodiments, in the method for preparing nalbuphine hydrochloride injection of the present invention, the temperature of adjusting the water temperature in step a is 40-60°C.

[0027] In some embodiments, in the method for preparing nalbuphine hydrochloride injection of the present invention, the excipients in step b include sodium citrate, anhydrous citric acid and sodium chloride.

[0028] In some embodiments, in the method for preparing nalbuphine hydrochloride injection of the present invention, the excipients in step b include sodium citrate, anhydrous citric acid, sodium calcium edetate and sodium chloride.

[0029] Beneficial effects of the present invention:

[0030] 1. Composition: The nalbuphine hydrochloride injection of the present invention has good stability, significantly reduced binalbuphine content, and significantly inhibits the generation of binalbuphine impurities during storage. At the same time, it avoids the use of sulfur-containing antioxidants and EDTA, which can significantly reduce a variety of possible side effects and is applicable to a wider range of patients;

[0031] 2. Preparation process: The preparation process described in the present invention can significantly shorten the process time and reduce production costs. At the same time, based on the reduction of the process time limit, the exposure time of the product is reduced, thereby indirectly reducing the contamination risk of the product. DETAILED DESCRIPTION

[0032] The present invention is further described in detail below in conjunction with the embodiments, but the present invention is not limited thereto. Any equivalent substitutions in the art made according to the disclosure of the present invention shall fall within the protection scope of the present invention.

[0033] In this application, the terms "include", "comprises", "contains" and their equivalents should be understood as open, non-exclusive meanings, i.e., "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included. In this document, unless the context clearly dictates otherwise, singular terms encompass plural referents and vice versa.

[0034] In this application, the term "about" means ±5% based on the original data.

[0035] In this application, all pharmaceutical excipients or reagents mentioned may be from commercial sources.

[0036] Example 1-7 Each unit preparation contains the following ingredients

[0037]

[0038] Preparation method:

[0039] Step a: Add water for injection into the liquid preparation tank and fill it with nitrogen.

[0040] Step b: adding the prescribed amount of sodium citrate, anhydrous citric acid and sodium chloride to the liquid preparation tank, stirring until the auxiliary materials are completely dissolved, and then continuing to add the prescribed amount of nalbuphine hydrochloride, stirring until the raw materials are completely dissolved; filtering and sterilizing;

[0041] Step c: After the ampoule is cleaned, sterilized and dried, it is filled and filled with nitrogen before and after filling;

[0042] Step d: sterilize and package at 121°C / 15min.

[0043] The pH values ​​of the samples of Examples 1-7 were measured. Without adding other pH adjusters, the pH value of the sample of Example 1 was highly acidic, the pH values ​​of the samples of Example 2 and Example 7 were approximately 2.8 and 4.2, respectively, and the pH values ​​of the products of Examples 3-6 were in the range of 3.0-4.0.

[0044] The samples of Examples 1-7 were placed at 60°C ± 2°C for 6 months, and their properties and pH changes were examined as follows.

[0045] Table 1a Results of property changes of samples in Examples 1-7

[0046]

[0047] Table 1b pH change results of samples in Examples 1-7

[0048]

[0049] The test results show that when the mass ratio of citric acid to sodium citrate is within the range of 1:0.55-0.9, as in Examples 3-6, the pH value of the injection can be stably adjusted and the generation of impurities can be reduced.

[0050] Example 8-13 Each unit preparation contains the following ingredients

[0051]

[0052] Comparative Example 1: Nalbuphine hydrochloride injection solution was prepared with reference to Example 4-1 of RU2254852C1.

[0053] Comparative Example 2: Nalbuphine hydrochloride injection solution was prepared with reference to Example 1 of RU2483731C1.

[0054] The injection samples of Examples 8-13 and Comparative Examples 1-2 were placed under illumination of 4500±500 lx for 5 days, and samples were taken for determination of pH, content, bisnalbuphine (P0Z5) and other related substances to investigate the quality changes of the samples under the above conditions. The results are shown in Table 2.

[0055] Table 2 Test results

[0056]

[0057] During the research and development process, the inventors found that by adjusting the dosage of citric acid / sodium citrate and the ratio of nalbuphine hydrochloride to citric acid + sodium citrate, the stability of the injection can be significantly improved; in the above test, while keeping the ratio of citric acid to sodium citrate unchanged, the osmotic pressure of each embodiment was consistent by adjusting the dosage of sodium chloride, and the ratio of nalbuphine hydrochloride to citric acid + sodium citrate was changed; the test results show that the generation of impurities in the nalbuphine hydrochloride injection sample, especially the generation of dinalbuphine impurities, is easily affected by light, and the stability of Examples 8-13 under light conditions is significantly improved compared with Comparative Examples 1-2.

[0058] Examples 14-19 Each unit preparation contains the following ingredients

[0059]

[0060] The injection products of Examples 14-19 and Comparative Examples 1-2 were placed at 60°C ± 2°C for 6 months, and the percentages of bisnalbuphine impurities and other impurities were investigated under the conditions. The results are shown in Table 3a.

[0061] Table 3a Test results

[0062]

[0063] The injection products of Examples 14-19 were placed under a light condition of 4500±500 lx for 5 days to investigate the percentage of bisnalbuphine (P0Z5) impurities and other impurities. The results are shown in Table 3b.

[0064] Table 3b Test results

[0065]

[0066] The test results show that by further adding sodium calcium edetate to the prescription and controlling the ratio of sodium calcium edetate to citric acid / sodium citrate, the stability of nalbuphine hydrochloride injection under high temperature and light conditions can be further significantly improved. The samples of Examples 14-19 have significantly improved stability under high temperature and light conditions compared to Comparative Examples 1-2, meeting the drug quality requirements.

[0067] (I) The preparation process was designed according to the prescription composition of Examples 16 and 17 as follows

[0068]

[0069] The preparation process is as follows:

[0070] Step a: Add water for injection into 6 liquid preparation tanks respectively, and place every 2 liquid preparation tanks in a 25°C water bath (1-1 batch, 2-1 batch), a 40°C water bath (1-2 batch, 2-2 batch), and a 60°C water bath (1-3 batch, 2-3 batch); fill with nitrogen;

[0071] Step b: adding the sodium citrate, anhydrous citric acid and sodium chloride in the amount of Example 16 to the 1-1 batch, 1-2 batch and 1-3 batch preparation tanks, adding the sodium citrate, anhydrous citric acid and sodium chloride in the amount of Example 17 to the 2-1 batch, 2-2 batch and 2-3 batch preparation tanks, stirring until the auxiliary materials are completely dissolved, and then continuing to add the corresponding amount of nalbuphine hydrochloride, stirring until the raw materials are completely dissolved, and recording the dissolution time of the raw materials; lowering the temperature of the liquid, filtering and sterilizing;

[0072] Step c: After the ampoule is cleaned, sterilized and dried, it is filled and nitrogen is filled before and after filling;

[0073] Step d: sterilize at 121°C / 15min and package.

[0074] The properties, pH value, content, nalbuphine (P0Z5) and other related substances of each batch of samples were tested, and the results are shown in Table 4a.

[0075] Table 4a Test results

[0076]

[0077] The test results show that the raw materials take a long time to dissolve at 25°C. Considering the feasibility of large-scale production, the liquid preparation temperature is determined to be 40~60°C, which can significantly reduce production time and thus reduce the exposure time of the product. The product quality meets the requirements.

[0078] (II) Investigate the effect of oxygen on product degradation: Nitrogen filling can reduce the oxygen content in the product and slow down the degradation rate of the product. Therefore, the effects of different nitrogen filling methods of liquid preparation and potting on product stability were investigated. Samples were prepared according to the prescriptions of Examples 16-17. The preparation method was the same as that of Example 1 except for the nitrogen filling method. The design of nitrogen filling method investigation was as follows:

[0079]

[0080] Note: (1) Before preparing the solution, the water for injection should be filled with nitrogen to below 1.0 mg / L. The liquid medicine should be filled with nitrogen until the dissolved oxygen value is below 1.0 mg / L before filling. (2) When filling with nitrogen, it is necessary to fill with nitrogen before and after filling.

[0081] The above samples were placed under high temperature conditions of 60℃±2℃, and samples were taken on 0 day and 30 day respectively to test properties, pH value, related substances and content. On 0 day, headspace residual oxygen detection was added. The test results are shown in Table 4b.

[0082] Table 4b Test results

[0083]

[0084] The test results show that for the samples with liquid-filled nitrogen and no nitrogen filling, and the samples with liquid-filled nitrogen and no nitrogen filling: after 30 days at high temperature, the impurity P0Z5 increased significantly and exceeded the quality standard limit (0.5%), the properties changed, and the other test indicators showed no obvious changes; for the samples with liquid-filled nitrogen and no nitrogen filling, and the samples with liquid-filled nitrogen and no nitrogen filling, the impurity P0Z5 increased slightly after 30 days at high temperature and the growth trend was consistent.

[0085] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementations and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, which all fall within the scope of protection of the present application.

Claims

1. A nalbuphine hydrochloride injection, characterized in that: Each unit of injection contains the following ingredients: 5-20 mg nalbuphine hydrochloride, 1.5-7.5 mg sodium chloride, buffer mixture, and water for injection; the pH value of the injection is 3.0-4.0; the buffer mixture contains citric acid and sodium citrate; the mass ratio of citric acid to sodium citrate is 1:0.55-0.9; the mass ratio of nalbuphine hydrochloride: citric acid + sodium citrate is 1:0.35-0.

75.

2. The injection according to claim 1, characterized in that: The mass ratio of nalbuphine hydrochloride: citric acid + sodium citrate is 1:0.45-0.

55.

3. The injection according to claim 1, characterized in that: Each unit of injection contains the following ingredients: 10-20 mg nalbuphine hydrochloride, 2-7 mg sodium chloride, citric acid, sodium citrate, and water for injection; wherein the mass ratio of citric acid to sodium citrate is 1:0.55-0.

9.

4. The injection according to claim 1, characterized in that: The injection also contains a chelating agent, which is sodium calcium edetate.

5. The injection according to claim 4, characterized in that: The mass ratio of citric acid+sodium citrate:complexing agent in the buffer mixture is 1:0.005-0.

015.

6. The injection according to claim 5, characterized in that: Each unit of injection contains the following ingredients: 10-20 mg nalbuphine hydrochloride, 2-7 mg sodium chloride, citric acid, sodium citrate, calcium sodium edetate, and water for injection; among them, the mass ratio of citric acid and sodium citrate is 1:0.55-0.9; the mass ratio of nalbuphine hydrochloride: citric acid + sodium citrate is 1:0.35-0.75; the mass ratio of citric acid + sodium citrate: chelating agent is 1:0.005-0.

015.

7. A method for preparing the nalbuphine hydrochloride injection according to any one of claims 1 to 6, comprising the following steps: Step a: Add water for injection into the liquid preparation tank, adjust the water temperature, and fill with nitrogen; Step b: adding the prescribed amount of auxiliary materials to the liquid preparation tank, stirring until the auxiliary materials are completely dissolved, and then continuing to add the prescribed amount of nalbuphine hydrochloride, stirring until the raw materials are completely dissolved; lowering the temperature of the liquid medicine, filtering and sterilizing; Step c: After the ampoule is cleaned, sterilized and dried, it is sealed; nitrogen is filled before and after sealing; Step d: Sterilization and packaging.

8. The preparation method according to claim 7, characterized in that: In step a, the water temperature is adjusted to 40-60°C.

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