Nalloxone hydrochloride injection and preparation method thereof

Abstract

The invention belongs to the technical field of pharmacy, and particularly relates to a naloxone hydrochloride injection and a preparation method thereof. The injection takes water as a solvent and comprises the following components: 1 mg / mL of naloxone hydrochloride, 0.01 mg / mL to 0.05 mg / mL of polyacrylamide, 6 mg / mL to 10 mg / mL of sodium chloride and 0.02 mg / mL to 0.05 mg / mL of sodium thiosulfate. The polyacrylamide in the injection can be combined with naloxone hydrochloride through a chemical bond or a physical effect, so that the interaction between molecules is enhanced, the thermal stability of drug molecules is improved, meanwhile, a stable compound can be formed, and direct exposure of the drug molecules is reduced, so that the degradation rate of the drug molecules at high temperature is reduced; the sodium thiosulfate can form a stable complex with metal ions to remove free radicals in a solution and prevent the free radicals from attacking phenolic groups in naloxone molecules, so that oxidation reaction is reduced, and the product can tolerate an end sterilization process.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceuticals, and in particular relates to a naloxone hydrochloride injection and a preparation method thereof. Background Art

[0002] Naloxone hydrochloride is an opioid antagonist and a synthetic analog of oxymorphone. This product is an opioid receptor antagonist and has almost no pharmacological activity itself, but it can competitively antagonize various opioid receptors and has a strong affinity for μ receptors. However, naloxone hydrochloride is prone to oxidative degradation in aqueous solution. The naloxone hydrochloride molecule contains a phenolic group (-OH), which is easily oxidized in an aerobic environment, resulting in drug degradation and reduced efficacy. The terminal sterilization process is a necessary step in the production of injections, but high temperature will accelerate the oxidation reaction and further reduce the stability of the drug. Therefore, how to maintain its sterilization stability is a key issue. Although adjusting the pH value of the injection to an acidic range (such as 3.0-4.0) can improve the stability of naloxone hydrochloride, it is difficult to completely solve the oxidation problem by pH adjustment alone. Although traditional antioxidants (such as ascorbic acid and sodium bisulfite) can reduce oxidation reactions, they may not be sufficient to completely protect the drug under high-temperature sterilization conditions. In view of this, providing a naloxone hydrochloride injection with good stability is a technical problem that needs to be solved urgently. Summary of the invention

[0003] The object of the present invention is to provide a naloxone hydrochloride injection and a preparation method thereof, so as to comprehensively improve the stability of the naloxone hydrochloride injection.

[0004] The present invention provides a naloxone hydrochloride injection, which uses water as a solvent and comprises the following components: 1 mg / mL naloxone hydrochloride, 0.01-0.05 mg / mL polyacrylamide, 6-10 mg / mL sodium chloride, and 0.02-0.05 mg / mL sodium thiosulfate.

[0005] Preferably, the injection uses water as solvent and includes the following components: naloxone hydrochloride 1 mg / mL, polyacrylamide 0.05 mg / mL, sodium chloride 8.4 mg / mL, and sodium thiosulfate 0.035 mg / mL.

[0006] The present invention also provides a method for preparing the injection described in the above technical solution, which comprises the following steps: mixing naloxone hydrochloride with 1-5 w / v% polyacrylamide solution, stirring and reacting at 30° C.-40° C. for 2-4 hours to obtain a modified naloxone hydrochloride solution; dissolving the modified naloxone hydrochloride solution, sodium chloride and sodium thiosulfate in water under nitrogen filling conditions, adjusting the pH value to 3.0-4.0, stirring evenly after constant volume, filtering, sterilizing and filling.

[0007] Preferably, the nitrogen filling level is dissolved oxygen ≤ 0.5 mg / L.

[0008] Preferably, the stirring is carried out at a frequency of 45 Hz ± 1 Hz and a circulation frequency of 30 Hz ± 2 Hz for 5 - 10 min.

[0009] Preferably, the filter element used for filtration is a PES filter element.

[0010] Preferably, the sterilization condition is moist heat sterilization at 121 °C for 8 - 30 min.

[0011] Preferably, the sterilization condition is: moist heat sterilization at 121 °C for 12 min.

[0012] Preferably, the filling specification is 2.15 mL - 2.25 mL per bottle.

[0013] Advantages of the present invention: During the production process of injection products, trace amounts of metal ions and oxygen may be introduced by raw materials, auxiliary materials, packaging materials and production processes. Under high-temperature conditions, catalyzed by metal ions and oxidized by oxygen, the degradation of the product is accelerated under the dual action, making it unable to withstand the terminal sterilization process. Polyacrylamide in the injection of the present invention can combine with naloxone hydrochloride through chemical bonds or physical interactions, enhance the intermolecular interactions, improve the thermal stability of drug molecules, and at the same time can form stable complexes, reducing the direct exposure of drug molecules, thereby reducing their degradation rate at high temperatures; sodium thiosulfate can form stable complexes with metal ions, and then scavenge free radicals in the solution, preventing free radicals from attacking the phenolic group in the naloxone molecule, thereby reducing the occurrence of oxidation reactions, enabling the product to withstand the terminal sterilization process.

[0014] The modification of polyacrylamide can provide a protective shell for naloxone hydrochloride, making it more stable in a complex physiological environment. This protective effect can reduce the degradation of the drug during storage and transportation, and extend the shelf life of the drug. In addition, in the in-vivo environment, the modified naloxone can better resist the degradation by enzymes, thereby improving the bioavailability of the drug.

[0015] The present invention comprehensively considers factors such as oxidation protection, metal ion complexation and high-temperature sterilization tolerance, and comprehensively improves the stability of naloxone hydrochloride injection by adding specific antioxidants (such as sodium thiosulfate), adjusting the pH value, controlling the dissolved oxygen level and optimizing the sterilization process. Specific embodiments

[0016] In order to further illustrate the present invention, the following describes in detail a naloxone hydrochloride injection and its preparation method provided by the present invention in combination with examples, but they cannot be construed as limiting the protection scope of the present invention.

[0017] In the embodiments of the present invention, a commercially available naloxone hydrochloride injection was used as a reference preparation for experiments.

[0018] Test Example 1 Naloxone hydrochloride was mixed with a 5 w / v% polyacrylamide solution and stirred at 40 °C for 2 h to obtain a naloxone hydrochloride modified solution; under a nitrogen atmosphere, the naloxone hydrochloride modified solution, sodium chloride, and sodium thiosulfate were dissolved in water, the pH value was adjusted to 3.0 - 4.0, the volume was fixed, and the mixture was stirred evenly. After filtration, the product was divided into 20220218 - 5, 20220218 - 6, 20220218 - 7, 20220218 - 8, and 20220218 - 9, and sterilized under the conditions shown in Table 1, and then its properties were detected to screen out the optimal sterilization conditions. The results are shown in Table 1 and Table 2.

[0019] Table 1 Results of Screening Sterilization Conditions

[0020] Table 2 Comparison of the Properties of the Product Sterilized for 12 min and the Reference Preparation

[0021] Compared with the non - sterilized samples, the properties of each sample after sterilization did not change significantly, the related substances and pH value increased slightly, but neither exceeded the limit. There were no significant differences in the related substances, properties, and pH value of the samples under different sterilization conditions; under high - temperature conditions, after sterilization (121 °C, 12 min), the properties, pH value, and related substances of the generic preparation did not change significantly compared with day 0, and the total impurities of the reference preparation exceeded the limit after 30 days at high temperature. After 10 days of light exposure, the related substances of both the generic preparation and the reference preparation increased significantly.

[0022] Combining the above content, the sterilization condition of the injection in the embodiments of the present invention is moist heat sterilization, and the sterilization parameters are 121 °C for 12 min.

[0023] Note: Through the analysis of the impurity degradation principle, the degradation principles of impurity A and impurity E are as follows: Catalyzed by metal ions to oxidize oxygen, the N - allyl group generates a carbon - nitrogen double - bond positive ion, and then the allyl group is removed to generate impurity A:

[0024] Catalyzed by metal ions and oxygen, the phenolic hydroxyl group is converted into a keto form to form a carbon positive ion, and two molecules of carbon positive ions polymerize, and then the keto form is converted back into a phenol to generate impurity E.

[0025]

[0026] Test Example 2 Confirm the functions of each excipient in the preparation according to the prescription composition, prepare the liquid medicine, and compare each prescription with the full-prescription preparation by reducing one excipient in each prescription to conduct the compatibility study of raw materials and excipients. The specific formula is shown in Table 3.

[0027] The results of the compatibility test of raw materials and excipients are shown in Table 4 and Table 5.

[0028] Table 3 Compatibility formula table of raw materials and excipients

[0029] Table 4 Results of the compatibility test of raw materials and excipients

[0030] Table 5 Results of the compatibility test of raw materials and excipients

[0031] As can be seen from Table 4 and Table 5, for the aqueous solution of the raw material medicine (20220218-1), under high temperature and light conditions, the appearance has no obvious change, but the related substances have increased significantly. After 30 days at high temperature, the impurity E and impurity A have increased slightly, and the individual impurities and total impurities exceed the limit; under light conditions, unknown impurities are generated, and the individual impurities and total impurities far exceed the limit. The stability of the aqueous solution of the raw material of this product is poor, and it is unstable under both high temperature and light.

[0032] Compared with the prescription without sodium thiosulfate in the original reference preparation, the addition of sodium thiosulfate increases the stability of the solution under high temperature conditions, and there is no obvious change in each impurity under high temperature conditions. After the 20220218-3 batch was sterilized, the impurity A, impurity E and total impurities on the 0th day had exceeded the limit, so the prescription of the reference preparation could not withstand high temperature sterilization.

[0033] Compared with the prescription without polyacrylamide, the addition of polyacrylamide increases the stability of the solution under high temperature conditions, and there is no obvious change in each impurity under high temperature conditions.

[0034] Compared with the prescription without sodium thiosulfate, the addition of sodium thiosulfate increases the stability of the solution under high temperature conditions, and there is no obvious change in each impurity under high temperature conditions.

[0035] Compared with the prescription without sodium chloride, the addition of sodium chloride as an osmotic pressure regulator has no obvious effect on the stability and appearance of the preparation.

[0036] Compared with the prescription without nitrogen, the stability of the prescription with nitrogen is not better than that of the group without nitrogen filling. Referring to the nitrogen filling in the reference preparation solution, the preparation of the present invention needs to be protected by nitrogen filling.

[0037] Based on the above analysis, it can be seen that the addition of sodium thiosulfate increases the stability of the preparation under high-temperature conditions, enabling this product to withstand high temperatures. The related substances of the preparation sample increase significantly under light conditions. Considering the instructions of the reference preparation, this product should be stored in the dark. Therefore, attention should be paid to avoiding light during subsequent storage.

[0038] Test Example 3 Prepare naloxone hydrochloride injection in three batches (batch numbers: 20231101, 20231102, 20231103) in the following manner: Mix naloxone hydrochloride with 5 w / v% polyacrylamide solution and stir at 40 °C for 2 h to obtain a modified solution of naloxone hydrochloride. Under nitrogen filling conditions, dissolve the modified solution of naloxone hydrochloride, sodium chloride, and sodium thiosulfate in water, adjust the pH value to 3.0 - 4.0, make up the volume and stir evenly, filter, sterilize, and fill into vials of 2.15 mL - 2.25 mL per vial to obtain naloxone hydrochloride injection. The final concentrations of each substance are: naloxone hydrochloride 1 mg / mL, polyacrylamide 0.05 mg / mL, sodium chloride 8.4 mg / mL, and sodium thiosulfate 0.035 mg / mL.

[0039] Place the prepared naloxone hydrochloride injection (specification: 2 mL:2 mg, batch numbers: 20231101, 20231102, 20231103) under accelerated test conditions (temperature 40 °C ± 2 °C, relative humidity 75% ± 5%) and long-term test II conditions (temperature 30 °C ± 2 °C, relative humidity 65% ± 5%) for 6 months, and detect V, Co, Ni, As, Cd, Hg, Pb, Li, Cr, Mo, Cu, Sn, Sb, Ba, Si, B, and Al by ICP-MS. The results show that the detected amounts of each element in the preparation at 0 day, after 6 months of accelerated test, and after 6 months of long-term test II do not exceed 30% of the AET value.

[0040] As can be seen from the above examples, the naloxone hydrochloride injection provided by the present invention has good stability.

[0041] Although the above examples have described the present invention in detail, they are only a part of the embodiments of the present invention, not all embodiments. People can also obtain other embodiments based on these embodiments without creative efforts, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A naloxone hydrochloride injection, characterized in that, The injection uses water as a solvent and comprises the following components: naloxone hydrochloride 1 mg / mL, polyacrylamide 0.01 - 0.05 mg / mL, sodium chloride 6 - 10 mg / mL, and sodium thiosulfate 0.02 - 0.05 mg / mL.

2. The injection according to claim 1, characterized in that, The injection uses water as a solvent and comprises the following components: naloxone hydrochloride 1 mg / mL, polyacrylamide 0.05 mg / mL, sodium chloride 8.4 mg / mL, and sodium thiosulfate 0.035 mg / mL.

3. The preparation method of the injection according to claim 1, characterized in that, The method comprises the following steps: Mix naloxone hydrochloride with a 1 - 5 w / v% polyacrylamide solution, and stir and react at 30°C - 40°C for 2 - 4 h to obtain a modified naloxone hydrochloride solution; Under nitrogen filling conditions, dissolve the modified naloxone hydrochloride solution, sodium chloride, and sodium thiosulfate in water, adjust the pH value to 3.0 - 4.0, make up the volume and stir evenly, filter, sterilize, and then fill.

4. The method according to claim 3, wherein The nitrogen filling level is that the dissolved oxygen ≤ 0.5 mg / L.

5. The method according to claim 3, wherein The stirring is: stir at a frequency of 45 Hz ± 1 Hz and a circulation frequency of 30 Hz ± 2 Hz for 5 - 10 min.

6. The method according to claim 3, characterized in that, The filter element used for filtration is a PES filter element.

7. The method according to claim 3, wherein The sterilization conditions are moist heat sterilization at 121°C for 8 - 30 min.

8. The method according to claim 7, wherein The sterilization conditions are: moist heat sterilization at 121°C for 12 min.

9. The method according to claim 3, wherein The filling specification is 2.15 mL - 2.25 mL / bottle.

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