Naloxone hydrochloride injection and preparation method thereof

Abstract

The invention discloses a naloxone hydrochloride injection, which is composed of the following components: naloxone hydrochloride, calcium sodium edetate and injection excipients. The formula of the invention adds calcium sodium edetate, and after high-temperature terminal sterilization, the total impurity content can be as low as 0.11%, and even in an accelerated test, the total impurity content is less than 0.25%, has good thermal stability, significantly improves the safety of the injection, and is conducive to long-term storage.

Description

Technical Field

[0001] The present invention belongs to the pharmaceutical field, and more specifically, relates to a naloxone hydrochloride injection and a preparation method thereof. Background Art

[0002] Naloxone hydrochloride, chemical name: 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride dihydrate, molecular formula: C 19 H 21 NO 4 •HCl, molecular weight is 399.87. Naloxone hydrochloride is white crystal or crystalline powder, odorless, easily soluble in water, soluble in methanol, and almost insoluble in chloroform or ether.

[0003] Since naloxone hydrochloride has poor heat resistance in aqueous solution, the quality indicators of the injection such as clarity, color, related substances and content are easy to fail to meet the standards after high-temperature sterilization or long-term storage, which is not conducive to high-temperature sterilization or long-term storage. In the face of this defect, manufacturers currently choose to develop non-liquid preparations such as naloxone hydrochloride powder injection to avoid the problem of heat resistance.

[0004] CN103877016A discloses a naloxone hydrochloride injection pharmaceutical composition and a preparation method thereof, in which a certain amount of malic acid is added to the prescription to improve the stability of naloxone hydrochloride in aqueous solution, but the sterilization process is 100°C circulating steam sterilization for 30 minutes or 45 minutes, and does not involve terminal sterilization above 120°C and thermal stability research. If the sterilization temperature is too low, the sterilization requirements may not be met, thereby affecting the quality of the injection.

[0005] CN110269837A provides a naloxone hydrochloride injection and a preparation method thereof, wherein disodium ethylenediaminetetraacetate is added to the prescription, which can improve the thermal stability of the injection after sterilization at 121°C for 15 minutes. According to its embodiment, the amount of disodium ethylenediaminetetraacetate added is 0.001 mg / mL, the pH of the solution is 4.5, and the total impurity content in the solution is the lowest at 0.25% after terminal sterilization of the injection. However, after an accelerated test at 40°C for 6 months, the total impurity content reached 0.59%, and the stability needs to be strengthened. Summary of the invention

[0006] The object of the present invention is to overcome at least one disadvantage of the prior art and to provide a naloxone hydrochloride injection and a preparation method thereof.

[0007] The technical solution adopted by the present invention is:

[0008] In a first aspect, the present invention provides a naloxone hydrochloride injection, which is composed of the following components: naloxone hydrochloride, calcium sodium edetate and excipients.

[0009] In some examples, the content of calcium sodium edetate is 0.001-0.1 mg / mL.

[0010] In some examples, the naloxone hydrochloride content is 0.1-1 mg / mL.

[0011] In some examples, the pH of the injection solution is 3-4.

[0012] In some examples, the excipients include an isotonicity regulator, a pH regulator, and water for injection.

[0013] In some examples, the isotonicity regulator is selected from any one of sodium chloride and glucose, and the pH regulator is selected from any one of malic acid, fumaric acid, acetic acid, sodium acetate, citrate, tartaric acid, sodium hydroxide, concentrated ammonia solution, hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.

[0014] In a second aspect, the present invention provides a method for preparing naloxone hydrochloride injection, comprising the following steps:

[0015] 1) dissolving an isotonicity regulator and edetate calcium sodium in water for injection having a dissolved oxygen content of less than 3 ppm to obtain a stabilizer solution;

[0016] 2) adding naloxone hydrochloride to the stabilizer solution obtained in step 1) and stirring until completely dissolved, and then adding a pH adjuster to adjust the pH to 3-4 to obtain a naloxone hydrochloride solution;

[0017] 3) Filtering, filling and sterilizing the naloxone hydrochloride solution to obtain the naloxone hydrochloride injection.

[0018] In some examples, the concentration of the isotonicity adjusting agent added in step 1) is 5-10 mg / mL, and the concentration of the pH adjusting agent added in step 2) is 0.01-1 mol / L.

[0019] In some examples, the filter element used for filtering in step 3) is selected from any one of a 0.22 μm polyethersulfone filter element, a polyvinylidene fluoride filter element, a polypropylene filter element, and a polytetrafluoroethylene filter element.

[0020] In some examples, in step 3), the sterilization temperature is 121-126° C., the sterilization time is 12-15 minutes, and the standard sterilization time F0 value is ≥12 minutes.

[0021] The beneficial effects of the present invention are:

[0022] The invention adds calcium sodium edetate to the prescription. After terminal sterilization at 121° C., the total impurity content can be as low as 0.11%. Even in an accelerated test (60° C., 30 days), the total impurity content is lower than 0.25%. The invention has good thermal stability, improves the safety of the injection, and is conducive to long-term storage. DETAILED DESCRIPTION

[0023] In a first aspect, the present invention provides a naloxone hydrochloride injection, which is composed of the following components: naloxone hydrochloride, calcium sodium edetate and excipients.

[0024] In some examples, the content of calcium sodium edetate is 0.001-0.1 mg / mL, and its dosage can be adjusted accordingly according to the amount of naloxone hydrochloride.

[0025] In some examples, the naloxone hydrochloride content is 0.1-1 mg / mL.

[0026] In some examples, the pH of the injection is 3 to 4. This is more conducive to the stability of the injection.

[0027] In some examples, the excipients include an isotonicity regulator, a pH regulator, and water for injection.

[0028] The isotonicity adjusting agent can be any acceptable common isotonicity adjusting agent. In some examples, the isotonicity adjusting agent is selected from any one of sodium chloride and glucose.

[0029] The pH adjuster can be a pharmaceutically acceptable pH adjuster. In some examples, the pH adjuster is selected from any one of malic acid, fumaric acid, acetic acid, sodium acetate, citrate, tartaric acid, sodium hydroxide, concentrated ammonia solution, hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.

[0030] In a second aspect, the present invention provides a method for preparing naloxone hydrochloride injection, comprising the following steps:

[0031] 1) dissolving an isotonicity regulator and edetate calcium sodium in water for injection having a dissolved oxygen content of less than 3 ppm to obtain a stabilizer solution;

[0032] 2) adding naloxone hydrochloride to the stabilizer solution obtained in step 1) and stirring until completely dissolved, and then adding a pH adjuster to adjust the pH to 3-4 to obtain a naloxone hydrochloride solution;

[0033] 3) Filtering, filling and sterilizing the naloxone hydrochloride solution to obtain the naloxone hydrochloride injection.

[0034] In some examples, the concentration of the isotonicity adjusting agent added in step 1) is 5-10 mg / mL, and the concentration of the pH adjusting agent added in step 2) is 0.01-1 mol / L.

[0035] In some examples, the filter element used for filtering in step 3) is selected from any one of a 0.22 μm polyethersulfone filter element, a polyvinylidene fluoride filter element, a polypropylene filter element, and a polytetrafluoroethylene filter element.

[0036] Sterilization can be high temperature sterilization or filtration sterilization, preferably high temperature sterilization. In some examples, the sterilization temperature in step 3) is 121-126°C, the sterilization time is 12-15 minutes, and the standard sterilization time F0 value is ≥12 minutes.

[0037] The following disclosure provides many different embodiments or examples for implementing different solutions of the present invention.

[0038] Calcium sodium edetate and disodium edetate have very similar names and basically similar effects, but due to the presence of calcium ions in calcium sodium edetate, their effects are greatly different. The present invention aims to provide a new naloxone hydrochloride injection and a preparation method. Adding calcium sodium edetate to the prescription can not only greatly improve the thermal stability of the injection, but also improve its safety.

[0039] Example 1

[0040] 1. The formula of naloxone hydrochloride injection is shown in Table 1:

[0041] Table 1

[0042]

[0043] 2. Preparation method

[0044] Add 50% to 95% of the prescribed amount of water for injection, and introduce nitrogen into the liquid until the dissolved oxygen is less than 3 ppm; add the prescribed amount of sodium chloride and sodium calcium edetate in sequence, and stir until completely dissolved; add the prescribed amount of naloxone hydrochloride, and stir until completely dissolved; adjust the pH to 3 to 4; add water for injection to the prescribed amount, and stir evenly to obtain naloxone hydrochloride injection.

[0045] 3. The performance test results of naloxone hydrochloride injection in experimental groups 1 to 5 are shown in Table 2.

[0046] Table 2

[0047]

[0048] From the above data, we can see that in the experimental group 1 without calcium sodium edetate, the total impurity content before sterilization was 0.18%, and reached 0.4% after terminal sterilization (121℃, 12min), and even reached 1.19% after accelerated test (60℃, 30d). However, after adding calcium sodium edetate, the total impurity content before and after terminal sterilization did not change much, all less than 0.15%, and even after accelerated test (60℃, 30d), it did not exceed 0.25%.

[0049] The difference between the present invention and CN110269837A is that disodium edetate is added to the prescription of CN110269837A, the addition amount of disodium edetate is 0.001 mg / mL, the pH value of the solution is 4.5, and the total impurity content in the solution after terminal sterilization of the injection is as low as 0.25%, and the total impurity content reaches 0.59% in the accelerated test at 40°C for 6 months, which are all higher than those of experimental groups 2 to 5 in which sodium calcium edetate is added in the present invention.

[0050] It can be seen that the addition of calcium sodium edetate can greatly improve the thermal stability of the injection, and the thermal stability is best when the added amount is 0.075 mg / mL.

[0051] Example 2

[0052] 1. The formula of naloxone hydrochloride injection is shown in Table 3:

[0053] Table 3

[0054]

[0055] 2. Preparation method

[0056] The preparation method of this embodiment is consistent with that of embodiment 1.

[0057] 3. The performance test results of naloxone hydrochloride injection in experimental groups 6 to 10 are shown in Table 4.

[0058] Table 4

[0059]

[0060] In order to determine the effect of pH on the thermal stability of injection, the performance of injections with terminal sterilization of pH 3, 3.5, 4, 5, and 6.5 was tested after accelerated testing (60°C). From the above data, it can be seen that when the pH is 3-4, the total impurities are less than 0.2% after 30 days of acceleration. When the pH is 5, the injection pH is increased to 5.5 after 30 days of acceleration, and the total impurities are 0.49%. The impurity content is high, but it also meets the requirements of internal control impurities (<0.8%). However, when the pH is 6.5, the pH is accelerated for 30 days, the pH is 6.8, and the total impurities are 3.51%, which does not meet the requirements. It can be seen that pH has a greater effect on the thermal stability of the injection, and the pH is between 3 and 4, which has good stability.

[0061] The above is a further detailed description of the present invention, which should not be regarded as a limitation on the specific implementation of the present invention. For ordinary technicians in the technical field to which the present invention belongs, simple deduction or replacement without departing from the concept of the present invention is within the protection scope of the present invention.

Claims

1. A naloxone hydrochloride injection, It is characterized in that The naloxone hydrochloride injection is composed of the following components: naloxone hydrochloride, calcium sodium edetate and auxiliary materials. The pH of the injection is 3-4, and the auxiliary materials are composed of an isotonicity regulator, a pH regulator and water for injection.

2. The injection according to claim 1, It is characterized in that The content of calcium sodium edetate is 0.001-0.1 mg / mL.

3. The injection according to claim 1, It is characterized in that The naloxone hydrochloride content is 0.1-1 mg / mL.

4. The injection according to claim 1, It is characterized in that The isotonicity regulator is selected from any one of sodium chloride and glucose, and the pH regulator is selected from any one of malic acid, fumaric acid, acetic acid, sodium acetate, citrate, tartaric acid, sodium hydroxide, concentrated ammonia solution, hydrochloric acid, sulfuric acid, phosphoric acid, lactic acid, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.

5. The method for preparing naloxone hydrochloride injection according to claims 1 to 4, It is characterized in that The following steps are involved: Dissolving an isotonicity regulator and calcium sodium edetate in water for injection having a dissolved oxygen content of less than 3 ppm to obtain a stabilizer solution; Adding naloxone hydrochloride to the stabilizer solution obtained in step 1) and stirring until completely dissolved, then adding a pH adjuster to adjust the pH to 3-4 to obtain a naloxone hydrochloride solution; The naloxone hydrochloride solution is filtered, filled and sterilized to obtain the naloxone hydrochloride injection.

6. The preparation method according to claim 5, It is characterized in that The concentration of the isotonicity adjusting agent added in step 1) is 5-10 mg / mL, and the concentration of the pH adjusting agent added in step 2) is 0.01-1 mol / L.

7. The preparation method according to claim 5, It is characterized in that The filter element used for filtering in step 3) is selected from any one of a 0.22 μm polyethersulfone filter element, a polyvinylidene fluoride filter element, a polypropylene filter element, and a polytetrafluoroethylene filter element.

8. The preparation method according to claim 5, It is characterized in that In step 3), the sterilization temperature is 121-126 °C, the sterilization time is 12-15 minutes, and the standard sterilization time F 0 value ≥ 12 minutes.

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