Methylnaltrexone bromide injection tolerant to terminal sterilization and preparation method of methylnaltrexone bromide injection

Abstract

The invention discloses a methyhaaltrexone bromide injection tolerant to terminal sterilization and a preparation method thereof, and belongs to the technical field of preparation of pharmaceutical preparations. According to the method, a terminal sterilization production process is adopted, and the sterility probability can be theoretically smaller than or equal to 10 <-6 > and far exceeds the sterility probability in the prior art. Therefore, through the preparation method, the sterility assurance level of the preparation can be improved, so that the clinical use safety is ensured, the production cost and the environmental control risk can be reduced, and the supervision requirements are met. And the potential safety hazard that the highest sterile level cannot be ensured when the medicines on the market are subjected to a filtering and sterilizing process is solved. In the preparation process of the injection finished product, specified impurity limits are clearly defined, known impurities do not exceed 0.15%, unknown impurities do not exceed 0.1%, total impurities do not exceed 1.0%, the product quality of the preparation is controllable after the preparation is accelerated for 6 months and 24 months, and clinical test data prove that the injection is safe and effective.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation of pharmaceutical preparations, and particularly relates to a methylnaltrexone bromide injection resistant to terminal sterilization and a preparation method thereof. Background Art

[0002] Methylnaltrexone bromide is a μ-opioid receptor antagonist, which is used to treat opioid-induced constipation (OIC) when other laxatives are ineffective. Methylnaltrexone bromide injection was jointly researched and developed by Wyeth, a subsidiary of Wyeth Pharmaceuticals in the United States, and Progenics Pharmaceuticals. In April 2008, Health Canada, the US FDA, and the EU EMA respectively approved the listing of methylnaltrexone bromide injection (Relistor). The administration method is subcutaneous injection. The FDA Orange Book shows that Relistor has the status of RLD and RS. Currently, methylnaltrexone bromide injection has not been listed in Japan and China.

[0003] The methylnaltrexone bromide raw material exists in a solid form with stable quality, but when it exists in a solution form, it is unstable to acids, alkalis, oxidation, light, high temperature, etc. The original preparation patent CN101405031B discloses a methylnaltrexone bromide injection composition, and the preparation process is a sterile filtration process; the domestic patent CN102525911B discloses a methylnaltrexone bromide injection and a preparation method thereof. The patent protects the preparation composition and the preparation method. Activated carbon is added during the preparation process, which does not meet the current regulatory requirements for the production of injections. Moreover, the patent does not stipulate the impurity limit of the produced product and there is no clinical data, resulting in a quality control blind spot. Summary of the Invention

[0004] In view of the technical problems in the prior art that the sterile filtration process is adopted, which relies on the filter membrane to intercept microorganisms, there are risks of filter membrane integrity and the possibility of microbial penetration, and the sterility assurance level is usually ≤10 -3 , and it is impossible to achieve a higher sterility level; and the high impurity content of the products caused by the preparation processes of the prior art, and the product quality cannot be effectively controlled. The first object of the present invention is to provide a preparation method of a methylnaltrexone bromide injection resistant to terminal sterilization. In this method, by adopting a terminal sterilization production process, theoretically, the sterility probability can be ≤10 -6 , far exceeding the sterility probability in the prior art. Therefore, through this preparation method, the sterility assurance level of the preparation can be improved, thereby ensuring the safety of clinical use, and reducing the production cost and environmental control risk.

[0005] The second object of the present invention is to provide a naloxone methanesulfonate injection resistant to terminal sterilization. The limits of each impurity clearly specified during the preparation of the finished injection are as follows: the known impurities shall not exceed 0.15%, the unknown impurities shall not exceed 0.1%, and the total impurities shall not exceed 1.0%. Moreover, the product quality of the preparation is controllable after 6 months of accelerated testing and 24 months of long-term testing, and its safety and effectiveness have been proven through clinical trial data.

[0006] The present invention is achieved through the following technical solutions:

[0007] A preparation method of a naloxone methanesulfonate injection resistant to terminal sterilization, comprising the following steps:

[0008] S1. Weigh 75% by volume of the injection water according to the prescription, then successively add the metal ion chelating agent, osmotic pressure regulator, and stabilizer according to the prescription and dissolve them. Then add the naloxone methanesulfonate raw material and stir until dissolved to obtain solution A;

[0009] S2. Select an inorganic acid to adjust the pH value of solution A to 3.10 - 3.35, then make up the injection water to the full volume, and filter it with a 0.22 μm polyethersulfone filter membrane to obtain solution B;

[0010] S3. Fill solution B into the container according to the target filling volume. After filling, fill the headspace with nitrogen, control the residual oxygen content ≤ 4.0%, seal it by melting, and sterilize it at 121 °C for 20 min to obtain the product.

[0011] The design principle of the preparation method of the naloxone methanesulfonate injection resistant to terminal sterilization is as follows: According to the "Guidelines for the Research and Verification of Sterilization and Aseptic Processes for Chemical Injectables (Trial)" issued by the NMPA, "To ensure the sterility assurance level of injectables, the overkill method is preferred for injectables, that is, the sterilization process with F0 ≥ 12". Therefore, the terminal sterilization process is preferred during the development of this project, and it is sterilized at 121 °C for 20 min.

[0012] Regarding the requirement to adjust the pH value, this product can meet the proposed standard requirements within the range of pH 3.0 - 4.0. As the pH increases, the growth of mono-hydroxyquinone and di-hydroxyquinone is obvious, and the lower the pH of the injection, the stronger the irritation during injection. Therefore, 3.10 - 3.35 is preferred.

[0013] Regarding the sterilization temperature, generally, the overkill temperature is 121 °C - 124 °C, which can meet the sterility requirements. Higher temperatures (above 121 - 124 °C) are not necessary and may cause instability in product quality, while lower temperatures may not achieve the sterilization effect.

[0014] Preferably, the mass of each raw and auxiliary material in the prescription per 1000 ml of the liquid medicine batch is as follows:

[0015] 0.36 g of metal ion chelator, 6.5 g of osmotic pressure regulator, 0.20 g of stabilizer and 20 g of methylnaltrexone bromide.

[0016] Preferably, the metal ion chelator is disodium edetate or calcium disodium edetate;

[0017] The osmotic pressure regulator is any one of sodium chloride, mannitol and potassium chloride;

[0018] The stabilizer is glycine or its hydrochloride derivative;

[0019] The inorganic acid is 0.1 M hydrochloric acid or sulfuric acid.

[0020] Preferably, the metal ion chelator is disodium edetate;

[0021] The osmotic pressure regulator is sodium chloride;

[0022] The stabilizer is glycine;

[0023] The inorganic acid is 0.1 M hydrochloric acid.

[0024] A methylnaltrexone bromide injection resistant to terminal sterilization, and the injection is obtained by the preparation method as described above.

[0025] Compared with the prior art, the present invention has at least the following technical effects:

[0026] The present invention provides a preparation method of a methylnaltrexone bromide injection resistant to terminal sterilization. In this method, by adopting the production process of terminal sterilization, the theoretical probability of sterility can be ≤ 10 -6 , far exceeding the probability of sterility in the prior art. Therefore, through this preparation method, the sterility assurance level of the preparation can be improved, thereby ensuring the safety of clinical use, and the production cost and environmental control risk can be reduced. For the methylnaltrexone bromide injection resistant to terminal sterilization, the limits of each impurity clearly specified during the preparation process of the finished product are that the known impurities shall not exceed 0.15%, the unknown impurities shall not exceed 0.1%, and the total impurities shall not exceed 1.0%. Moreover, the product quality of the preparation is controllable after 6 months of accelerated testing and 24 months of long-term testing, and its safety and effectiveness have been proven by clinical trial data.

[0027] The technical solution provided in this application has been verified by continuous production of 3 batches, and the obtained product quality is uniform and meets the standard requirements, further ensuring the stability and quality of the product. Description of the Drawings

[0028] Figure 1 It is the chromatogram of related substances of the terminal sterilization preparation;

[0029] Figure 2 It is the chromatogram of mono-hydroxyquinone of the terminal sterilization preparation;

[0030] Figure 3 Chromatogram of dihydroxyquinone for terminally sterilized preparation;

[0031] Figure 4 Chromatogram of related impurity A for terminally sterilized preparation;

[0032] Figure 5 Chromatogram of content for terminally sterilized preparation. Detailed implementation mode

[0033] The embodiments of the present invention will be described in detail below in conjunction with the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. The specific conditions not specified in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments not specified by the manufacturer can be obtained as conventional products through commercial purchase.

[0034] Example 1:

[0035] Prescription composition:

[0036] Raw and auxiliary materials Single-dose prescription (mg) Ratio (w / v, %) Dosage of 1000 ml liquid medicine (g) Methylnaltrexone bromide 12 2 20 Disodium edetate 0.216 0.036 0.36 Sodium chloride 3.9 0.02 6.5 Glycine 0.12 0.65 0.20 0.1 M hydrochloric acid Appropriate amount Appropriate amount Appropriate amount Add water for injection to 0.6ml 0.6ml 1000ml

[0037] Preparation process:

[0038] A preparation method of naltrexone bromide injection resistant to terminal sterilization includes the following steps:

[0039] S1. Weigh 75% by volume of the injection water in the prescription amount, then successively add the prescription amounts of disodium edetate, sodium chloride, and glycine and dissolve them, and then add the naltrexone bromide raw material and stir until dissolved to obtain solution A;

[0040] S2. Select hydrochloric acid to adjust the pH value of solution A, supplement the injection water to the full volume, filter, and obtain solution B;

[0041] S3. Fill solution B into the container according to the target filling volume, fill the headspace of the filled container with an inert gas, control the residual oxygen content, seal and sterilize to obtain the product.

[0042] The mass of each raw and auxiliary material in the prescription amount of every 1000 ml of liquid medicine batch is:

[0043] Disodium edetate 0.36 g, sodium chloride 6.5 g, glycine 0.20 g, and naltrexone bromide 20 g.

[0044] In S2, the molar concentration of hydrochloric acid is 0.1 M.

[0045] In S2, the adjusted pH value is 3.10 - 3.35.

[0046] In S2, filtration is carried out using a 0.22 μm polyethersulfone filter membrane.

[0047] In S3, the inert gas is nitrogen.

[0048] In S3, the residual oxygen content is controlled to be ≤ 4.0%.

[0049] In S3, sterilization is carried out at 121 °C for 20 min.

[0050] Example 2:

[0051] Based on Example 1, step S3 is modified as follows: Solution B is filled into the container according to the target filling volume, the headspace of the filled container is filled with an inert gas, the residual oxygen content is controlled, and then it is heat-sealed to obtain the product. The rest of the content is the same as in Example 1.

[0052] Example 3:

[0053] Based on Example 1, step S2 is modified to select 0.1 M hydrochloric acid to adjust the pH to 3.0. The rest of the content is the same as in Example 1.

[0054] Example 4:

[0055] Based on Example 1, step S2 is modified to select 0.1 M hydrochloric acid to adjust the pH to 3.4. The rest of the content is the same as in Example 1.

[0056] Example 5:

[0057] Based on Example 1, step S2 is modified to select 0.1 M hydrochloric acid to adjust the pH to 3.6. The rest of the content is the same as in Example 1.

[0058] Example 6:

[0059] Based on Example 1, step S2 is modified to select 0.1 M hydrochloric acid to adjust the pH to 4.0. The rest of the content is the same as in Example 1.

[0060] Comparative Example 1:

[0061] Control preparation

[0062] Prescription composition

[0063]

[0064]

[0065] Preparation process:

[0066] A preparation method of a filtered and sterilized bromonatriptan methylbromide injection, comprising the following steps:

[0067] S1. Weigh a certain proportion of the injection water according to the prescription. Then, add calcium disodium edetate, sodium chloride, and glycine hydrochloride in the prescription amounts in sequence and dissolve them. After that, add the brominertrexone raw material and stir until dissolved to obtain Solution A.

[0068] S2. Select hydrochloric acid to adjust the pH value of Solution A to 3.5 ± 0.2. Then, make up the injection water to the full volume and filter to obtain Solution B.

[0069] S3. Fill Solution B into the containers according to the target filling volume. Fill the headspace of the filled containers with an inert gas, control the residual oxygen content at about 5%, and seal by fusion to obtain the product.

[0070] Experimental example:

[0071] Stability test

[0072] Experimental example 1:

[0073] As Figure 1 shown, it is the chromatogram of related substances of the terminally sterilized preparation;

[0074] As Figure 2 shown, it is the chromatogram of mono-hydroxyquinone of the terminally sterilized preparation;

[0075] As Figure 3 shown, it is the chromatogram of di-hydroxyquinone of the terminally sterilized preparation;

[0076] As Figure 4 shown, it is the chromatogram of related impurity A of the terminally sterilized preparation;

[0077] As Figure 5 shown, it is the chromatogram of the content of the terminally sterilized preparation.

[0078] Take the samples of Examples 1 - 2 of the present invention and Comparative Example 1, place them under accelerated conditions (40°C ± 2°C, 75% RH ± 5%) for 3 and 6 months, and under long-term conditions (30°C ± 2°C, 65% RH ± 5%) for 12 and 24 months to investigate the stability of the preparation. Taking the key quality attributes of appearance, pH value, related substances, mono-hydroxyquinone, di-hydroxyquinone, related impurity A, and content as indicators, the research results are combined with Figure 1 - Figure 5 and Tables 1 - 3.

[0079] Table 1 Results of the stability test of the sample of Example 1

[0080]

[0081] Table 2 Results of the stability test of the sample of Example 2 (self-made product, filtration and sterilization process)

[0082]

[0083]

[0084] Table 3 Results of the stability test of the sample of Comparative Example 1 (control preparation)

[0085]

[0086] Experimental conclusion:

[0087] Combined with the research results Figure 1 - Figure 5 and Tables 1 to 3, it can be seen that for the samples prepared by the terminal sterilization process, the impurity level is relatively low and does not exceed that of the samples prepared by the filtration sterilization process. Moreover, the quality of the preparations sterilized terminally is controllable within 6 months of accelerated testing and 24 months of long-term testing. This shows that the formulation of the present invention is stable in quality under high-temperature conditions and can withstand the terminal sterilization process.

[0088] Experimental Example 2:

[0089] Take the samples of Examples 3 to 6 of the present invention, and place them under high temperature (60°C ± 2°C) and light (4500 Lx ± 500 Lx, total illuminance not less than 1.2×10 6 Lux·hr, near-ultraviolet energy not less than 200 W·hr / m 2 ) for 10 days to investigate the change of related substances, so as to judge the influence of different pH values on this preparation. The research results are shown in Table 4.

[0090] Table 3 Results of the stability test of samples with different pH values

[0091]

[0092] Experimental conclusion:

[0093] For the preparation of the present invention, within the range of pH 3.0 to 4.0, the quality of the preparation meets the proposed standard requirements on the 0th day. However, as the pH value increases, under high-temperature conditions, the degradation amplitude of dihydroxyquinone increases; under light conditions, the growth amplitude of monohydroxyquinone will increase.

[0094] Therefore, to ensure a lower impurity level of the product, it is determined that the pH of the preparation of the present invention is preferably adjusted to 3.10 to 3.35.

[0095] Finally, it should be noted that the above are only the preferred embodiments of the present invention and are not used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A preparation method of naloxone methobromide injection resistant to terminal sterilization, characterized in that, It includes the following steps: S1. Weigh 75% of the volume of water for injection in the prescription amount. Then, sequentially add the metal ion chelating agent, osmotic pressure regulator, and stabilizer in the prescription amount and dissolve them. After that, add the naloxone methobromide raw material and stir until it is dissolved to obtain Solution A; S2. Select an inorganic acid to adjust the pH value of Solution A to 3.10 - 3.

35. Then, make up the volume with water for injection to the full amount. Select a 0.22μm polyethersulfone filter membrane for filtration to obtain Solution B; S3. Fill Solution B into the container according to the target filling volume. After filling, fill the headspace with nitrogen, control the residual oxygen content ≤ 4.0%, seal it by melting, and sterilize it at 121°C for 20 minutes to obtain the product.

2. The preparation method of a bromonatriptyline injection resistant to terminal sterilization according to claim 1, characterized in that, The mass of each raw and auxiliary material in the prescription amount per 1000 ml of the liquid medicine batch is: 0.36 g of metal ion chelating agent, 6.5 g of osmotic pressure regulator, 0.20 g of stabilizer, and 20 g of naloxone methobromide.

3. The preparation method of the bromonaltrexone methylbromide injection resistant to terminal sterilization according to any one of claims 1 to 2, characterized in that, The metal ion chelating agent is disodium edetate or calcium disodium edetate; The osmotic pressure regulator is any one of sodium chloride, mannitol, and potassium chloride; The stabilizer is glycine or its hydrochloride derivative; The inorganic acid is 0.1M hydrochloric acid or sulfuric acid.

4. The preparation method of the brominertroban injection resistant to terminal sterilization according to claim 3, characterized in that, The metal ion chelating agent is disodium edetate; The osmotic pressure regulator is sodium chloride; The stabilizer is glycine; The inorganic acid is 0.1M hydrochloric acid.

5. A bromocriptine mesylate injection resistant to terminal sterilization, characterized in that, The injection is obtained by the preparation method described in any one of claims 1 - 4.

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