Octreotide acetate injection and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of an octreotide acetate injection. The method comprises the following steps: dissolving lactic acid in water for injection, and heating for depolymerization; dissolving mannitol in water for injection, and mixing with the depolymerized lactic acid solution; then adding octreotide acetate; adding a sodium lactate solution, adjusting the pH value to 3.9-4.5, and adding water for injection to a constant volume; and finally, carrying out two-stage filtration on the liquid medicine through a 0.22 mu m polyether sulfone filter element, filling a brown medium borosilicate ampoule with the liquid medicine, filling inert gas, and carrying out melt sealing. The lactic acid is subjected to depolymerization treatment and forms a buffer system with the sodium lactate, so that the problem that the pH value of the injection is reduced in the storage process is effectively solved, and the growth of impurities is inhibited. And meanwhile, the stability of the product is improved by multiple technologies of filling protective gas to reduce the oxygen content, reducing photodegradation by adopting a brown medium borosilicate ampoule and the like. 18-month long-term stability test results show that the injection prepared by the invention is stable in pH value and excellent in product stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to an octreotide acetate injection and its preparation method. Background Technology

[0002] Octreotide is a synthetic octapeptide derivative of natural somatostatin (SS), with a molecular weight of 1019.3. First synthesized by Bauer et al. in 1982, it contains the essential amino acids and disulfide bonds necessary for somatostatin's activity, allowing it to bind to the somatostatin receptor. Octreotide has the following characteristics: short peptide chain, easy to synthesize, long half-life of up to 2 hours, stronger inhibitory activity against endocrine hormones than natural growth hormone, and no rebound effect after discontinuation, thus having wider applications. It is used to control and treat acromegaly, alleviate symptoms associated with functional gastrointestinal and pancreatic endocrine tumors, prevent post-pancreatic surgery complications, and treat gastrointestinal issues in patients with cirrhosis. It is used for emergency treatment of bleeding caused by esophageal varices, and has the functions of hemostasis and prevention of rebleeding. Clinically, it is mainly available as a small-volume injection, which is convenient to use and has reliable efficacy.

[0003] Octreotide Acetate Injection (Shanning) ® Octreotide acetate is an octreotide-8 peptide somatostatin analog developed by Novartis Pharm Schweiz AG. It was launched in the United States in 1988, and in 1998 Novartis introduced a long-acting formulation of octreotide acetate microspheres for injection. Novartis' octreotide acetate injection entered the Chinese market in 1993. After the patent expired, a flood of domestic generic drugs appeared, and currently there are more than 30 domestic manufacturers of octreotide acetate injection / octreotide acetate for injection.

[0004] The original drug instructions for octreotide acetate injection (1mL:0.1mg) marketed in the United States clearly state that each milliliter contains 0.1mg octreotide, 3.4mg lactic acid, 45mg mannitol, sodium bicarbonate to adjust the pH to 4.2±0.3, and water for injection to a final volume of 1mL. Octreotide acetate injection (Shanning) ® The marketed specification is 1mL:0.1mg (as C). 49 H 66 N 10 O 10 The injection solution meets the following conditions: S2 content, packaging (colorless borosilicate glass ampoules), etc. This injection solution has been designated as a reference preparation for generic chemical drugs by the National Medical Products Administration of the People's Republic of China.

[0005] However, this drug molecule has poor stability and is highly susceptible to degradation under conditions such as high temperature, light exposure, and pH changes, leading to increased impurity content and affecting drug safety and efficacy. In existing technologies, the formulation of octreotide acetate injection typically includes lactic acid and sodium bicarbonate as pH adjusters and mannitol as an isotonic agent.

[0006] The excipient lactic acid is a mixture of 2-hydroxypropionic acid and its condensate, a colorless or nearly colorless clear viscous liquid. During solution storage, it slowly hydrolyzes into lactic acid monomers, causing a decrease in the solution's pH. This, in turn, accelerates the degradation of octreotide acetate, leading to an increase in the content of related substances (impurities) in the solution and affecting the long-term stability of the product. Therefore, it is necessary to depolymerize the lactic acid to meet the required lactic acid monomer content, thereby further ensuring product quality.

[0007] While some techniques have attempted to improve stability by adding antioxidants (such as CN116036014A) or introducing protective gases (such as CN114288385A), these methods have failed to fundamentally solve the pH drift problem caused by lactic acid polymers. Therefore, there is an urgent need for a preparation method that can fundamentally stabilize the pH value of the formulation and effectively control the growth of impurities.

[0008] Wuhan Humanwell Pharmaceutical Co., Ltd. disclosed in patent CN116036014A that, based on optimized buffers, the addition of disodium edetate enhances the high-temperature and light stability of the active ingredient, significantly improving the stability of octreotide acetate injection. The production and use process can proceed without light protection, and the prepared octreotide acetate injection can be stored for 18 months or more at temperatures not exceeding 20°C. Furthermore, the stable injection can be prepared without the need for inert gas to control residual oxygen. While the disodium edetate added in this patent is generally considered relatively safe, it may bind with calcium ions in the body, leading to decreased blood calcium levels. Therefore, dosage control is necessary when administering it intravenously, and it must be strictly followed according to medical advice to avoid adverse reactions such as hypocalcemia due to overdose.

[0009] Patent CN114288385A relates to a method for preparing octreotide acetate injection, comprising the following steps: taking a total amount of 50 80% water for injection is used, and a protective gas is introduced until the residual oxygen content is below 8%. An antioxidant and octreotide acetate raw material are added to obtain solution a. An isotonic agent and lactic acid are added to the water for injection to adjust the pH value, resulting in solution b. Solution a and solution b are mixed evenly, and the pH value is adjusted to 3.9-4.5 to obtain octreotide acetate injection. The encapsulation method provided in this invention further improves the stability of octreotide acetate injection by adding a carbon dioxide protective gas process to control the residual oxygen content. After 30 days of storage, the octreotide acetate content is high, and the percentage of maximum single impurity and total impurities is low. However, this patent introduces a new antioxidant, metabisulfite.

[0010] Therefore, it is particularly important to solve the problems of peptide degradation and increased impurity content caused by pH instability, oxidation, and photodegradation in octreotide acetate injection. Summary of the Invention

[0011] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for preparing octreotide acetate injection. This method, by employing a specific lactic acid pretreatment process combined with buffer system technology, effectively solves the problem of pH instability during storage of the injection without adding antioxidants. Furthermore, by combining oxygen content control and light-shielding packaging, it effectively controls impurity growth and significantly improves the long-term storage stability of the product.

[0012] The octreotide acetate injection provided by this invention is prepared by a method comprising the following steps:

[0013] 1) Pretreatment (depolymerization) of lactic acid solution: Lactic acid and water for injection are prepared into a solution, heated to depolymerize, and then cooled to room temperature to obtain a depolymerized lactic acid solution mainly composed of lactic acid monomers; 2) Solution preparation: Add the prescribed amount of mannitol to water for injection, and then mix it with the depolymerized lactic acid solution obtained in step 1); 3) Add the main drug: Add the prescribed amount of octreotide acetate and stir well; 4) Adjust pH value: Add alkali to the solution obtained in step 3) to adjust the pH value to 3.9-4.5; 5) Volume adjustment and filtration: Add water for injection to the total volume and stir well; perform two-stage sterilization filtration on the drug solution and introduce inert gas to remove dissolved oxygen from the drug solution; 6) Filling and sealing: Fill the filtered liquid medicine into the container, fill it with inert gas and then seal it with a molten seal.

[0014] In step 1) of the above method, the mass ratio of lactic acid to water for injection can be 1:1 to 1:3, specifically 1:3; The heating and depolymerization temperature can be 80℃-121℃, and the time can be 30-120 minutes, preferably 90 minutes at 121℃; In step 2) of the above method, the temperature of the water for injection is controlled below 30℃; In step 3) of the above method, the alkali is sodium lactate, and a stable lactate-sodium lactate buffer system is formed after the addition of sodium lactate; the pH value can specifically be 4.0-4.3; In the above method, the ratio of octreotide acetate, lactic acid, mannitol, and water for injection can be: 0.1mg:3.4mg:45mg:1mL.

[0015] In step 6) of the above method, a 0.22μm polyethersulfone (PES) filter element is used for sterilization filtration; The inert gas may specifically be nitrogen or carbon dioxide; The introduction of inert gas aims to control the oxygen content in the drug solution to be below 3%; In step 7) of the above method, the ampoule is filled into a brown borosilicate glass ampoule; The headspace residual oxygen content of the ampoule is less than 1%; The inert gas may specifically be nitrogen or carbon dioxide.

[0016] The octreotide acetate injection prepared by the above method is also within the scope of protection of this invention.

[0017] Compared with the prior art, the present invention has the following significant advantages: 1) Significantly improved pH stability: High-temperature depolymerization pretreatment of lactic acid significantly increases the initial lactic acid monomer content in the formulation (up to over 95%). This fundamentally reduces the pH drop caused by the continued dissociation of 2-hydroxypropionic acid and its condensate mixture in lactic acid during storage. Combined with a lactic acid-sodium lactate buffer system, this dual protection mechanism ensures long-term pH stability.

[0018] 2) Significantly reduced impurity levels: The stable pH environment greatly inhibited the degradation pathway of octreotide acetate. Long-term stability test results showed that the increase in related substances (total impurities) in the injection solution prepared by this invention was significantly lower than that in the untreated comparative sample.

[0019] 3) Enhanced stability: By introducing a protective gas to reduce oxygen content, the dissolved oxygen content of the drug solution and the headspace residual oxygen content of the ampoules are better controlled, effectively preventing oxidative degradation and reducing the growth rate of related substances (total impurities) in the injection solution; the use of brown ampoules provides excellent light protection, preventing photodegradation. Multiple technologies work synergistically to ensure the high quality and high stability of the product.

[0020] 4) Simple process and easy to industrialize: The method described in this invention has clear steps and controllable conditions. It does not require the use of complex equipment or special expensive auxiliary materials and is suitable for large-scale commercial production. Attached Figure Description

[0021] Figure 1 Liquid phase diagram showing the content of commercially available lactic acid monomers.

[0022] Figure 2 This is a liquid phase diagram showing the monomer content after lactic acid is depolymerized by heating. Detailed Implementation

[0023] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0024] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0025] Example 1 Prescription: Octreotide acetate injection, comprising the following components: octreotide 0.1 mg / mL, mannitol 45 mg / mL, lactic acid 3.4 mg / mL, appropriate amount of sodium lactate solution (60% by mass), and water for injection as solvent. N2 is used as the protective gas.

[0026] The specific preparation process is as follows: (1) Weigh the prescribed amount of lactic acid, mix lactic acid and water for injection at a ratio of 1:3 (mass ratio), and heat at 121°C for 90 minutes to depolymerize and obtain a lactic acid solution. The monomer content after heating and depolymerization is as follows: Figure 2 As shown.

[0027] (2) Weigh out the prescribed amounts of mannitol, octreotide acetate, and sodium lactate solution for later use.

[0028] (3) Take an appropriate amount of water for injection, add the prescribed amount of mannitol, mix with lactic acid solution (after depolymerization), and keep the water temperature below 30°C.

[0029] (4) Add octreotide acetate and stir well.

[0030] (5) Adjust the pH to 4.28 with sodium lactate solution.

[0031] (6) Add water for injection to the full volume and stir; pressurize and feed with N2 gas. After the drug solution is sterilized and filtered through two 0.22μm sterile filters, it is transported to the filling buffer tank. N2 gas is introduced to control the oxygen content of the solution to <3%.

[0032] (7) Fill brown borosilicate ampoules, fill with N2 and seal, control the headspace residual oxygen content of the ampoules to be less than 1%, and filter the N2 for sterilization.

[0033] Example 2 Prescription: Octreotide acetate injection, comprising the following components: octreotide 0.1 mg / mL, mannitol 45 mg / mL, lactic acid 3.4 mg / mL, appropriate amount of sodium lactate solution (60% by mass), and water for injection as solvent. CO2 is used as protective gas.

[0034] The specific preparation process is as follows: (1) Weigh the prescribed amount of lactic acid, mix the lactic acid and water for injection at a ratio of 1:3 (mass ratio), and heat at 121°C for 90 minutes to depolymerize and obtain a lactic acid solution.

[0035] (2) Weigh out the prescribed amounts of mannitol and octreotide acetate, and prepare sodium lactate solution for later use.

[0036] (3) Take an appropriate amount of water for injection, add the prescribed amount of mannitol, mix with lactic acid solution (after depolymerization), and keep the water temperature below 30°C.

[0037] (4) Add octreotide acetate and stir well.

[0038] (5) Adjust the pH to 4.28 with sodium lactate solution.

[0039] (6) Add water for injection to the full volume and stir; pressurize and feed with CO2 gas. After the drug solution is sterilized by two 0.22μm sterilization filters, it is transported to the filling buffer tank. CO2 gas is introduced to control the oxygen content of the solution to <3%.

[0040] (7) Fill into brown borosilicate ampoules, fill with CO2 and seal, and control the residual oxygen content in the headspace of the ampoule to be <1%. The CO2 needs to be sterilized and filtered.

[0041] Comparative Example 1 Prescription: Octreotide acetate injection, comprising the following components: octreotide 0.1 mg / mL, mannitol 45 mg / mL, lactic acid 3.4 mg / mL, appropriate amount of sodium bicarbonate, and water for injection as solvent. CO2 is used as the protective gas.

[0042] The specific preparation process is as follows: (1) Weigh out the prescribed amounts of mannitol, octreotide acetate, lactic acid and sodium bicarbonate.

[0043] (2) Take an appropriate amount of water for injection and add the prescribed amounts of mannitol, lactic acid, and octreotide acetate. The water temperature should be controlled below 30℃.

[0044] (3) Adjust the pH to 4.28 with sodium bicarbonate solution.

[0045] (4) Add water for injection to the total volume and stir.

[0046] (5) The liquid is fed under pressure with CO2. After being sterilized and filtered by two 0.22μm sterilization filters, it is transported to the filling buffer tank. CO2 gas is introduced to control the oxygen content of the solution to <3%.

[0047] (6) Filling is carried out under CO2 gas protection. The ampoule is sealed with CO2 and the headspace oxygen content of the ampoule is controlled to be <1%. The CO2 needs to be sterilized and filtered.

[0048] The difference between Comparative Example 1 and Example 1 is that the lactic acid was not treated, the pH was adjusted using sodium bicarbonate, and CO2 gas was used for protection.

[0049] Comparative Example 2 Prescription: Octreotide acetate injection, comprising the following components: octreotide 0.1 mg / mL, mannitol 45 mg / mL, lactic acid 3.4 mg / mL, appropriate amount of sodium bicarbonate, and water for injection as solvent. CO2 is used as the protective gas.

[0050] The specific preparation process is as follows: (1) Weigh the prescribed amount of lactic acid, mix the lactic acid and water for injection at a ratio of 1:3 (mass ratio), and heat at 121°C for 90 minutes to obtain a lactic acid solution.

[0051] (2) Take an appropriate amount of water for injection, add the prescribed amount of mannitol, mix with lactic acid solution (after depolymerization), and keep the water temperature below 30°C.

[0052] (4) Add octreotide acetate and stir well.

[0053] (5) Adjust the pH to 4.28 with sodium bicarbonate solution.

[0054] (6) Add water for injection to the total volume and stir. Pressurize and feed with CO2 gas. After the drug solution is sterilized by two-stage 0.22μm sterilization filters, it is delivered to the filling buffer tank. CO2 gas is introduced to control the oxygen content of the solution to <3%.

[0055] (7) Filling is carried out under CO2 gas protection. The brown borosilicate ampoules are filled with CO2 for sealing, and the residual oxygen content in the headspace of the ampoules is controlled to be <1%. The CO2 needs to be sterilized and filtered.

[0056] Comparative Example 2 differs from Example 1 in that it uses sodium bicarbonate to adjust the pH and CO2 gas for protection.

[0057] Comparative Example 3 Prescription: Octreotide acetate injection, comprising the following components: octreotide 0.1 mg / mL, mannitol 45 mg / mL, lactic acid 3.4 mg / mL, appropriate amount of sodium lactate solution (60% by mass), and water for injection as solvent. N2 is used as the protective gas.

[0058] The specific preparation process is as follows: (1) Weigh the prescribed amount of lactic acid, mix lactic acid and water for injection at a ratio of 1:3 (mass ratio), adjust the pH to 4.27 with sodium lactate solution, and heat at 121°C for 90 minutes to obtain lactic acid-sodium lactate buffer solution.

[0059] (2) Weigh out the prescribed amounts of mannitol and octreotide acetate for later use.

[0060] (3) Take an appropriate amount of water for injection, add the prescribed amount of mannitol, and mix with lactate-sodium lactate buffer. The water temperature should be controlled below 30℃.

[0061] (4) Add octreotide acetate and stir well. Adjust the pH to 4.28 with sodium lactate solution.

[0062] (5) Add water for injection to the full volume and stir; pressurize and feed with inert gas N2. After the drug solution is sterilized and filtered through two 0.22μm sterilization filters, it is transported to the filling buffer tank and N2 gas is introduced to control the oxygen content <3%.

[0063] (6) Fill brown borosilicate ampoules, fill with N2 and seal, control the headspace residual oxygen content of the ampoules to be less than 1%, and the N2 needs to be sterilized and filtered.

[0064] The difference between Comparative Example 3 and the Example is that: lactate-sodium lactate buffer solution was prepared first, and the buffer solution was heated to depolymerize.

[0065] Comparative Example 4 Prescription: Octreotide acetate injection, comprising the following components: octreotide 0.1 mg / mL, mannitol 45 mg / mL, lactic acid 3.4 mg / mL, appropriate amount of sodium lactate solution (60% by mass), and water for injection as solvent. CO2 is used as protective gas.

[0066] The specific preparation process is as follows: (1) Weigh out the prescribed amounts of mannitol, octreotide acetate, lactic acid and sodium lactate solution.

[0067] (2) Take an appropriate amount of water for injection and add the prescribed amounts of mannitol, lactic acid, and octreotide acetate. The water temperature should be controlled below 30℃.

[0068] (3) Adjust the pH to 4.28 with sodium lactate solution.

[0069] (4) Add water for injection to the total volume and stir.

[0070] (5) The liquid is fed under pressure with CO2. After being sterilized and filtered by two 0.22μm sterilization filters, it is transported to the filling buffer tank. CO2 gas is introduced to control the oxygen content of the solution to <3%.

[0071] (6) Filling is carried out under CO2 gas protection. The ampoule is sealed with CO2 and the headspace oxygen content of the ampoule is controlled to be <1%. The CO2 needs to be sterilized and filtered.

[0072] The difference between Comparative Example 4 and Example 1 is that the lactic acid was not treated, and the pH value was directly adjusted with sodium lactate solution to form a buffer solution.

[0073] Example 3 According to the testing methods in the draft standard for lactic acid pharmaceutical excipients published by the National Pharmacopoeia Commission, the content of lactic acid monomers in Examples 1-2 (after lactic acid depolymerization), Comparative Example 1 (lactic acid solution), Comparative Example 2 (after lactic acid depolymerization), Comparative Example 3 (after lactic acid-sodium lactate depolymerization), and Comparative Example 4 (lactic acid solution) was tested.

[0074] The results of lactic acid monomer content detection in Examples 1-2 and Comparative Examples 1-4 are as follows: Table 1. Results of lactic acid monomer content detection in Examples 1-2 and Comparative Examples 1-4

[0075] The above results indicate that the lactic acid monomer content in Examples 1 and 2, and Comparative Example 2, after lactic acid depolymerization treatment, is higher than that in Comparative Examples 1, 3, and 4. The lactic acid monomer content in Examples 1, 2, and 2, and Comparative Example 2, all reach over 95%. This demonstrates that the depolymerization condition of mixing lactic acid and water for injection at a 1:3 (mass ratio) and heating at 121°C for 90 minutes can achieve a lactic acid monomer content of over 95%, providing strong assurance for the pH stability of octreotide acetate injection.

[0076] Example 4 According to the methods for determining pH, related substances, and content of octreotide acetate injection as described in the 2020 edition, Part II of the Chinese Pharmacopoeia, various indicators of Examples 1-2 and Comparative Examples 1-4 of this invention were determined at 0 days, long-term stability at 6 months, 9 months, 12 months, and 18 months. The long-term stability conditions were 5℃±3℃. The test results are as follows: Table 2. Results of 0-day and long-term testing for Examples 1-2 and Comparative Examples 1-4

[0077] Based on the test results from day 0, there was no significant difference in the quality of products prepared from lactic acid treated under different conditions. Further analysis will be conducted through stability tests.

[0078] All the injection solutions obtained in the experiment were colorless and clear liquids.

[0079] Long-term experimental results show that the pH values ​​of the solutions in Comparative Examples 1 and 4 are significantly reduced and exceed the lower limit of pH; the pH values ​​of the solutions in Comparative Examples 2 and 3 are slightly reduced; and the pH values ​​of the solutions in Examples 1 and 2 are not significantly changed. The total impurity content of the products in Examples 1 and 2 showed no significant change; the total impurity content of Comparative Examples 2 and 3 decreased, with varying degrees of change; the total impurity content of Comparative Examples 1 and 4 decreased significantly, with larger variations. This indicates that the products prepared in Examples 1 and 2 have better stability.

[0080] In Comparative Example 1, no heat treatment was performed on the lactic acid; only sodium bicarbonate was used to adjust the pH. The resulting sample showed a significant increase in impurities and a significant decrease in their content during the stability test. The pH also decreased significantly, exceeding the lower limit, exhibiting the largest variation. Compared to Examples 1 and 2, the stability was significantly reduced. This demonstrates that heat treatment of lactic acid and the preparation of a buffer solution using sodium lactate in step (1) of the present invention can improve sample stability and greatly reduce impurity formation.

[0081] In Comparative Example 2, after heat treatment of lactic acid, a buffer solution was not prepared using sodium lactate; instead, sodium bicarbonate was used to adjust the pH. In the stability test, compared with Examples 1 and 2, the impurities increased slightly, while the content decreased slightly. This indicates that after heat treatment of lactic acid, a buffer solution prepared using sodium lactate has a better stabilizing effect.

[0082] In Comparative Example 3, the lactate-sodium lactate buffer solution was heated to depolymerize, and compared with Example 1, the sample stability was slightly worse. This indicates that heating the lactate-sodium lactate buffer solution together may affect the depolymerization of lactate, resulting in a slight decrease in pH and octreotide acetate content in the long-term test results, suggesting that lactate should be heated and depolymerized separately.

[0083] In Comparative Example 4, no heat treatment was performed on the lactic acid; only sodium lactate solution was used to adjust the pH. The resulting sample showed a significant increase in impurities, a significant decrease in impurity content, and a significant drop in pH exceeding the lower limit, exhibiting a large fluctuation. Compared to Examples 1 and 2, the stability was significantly reduced. This demonstrates that relying solely on a lactic acid-sodium lactate buffer solution is insufficient to ensure stable pH and octreotide acetate content. The method of this invention, by first heat-treating the lactic acid and then preparing a buffer solution using sodium lactate in step (1), can better improve sample stability and significantly reduce impurity formation.

[0084] In summary, lactic acid should first undergo heat treatment to depolymerize it into lactic acid monomers, which can then form a lactic acid-sodium lactate buffer solution. This allows the pH of the injection solution to be controlled within a certain range to ensure its stability and thus guarantee the quality stability of octreotide acetate injection.

[0085] Conclusion: The above data fully demonstrate that the preparation method provided by this invention, especially the process of mixing lactic acid and water in a 1:3 ratio and then depolymerizing at 121°C for 90 minutes, combined with a lactic acid-sodium lactate buffer system, inert gas protection, and the use of brown ampoules, can produce octreotide acetate injection with significantly better quality and extremely high stability than existing technologies.

[0086] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. A method for preparing octreotide acetate injection, comprising the following steps: 1) Pretreatment of lactic acid solution: Lactic acid and water for injection are prepared into a solution, heated to depolymerize, and then cooled to room temperature to obtain a depolymerized lactic acid solution mainly composed of lactic acid monomers; 2) Solution preparation: Add the prescribed amount of mannitol to water for injection, and then mix it with the depolymerized lactic acid solution obtained in step 1); 3) Add the main drug: Add the prescribed amount of octreotide acetate and stir well; 4) Adjust pH value: Add alkali to the solution obtained in step 3) to adjust the pH value to 3.9-4.5; 5) Volume adjustment and filtration: Add water for injection to the total volume and stir well; 6) The drug solution is subjected to two-stage sterilization filtration, and inert gas is introduced to remove dissolved oxygen from the drug solution; 7) Filling and sealing: Fill the filtered liquid medicine into the container, fill it with inert gas and then seal it with a molten seal.

2. The method according to claim 1, characterized in that, In step 1), the mass ratio of lactic acid to water for injection is 1:1 to 1:3; The heating and depolymerization temperature is 80℃-121℃, and the time is 30-120 minutes; In step 2), the temperature of the water for injection is controlled below 30°C.

3. The method according to claim 1, characterized in that, In step 4), the base is sodium lactate, and the addition of sodium lactate forms a stable lactate-sodium lactate buffer system; Adjust the pH to 4.0-4.3; The ratio of octreotide acetate, lactic acid, mannitol, and water for injection is 0.1 mg: 3.4 mg: 45 mg: 1 mL.

4. The method according to claim 1, characterized in that, In step 6), a 0.22μm polyethersulfone filter element is used for sterilization filtration; The inert gas is nitrogen or carbon dioxide; Inert gas is introduced to control the oxygen content in the drug solution to be below 3%.

5. The method according to claim 1, characterized in that, In step 7), the ampoule is filled into brown borosilicate glass ampoules; The headspace residual oxygen content of the ampoule is less than 1%.

6. Octreotide acetate injection prepared by the method of any one of claims 1-5.

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