An octreotide acetate injection and its preparation method

Abstract

The present invention discloses an octreotide acetate injection and a preparation method thereof, which relates to the technical field of pharmaceuticals. On the basis of optimizing the buffer, antioxidants such as disodium edetate are used in combination, enhancing the high-temperature and light stability of the active ingredient, greatly improving the stability of the octreotide acetate injection, so that it is not necessary to avoid light during the production and use processes. The prepared octreotide acetate injection can be stored for 18 months or more at a temperature not higher than 20 °C, and an ideal stability can be obtained without using inert gas to control the residual oxygen during the preparation process.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, and particularly relates to an octreotide acetate injection and a preparation method thereof. Background Art

[0002] Octreotide acetate is an analogue of somatostatin, a synthetic octapeptide drug with the chemical name D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[(1R,2R)-2-hydroxy-1-(hydroxymethyl)propyl]-L-cysteinamide cyclic (2→7)-disulfide acetate. It has the functions of controlling and treating acromegaly, relieving symptoms related to functional gastroenteropancreatic (GEP) endocrine tumors, preventing complications after pancreatic surgery, emergency treatment of bleeding caused by gastroesophageal varices in cirrhotic patients, hemostasis and prevention of rebleeding, etc. Clinically, it is mainly a small-volume injection, which is convenient to use and has reliable curative effects.

[0003] The stability of the peptide chain is poor, and acids, alkalis, metal ions, etc. may cause peptide chain degradation. Octreotide acetate is extremely prone to degradation under conditions such as high temperature, light, acids, and alkalis. During production and transportation, it needs to be stored in the dark and refrigerated. Many improvements have been made in the prior art to improve the stability of octreotide acetate preparations.

[0004] Patent (CN114983936 A) discloses an octreotide acetate injection, which is composed of 0.001-0.05% (w / v) of octreotide acetate, an osmotic pressure regulator, a pH regulator, and water for injection. The pH of the injection is 4.0-4.5, and the osmotic pressure of the injection is 285-320 mOsmol / kg. By scientifically screening the components and ratios for preparing octreotide acetate injection, optimizing the preparation process and parameters, the stability of octreotide acetate injection has been significantly improved, and it is well compatible with any one or a combination of normal saline and 5% glucose, significantly reducing or even avoiding the risk of microbial infection, significantly improving the quality of the drug, and ensuring the safety and effectiveness of clinical medication.

[0005] Patent (CN 113318218A) and an octreotide acetate injection and its preparation process. The present invention uses CO 2 as a protective gas to prepare octreotide acetate injection, which improves the stability of octreotide acetate injection to a certain extent, and at the same time increases the osmotic pressure of octreotide acetate injection, making the osmotic pressure of octreotide acetate injection basically the same as that of the reference preparation.

[0006] The patent (CN114288385A) relates to a preparation method of octreotide acetate preparation, which comprises the following steps: taking 50-80% of the total amount of water for injection and introducing a protective gas until the residual oxygen content is below 8%, adding an antioxidant, dissolving and then adding octreotide acetate raw material drug to obtain solution a; adding an isotonic agent to water for injection, dissolving and then adding lactic acid to adjust the pH value to obtain solution b; mixing solution a and solution b evenly, and adjusting the pH value to 3.9-4.5 to obtain the octreotide acetate preparation. This method can effectively improve the stability of octreotide acetate injection, so that it still has a stable pH value, total amount of octreotide acetate, and low maximum single impurity and total impurity percentage on the day of preparation and after storage for 5 days and 10 days. The encapsulation method provided by the present invention further improves the stability of octreotide acetate injection by adding a process step of filling carbon dioxide protective gas, so that it still maintains a high octreotide acetate content and low maximum single impurity and total impurity percentage after storage for 30 days.

[0007] The patent (CN113350276A) discloses a preparation method and an encapsulation method of octreotide acetate injection. The preparation method includes: (1) mixing lactic acid and water for injection; (2) mixing mannitol and the mixture obtained in step (1); (3) adjusting the pH value of the mixture obtained in step (2), and then adding octreotide acetate; (4) filtering to obtain octreotide acetate injection; (5) adding water for injection to the total amount. This method can effectively improve the stability of octreotide acetate injection, so that the octreotide acetate injection still has a stable pH value, total amount of octreotide acetate, and low maximum single impurity and total impurity percentage after storage for 5 days and 10 days. The encapsulation method includes a step of filling carbon dioxide, which can improve the stability of octreotide acetate injection under high temperature and light conditions. After storage for 5 days, 10 days, and 30 days, it can still maintain a high octreotide acetate content and low maximum single impurity and total impurity percentage.

[0008] It can be seen that in the prior art, by optimizing the types of raw materials or preparation processes, especially by using an inert gas to control the residual oxygen, the stability of octreotide acetate injection can be improved to a certain extent. However, the stability of the obtained octreotide acetate injection is still not very ideal. Therefore, it is of great significance to screen a suitable formulation to further improve the stability of octreotide acetate injection. Summary of the Invention

[0009] In view of the problems existing in the prior art, the present invention provides an octreotide acetate injection and a preparation method thereof. On the basis of optimizing the buffer, antioxidants such as disodium edetate are used in combination, enhancing the high-temperature and light stability of the active ingredient, greatly improving the stability of the octreotide acetate injection. During the production and use processes, it is not necessary to avoid light, and it can be stored for 18 months or more under the condition of not higher than 20°C. Moreover, during the preparation process, it is not necessary to use inert gas to control the residual oxygen to obtain ideal stability.

[0010] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0011] In the first aspect, the present invention provides an octreotide acetate injection, which, based on every 1000 mL of the injection, comprises the following components: 50 - 1000 mg of octreotide acetate, 0.5 - 5 g of buffer, 0.1 - 1.0 g of antioxidant, 1 - 10 g of osmotic pressure regulator, an appropriate amount of pH regulator to adjust the pH to 2.0 - 6.0, and an appropriate amount of solvent to make up to 1000 ml; wherein, the buffer is selected from at least one of succinic acid, citric acid, and acetic acid, and the antioxidant is selected from at least one of disodium edetate, calcium disodium edetate, and methionine.

[0012] In a preferred embodiment, based on every 1000 mL of the injection, it comprises the following components: 100 mg of octreotide acetate, 0.5 - 5 g of buffer, 1 g of antioxidant, 7 g of osmotic pressure regulator, an appropriate amount of pH regulator to adjust the pH to 3.7 - 4.7, and an appropriate amount of solvent to make up to 1000 ml.

[0013] In a preferred embodiment, the buffer is succinic acid.

[0014] In a preferred embodiment, the pH regulator is selected from sodium hydroxide, sodium succinate, sodium citrate, and sodium acetate, and more preferably sodium hydroxide and sodium acetate trihydrate.

[0015] In a preferred embodiment, the antioxidant is disodium edetate.

[0016] In a preferred embodiment, the osmotic pressure regulator is selected from sodium chloride and / or mannitol, and more preferably sodium chloride.

[0017] In a preferred embodiment, the solvent is selected from water for injection, injection oil, ethanol, propanol, isopropanol, propylene glycol, ethyl acetate, dimethyl sulfoxide, and glycerol.

[0018] The buffer used in the present invention has better stability compared to the commonly used buffer lactic acid. When used in combination with antioxidants such as disodium edetate, the high-temperature and light stability of the active ingredient is enhanced, greatly improving the stability of octreotide acetate injection. During the production and use processes, it is not necessary to avoid light, and it can be stored for 18 months or more under the condition of not higher than 20°C. Moreover, during the preparation process, it is not necessary to use inert gas to control the residual oxygen to obtain ideal stability.

[0019] In a preferred embodiment, the injection further comprises a potentiator selected from one or more of β-cyclodextrin, polysorbate 80, glycerol, and propylene glycol.

[0020] In a second aspect, the present application also provides a preparation method of the above-mentioned octreotide acetate injection, comprising the following steps:

[0021] 1) Preparation of the liquid medicine

[0022] Take a cold solvent less than the preparation amount, add raw materials except octreotide acetate and pH regulator, stir to dissolve, adjust the pH using the pH regulator, add octreotide acetate, stir to dissolve, and make up the volume to the scale with the cold solvent;

[0023] 2) Sterilizing filtration;

[0024] 3) Filling;

[0025] 4) Visual inspection, leak detection, and packaging;

[0026] In a preferred embodiment, in step 2), the liquid medicine is filtered using a filter element or a filter membrane; the material of the filter element or the filter membrane is selected from PES, PVDF, and PTFE, and the pore size is 0.45 μm or 0.22 μm; in step 3), the liquid medicine is filled into the packaging container at 1.15 ml / branch; the packaging container is at least one of ampoules, vials, and cartridge vials. Among them, the PES filter element or filter membrane has less adsorption to the octreotide acetate active ingredient in addition to sterilization and quality removal.

[0027] In a preferred embodiment, in step 2), the material of the filter element or the filter membrane is PES, and the pore size is 0.22 μm; in step 3), the packaging container is an ampoule.

[0028] In a preferred embodiment, in step 4), the product is visually inspected and leak-detected and then packaged.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. Based on the optimization of the buffer, antioxidants such as disodium edetate are used in combination, enhancing the high-temperature and light stability of the active ingredient, greatly improving the stability of octreotide acetate injection, and achieving ideal stability without using inert gas to control residual oxygen during the preparation process.

[0031] 2. During the production and use processes of the present invention, it is not necessary to avoid light. The prepared octreotide acetate injection can be stored for 18 months or more under the condition of not higher than 20 °C. Detailed implementation manners

[0032] It should be noted that the raw materials used in the present invention are all ordinary commercially available products, and no specific limitation is imposed on their sources.

[0033] Example 1

[0034] The prescription is as follows:

[0035] Component Dosage Octreotide Acetate 100 mg Succinic Acid 1g Sodium Chloride 7g Disodium Edetate 1g Sodium Hydroxide Q.s. to adjust pH to 3.7 - 4.7 Water for Injection Volume made up to 1000 ml

[0036] Preparation method of octreotide acetate injection

[0037] Step 1: Add 800 ml of cooled injection water into a container, start stirring; add the prescribed amounts of sodium chloride, succinic acid and disodium edetate, stir to dissolve, adjust the pH to 4.2 using sodium hydroxide solution. Add the prescribed amount of octreotide acetate, stir to dissolve, and make up the volume to 1000 ml with cooled injection water.

[0038] Step 2: Perform aseptic filtration using a 0.22 μm PES filter.

[0039] Step 3: Sterilize and remove pyrogens from 1 ml ampoules through a tunnel oven, fill the medicinal liquid into 1 ml ampoules at 1.15 ml per vial, and seal by drawing and fusing.

[0040] Step 4: Inspect the products by light, check for leaks, and package them.

[0041] Example 2

[0042] The prescription is as follows:

[0043] Component Dosage Octreotide Acetate 100 mg Citric Acid 1g Mannitol 7g Calcium Disodium Edetate 1g Sodium Hydroxide Q.s. to adjust pH to 3.7 - 4.7 Water for Injection Volume made up to 1000 ml

[0044] Preparation method of octreotide acetate injection

[0045] Step 1: Add 800 ml of cooled injection water into a container, start stirring; add the prescribed amounts of mannitol, citric acid and calcium disodium edetate, stir to dissolve, adjust the pH to 4.2 using sodium hydroxide solution. Add the prescribed amount of octreotide acetate, stir to dissolve, and make up the volume to 1000 ml with cooled injection water.

[0046] Step 2: Perform aseptic filtration using a 0.22 μm PES filter.

[0047] Step 3: Sterilize and remove pyrogens from 1-ml ampoules in a tunnel oven, fill the medicinal liquid into 1-ml ampoules at 1.15 ml per vial, and perform wire drawing and sealing.

[0048] Step 4: Inspect the products by light, detect leaks, and package them.

[0049] Example 3

[0050] The prescription is as follows:

[0051] Component Dosage Octreotide Acetate 100 mg Glacial Acetic Acid 2g Sodium Chloride 7g Methionine 1g Sodium Acetate Trihydrate 2g Water for Injection Volume made up to 1000 ml

[0052] Preparation method of octreotide acetate injection

[0053] Step 1: Add 800 ml of cooled injection water into a container, start stirring; add the prescribed amounts of sodium chloride, glacial acetic acid, methionine, and sodium acetate trihydrate, and stir until dissolved. Add the prescribed amount of octreotide acetate, stir until dissolved, and make up the volume to 1000 ml with cooled injection water.

[0054] Step 2: Perform aseptic filtration using a 0.22 μm PES filter.

[0055] Step 3: Sterilize and remove pyrogens from 1-ml ampoules in a tunnel oven, fill the medicinal liquid into 1-ml ampoules at 1.15 ml per vial, and perform wire drawing and sealing.

[0056] Step 4: Inspect the products by light, detect leaks, and package them.

[0057] Comparative Example 1

[0058] The prescription is as follows:

[0059] Component Dosage Octreotide Acetate 100 mg Lactic Acid 3.4g Mannitol 45g Sodium Bicarbonate Q.s. to adjust pH to 3.7 - 4.7 Water for Injection Volume made up to 1000 ml

[0060] Preparation method of octreotide acetate injection

[0061] Step 1: Add 800 ml of cooled injection water into a container, start stirring, add the prescribed amounts of mannitol and lactic acid, stir until dissolved, add the prescribed amount of octreotide acetate, stir until dissolved, and adjust the pH to 4.2 with sodium bicarbonate solution. Make up the volume to 1000 ml with cooled injection water.

[0062] Step 2: Perform aseptic filtration using a 0.22 μm PES filter.

[0063] Step 3: Sterilize and remove pyrogens from 1-ml ampoules in a tunnel oven, fill the medicinal liquid into 1-ml ampoules at 1.15 ml per vial, and perform wire drawing and sealing.

[0064] Step 4: Inspect the products by light, detect leaks, and package them.

[0065] Comparative Example 2

[0066] The prescription is as follows:

[0067]

[0068]

[0069] Preparation method of octreotide acetate injection

[0070] Step 1: Add 800 ml of cooled injection water into a container, start stirring, introduce carbon dioxide under the liquid surface to make the dissolved oxygen less than 5 ppm, and continuously introduce carbon dioxide until the filtration is completed; add the prescribed amount of mannitol and lactic acid, stir to dissolve, add the prescribed amount of octreotide acetate, and stir to dissolve. Adjust the pH to 4.2 with sodium bicarbonate solution. Make up the volume to 1000 ml with cooled injection water.

[0071] Step 2: Perform sterile filtration using a 0.22 μm PES filter.

[0072] Step 3: Sterilize and remove pyrogens from 1 ml ampoules in a tunnel oven, fill the liquid medicine into 1 ml ampoules at 1.15 ml per vial, and displace the air in the vials with carbon dioxide, then seal by drawing and fusing.

[0073] Step 4: Inspect the products by light, detect leaks, and package them.

[0074] Comparative Example 3

[0075] The prescription is as follows:

[0076] Component Dosage Octreotide Acetate 100 mg Succinic Acid 1g Sodium Chloride 7g Sodium Pyrosulfite 0.1g Sodium Hydroxide Q.s. to adjust pH to 3.7 - 4.7 Water for Injection Volume made up to 1000 ml

[0077] Preparation method of octreotide acetate injection

[0078] Step 1: Add 800 ml of cooled injection water into a container, start stirring; add the prescribed amount of sodium chloride, succinic acid, and sodium metabisulfite, stir to dissolve, adjust the pH to 4.2 with sodium hydroxide solution. Add the prescribed amount of octreotide acetate, stir to dissolve, and make up the volume to 1000 ml with cooled injection water.

[0079] Step 2: Perform sterile filtration using a 0.22 μm PES filter.

[0080] Step 3: Sterilize and remove pyrogens from 1 ml ampoules in a tunnel oven, fill the liquid medicine into 1 ml ampoules at 1.15 ml per vial, and seal by drawing and fusing.

[0081] Step 4: Inspect the products by light, detect leaks, and package them.

[0082] Comparative Example 4

[0083] The prescription is as follows:

[0084]

[0085]

[0086] Preparation method of octreotide acetate injection

[0087] Step 1: Add 800 ml of cooled injection water into a container, and start stirring; add the prescribed amounts of sodium chloride, lactic acid and disodium edetate, stir to dissolve, adjust the pH to 4.2 with sodium hydroxide solution. Add the prescribed amount of octreotide acetate, stir to dissolve, and make up the volume to 1000 ml with cooled injection water.

[0088] Step 2: Perform aseptic filtration using a 0.22 μm PES filter.

[0089] Step 3: Sterilize and remove pyrogens from 1 ml ampoules in a tunnel oven, fill the medicinal liquid into 1 ml ampoules at 1.15 ml per vial, and seal by drawing and fusing.

[0090] Step 4: Inspect the product by light, check for leaks, and package.

[0091] Test Examples

[0092] Detect the related substances and content of Examples 1 - and Comparative Example - 2 according to the method in the Chinese Pharmacopoeia (Second Part, 2020 Edition).

[0093] The chromatographic conditions are as follows:

[0094] Chromatographic column: Xtimate C18 4.6 mm × 250 mm; use tetra - methylammonium hydroxide solution (take 20 ml of 10% tetra - methylammonium hydroxide solution, add 880 ml of water, adjust the pH value to 5.4 with 10% phosphoric acid solution) - acetonitrile (900:100) as mobile phase A, and tetra - methylammonium hydroxide solution (take 20 ml of 10% tetra - methylammonium hydroxide solution, add 380 ml of water, adjust the pH value to 5.4 with 10% phosphoric acid solution) - acetonitrile (400:600) as mobile phase B, perform gradient elution according to Table 1; the detection wavelength is 210 nm; the injection volume is 100 μl.

[0095] Table 1 Elution conditions

[0096] Time (min) Mobile Phase A (%) Mobile Phase B (%) 0 73 27 30 55 45 31 73 27 37 73 27

[0097] The detection results are shown in Table 2:

[0098] Table 2 Related substance content of Example 1 - and Comparative Example - 2

[0099]

[0100]

[0101] Note: "ND" indicates not detected.

[0102] The research results of influencing factors are shown in Table 3:

[0103] Table 3 Related substances and contents of Example 1- and Comparative Example -2 under different conditions

[0104]

[0105]

[0106] The light stability of the preparations of Example 1-3 has an unpredictable improvement, significantly higher than that of Comparative Examples 1-4. The thermal stability is also significantly higher than that of Comparative Examples 1-4.

[0107] The research results of stability are shown in Table 4:

[0108] Table 3 Long-term stability of Example 1- and Comparative Example -2

[0109]

[0110]

[0111]

[0112] For Comparative Examples 1, 2, 3 and 4, the impurities have exceeded the standard limit after 12 months of long-term storage (25°C, RH60%). The impurities of Example 1-3 are significantly less than those of the comparative examples and are within the standard limit, but exceed the standard limit after 18 months.

[0113] For Comparative Examples 1, 2, 3 and 4, the impurities are about to reach the standard limit after 12 months of long-term storage (20°C, RH60%) and have exceeded the standard limit after 18 months of long-term storage. The impurities of Example 1-3 are significantly less than those of the comparative examples, and the impurities are within the standard limit after 18 months of long-term storage, and can be stable for 18 months at this temperature.

[0114] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the protection scope of the present invention. Any simple modification or equivalent replacement of the technical solution of the present invention by those of ordinary skill in the art shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. An octreotide acetate injection, characterized in that, per 1000 mL of the injection, it comprises the following components: 100 mg of octreotide acetate, 1 g of succinic acid, 7 g of sodium chloride, 1 g of disodium edetate, an appropriate amount of sodium hydroxide to adjust the pH to 3.7 - 4.7, and water for injection is added to a volume of 1000 mL; The preparation method of the octreotide acetate injection described above: Step 1: Add 800 mL of cooled water for injection to a container, start stirring; add the prescribed amounts of sodium chloride, succinic acid and disodium edetate, stir to dissolve, use sodium hydroxide solution to adjust the pH to 4.

2. Add the prescribed amount of octreotide acetate, stir to dissolve, and use cooled water for injection to make up the volume to 1000 mL; Step 2: Perform sterile filtration using a 0.22 μm PES filter; Step 3: Sterilize and remove pyrogens from 1 mL ampoules through a tunnel oven, fill the liquid medicine into 1 mL ampoules at 1.15 mL per vial, and draw and seal; Step 4: Inspect the product by light, detect leaks and package.

2. An octreotide acetate injection, characterized in that, per 1000 mL of the injection, it comprises the following components: 100 mg of octreotide acetate, 1 g of citric acid, 7 g of mannitol, 1 g of calcium disodium edetate, an appropriate amount of sodium hydroxide to adjust the pH to 3.7 - 4.7, and water for injection is added to a volume of 1000 mL; The preparation method of the octreotide acetate injection described above: Step 1: Add 800 mL of cooled water for injection to a container, start stirring; add the prescribed amounts of mannitol, citric acid and calcium disodium edetate, stir to dissolve, use sodium hydroxide solution to adjust the pH to 4.

2. Add the prescribed amount of octreotide acetate, stir to dissolve, and use cooled water for injection to make up the volume to 1000 mL; Step 2: Perform sterile filtration using a 0.22 μm PES filter; Step 3: Sterilize and remove pyrogens from 1 mL ampoules through a tunnel oven, fill the liquid medicine into 1 mL ampoules at 1.15 mL per vial, and draw and seal; Step 4: Inspect the product by light, detect leaks and package.

3. An octreotide acetate injection, characterized in that, per 1000 mL of the injection, it comprises the following components: 100 mg of octreotide acetate, 2 g of glacial acetic acid, 7 g of sodium chloride, 1 g of methionine, sodium acetate trihydrate, and water for injection is added to a volume of 1000 mL; The preparation method of the octreotide acetate injection described above: Step 1: Add 800 mL of cooled water for injection to a container, start stirring; add the prescribed amounts of sodium chloride, glacial acetic acid, methionine and sodium acetate trihydrate, add the prescribed amount of octreotide acetate, stir to dissolve, and use cooled water for injection to make up the volume to 1000 mL; Step 2: Perform sterile filtration using a 0.22 μm PES filter; Step 3: Sterilize and remove pyrogens from 1 mL ampoules through a tunnel oven, fill the liquid medicine into 1 mL ampoules at 1.15 mL per vial, and draw and seal; Step 4: Inspect the product by light, detect leaks and package. ​

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