Octreotide acetate injection with good stability, preparation method and application thereof

Abstract

The present application relates to a kind of octreotide acetate injection, the injection is made of 0.001-0.05% (w / v) octreotide acetate, osmotic pressure regulator, pH regulator and water for injection, injection pH 4.0-4.5, the osmotic pressure of injection is 285-320 mOsmol / kg.The present application is scientifically screened for preparing octreotide acetate injection component and proportion, optimization preparation process and parameter, significantly improve the stability of octreotide acetate injection, and with physiological saline and 5% glucose any one or its combination is well matched, significantly reduce even avoid the risk of microbial infection, significantly improve the quality of medicine, guarantee the safety and effectiveness of clinical medication.

Description

Technical Field

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

[0002] Octreotide is a cyclic polypeptide compound composed of eight amino acids. It is a somatostatin analogue with antagonistic activity against growth hormone and glucagon. It reduces visceral blood flow, alleviating flushing and diarrhea associated with gastrointestinal tumors, but with a longer duration of action. Clinically, octreotide acetate injection is mainly used to treat acromegaly, gastrointestinal and pancreatic endocrine tumors, prevent postoperative complications of pancreatic surgery, and esophageal-gastric variceal bleeding.

[0003] Octreotide acetate injection has the following drawbacks: First, the use of activated carbon to adsorb pyrogens, impurities, and pigments in the lactated mannitol buffer solution prolongs the production cycle and causes material loss. Second, the filter cartridge affects the production cycle and increases the risk of microbial infection, affecting drug quality, safety, and efficacy. Third, the injection solution is stored at 2-8℃ away from light, exhibiting poor stability under light and high temperatures; long-term storage can easily lead to excessive levels of single and total impurities, affecting safety. Therefore, it is necessary to develop a stable octreotide acetate injection to ensure the safety and efficacy of clinical use. Summary of the Invention

[0004] The purpose of this invention is to provide an octreotide acetate injection solution, which is composed of 0.001-0.05% (w / v) octreotide acetate, an osmotic pressure regulator, a pH regulator, and water for injection. The pH of the injection solution is 4.0-4.5, and the osmotic pressure of the injection solution is 285-320 mOsmol / kg.

[0005] In a preferred embodiment of the present invention, the octreotide acetate content in the injection solution is 0.005-0.04%, preferably any one of 0.005%, 0.01%, or 0.03%.

[0006] In a preferred embodiment of the present invention, the pH adjuster is selected from any one or a combination of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, sodium carbonate, sodium hydroxide, and lactic acid.

[0007] In a preferred embodiment of the present invention, the phosphoric acid content in the injection solution is 0.01-1% (w / v), preferably 0.04-0.08% (w / v).

[0008] In a preferred embodiment of the present invention, the osmotic pressure regulator in the injection solution is mannitol, and the mannitol content in the injection solution is 1-10% (w / v), preferably 4.5-6% (w / v).

[0009] In a preferred embodiment of the present invention, the octreotide acetate injection contains 0.005% octreotide acetate, 0.08% phosphoric acid, and 4.5% mannitol by weight / volume percentage, with sodium hydroxide adjusting the pH to 4.0-4.5.

[0010] In a preferred embodiment of the present invention, the octreotide acetate injection contains 0.01% octreotide acetate, 0.08% phosphoric acid, 4.5% mannitol, and sodium hydroxide to adjust the pH to 4.0-4.5, by weight / volume percentage.

[0011] In a preferred embodiment of the present invention, the octreotide acetate injection contains 0.03% octreotide acetate, 0.08% phosphoric acid, 4.5% mannitol, and sodium hydroxide to adjust the pH to 4.0-4.5, by weight / volume percentage.

[0012] In a preferred embodiment of the present invention, the dethreonine in the injection solution 8 Octreotide content ≤0.5%, other single impurities content ≤0.5%, total impurities content ≤2.0%.

[0013] In a preferred embodiment of the present invention, each 1 mg of octreotide acetate in the injection solution contains ≤100 EU of bacterial endotoxin.

[0014] In a preferred embodiment of the present invention, the microbial content in the injection solution is ≤10cfu / 100ml.

[0015] In a preferred embodiment of the present invention, the single impurity content of the injection solution is ≤0.5% and the total impurity content is ≤2% under accelerated 6-month conditions.

[0016] In a preferred embodiment of the present invention, the single impurity content of the injection solution is ≤0.5% and the total impurity content is ≤2% under 10 days of light exposure.

[0017] In a preferred embodiment of the present invention, the injection solution is used in combination with 0.9% physiological saline or 5% glucose, and the single impurity content at the end of the effective period is ≤0.5%, and the total impurity content is ≤2%.

[0018] Another object of the present invention is to provide a method for preparing octreotide acetate injection, wherein the injection comprises 0.001-0.05% (w / v) octreotide acetate, an osmotic pressure adjuster, a pH adjuster, and water for injection, wherein the pH of the injection is 4.0-4.5, and the osmotic pressure of the injection is 285-320 mOsmol / kg. The method for preparing the injection includes the following steps:

[0019] (1) Under stirring conditions, add the required amount of phosphoric acid and mannitol to water for injection until completely dissolved, adjust the pH to 4.0-4.5 with sodium hydroxide solution, and then add the required amount of octreotide acetate to prepare the drug solution.

[0020] (2) The prepared drug solution is filtered through a 0.22μm polyethersulfone filter in two stages to obtain the final product.

[0021] In a preferred embodiment of the present invention, the stirring speed is 30-50Hz, preferably 38-42Hz.

[0022] In a preferred embodiment of the present invention, the filtration pressure is 0.1 MPa.

[0023] In a preferred embodiment of the present invention, the octreotide acetate content in the injection solution is 0.005-0.04%, preferably any one of 0.005%, 0.01%, or 0.03%.

[0024] In a preferred embodiment of the present invention, the pH adjuster is selected from any one or a combination of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium bicarbonate, sodium carbonate, sodium hydroxide, and lactic acid.

[0025] In a preferred embodiment of the present invention, the phosphoric acid content in the injection solution is 0.01-1% (w / v), preferably 0.04-0.08% (w / v).

[0026] In a preferred embodiment of the present invention, the osmotic pressure regulator in the injection solution is mannitol, and the mannitol content in the injection solution is 1-10% (w / v), preferably 4.5-6% (w / v).

[0027] In a preferred embodiment of the present invention, the octreotide acetate injection contains 0.005% octreotide acetate, 0.08% phosphoric acid, and 4.5% mannitol by weight / volume percentage, with sodium hydroxide adjusting the pH to 4.0-4.5.

[0028] In a preferred embodiment of the present invention, the octreotide acetate injection contains 0.01% octreotide acetate, 0.08% phosphoric acid, 4.5% mannitol, and sodium hydroxide to adjust the pH to 4.0-4.5, by weight / volume percentage.

[0029] In a preferred embodiment of the present invention, the octreotide acetate injection contains 0.03% octreotide acetate, 0.08% phosphoric acid, 4.5% mannitol, and sodium hydroxide to adjust the pH to 4.0-4.5, by weight / volume percentage.

[0030] In a preferred embodiment of the present invention, the dethreonine in the injection solution 8 Octreotide content ≤0.5%, other single impurities content ≤0.5%, total impurities content ≤2.0%.

[0031] In a preferred embodiment of the present invention, each 1 mg of octreotide acetate in the injection solution contains ≤100 EU of bacterial endotoxin.

[0032] In a preferred embodiment of the present invention, the microbial content in the injection solution is ≤10cfu / 100ml.

[0033] In a preferred embodiment of the present invention, the single impurity content of the injection solution is ≤0.5% and the total impurity content is ≤2% under accelerated 6-month conditions.

[0034] In a preferred embodiment of the present invention, the single impurity content of the injection solution is ≤0.5% and the total impurity content is ≤2% under 10 days of light exposure.

[0035] In a preferred embodiment of the present invention, the injection solution is used in combination with 0.9% physiological saline or 5% glucose, and the single impurity content at the end of the effective period is ≤0.5%, and the total impurity content is ≤2%.

[0036] Another objective of this invention is to provide an application of octreotide acetate injection in the preparation of drugs for the treatment of acromegaly, gastrointestinal and pancreatic endocrine tumors, prevention of postoperative complications of pancreatic surgery, and esophageal and gastric variceal bleeding.

[0037] In a preferred embodiment of the present invention, the injection solution is administered intravenously.

[0038] In a preferred embodiment of the present invention, the intravenous injection uses either physiological saline or 5% glucose, or a combination thereof.

[0039] Unless otherwise stated, when this invention relates to percentages between liquids, the percentage is volume / volume percentage; when this invention relates to percentages between liquids and solids, the percentage is volume / weight percentage; when this invention relates to percentages between solids and liquids, the percentage is weight / volume percentage; the remainder is weight / weight percentage.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] 1. This invention scientifically screens the components and ratios used to prepare octreotide acetate injection, optimizes the preparation process and parameters, significantly improves the stability of octreotide acetate injection, significantly reduces or even avoids the risk of microbial infection, significantly improves drug quality, and has good compatibility with any one or combination of physiological saline and 5% glucose, ensuring the safety and effectiveness of clinical use.

[0042] 2. The preparation method of the present invention is simple to operate, shortens the production cycle, reduces material loss and increases yield, requires no special equipment, has better cost, and is suitable for industrial production. Detailed Implementation

[0043] The present invention will be described below with reference to the embodiments, but the present invention is not limited to the embodiments.

[0044] Example 1Preparation of Octreotide Acetate Injection

[0045] The formulation of octreotide acetate injection is as follows (80,000 vials, specification: 0.05mg / ml):

[0046] Octreotide Acetate 4g Phosphoric acid 64g Mannitol 3600g Sodium hydroxide Appropriate amount Water for Injection Add to 80L

[0047] The preparation of octreotide acetate injection includes the following steps:

[0048] (1) Add approximately 85% of the total volume of water for injection below 30°C to the mixing tank, turn on the stirrer (40±2Hz), slowly add the required amount of phosphoric acid and mannitol, rinse the residual phosphoric acid with approximately 2% of the total volume of water for injection to the mixing tank, stir for 5 to 10 minutes to dissolve the mannitol, adjust the pH to 4.0-4.5 with sodium hydroxide solution, and add water for injection to 99% of the total volume;

[0049] (2) Cool the mannitol phosphate buffer to below 30°C, add the required amount of octreotide acetate, rinse the container holding the active ingredient with the remaining water for injection, pour it into the mixing tank, stir (40±2Hz) for 20 minutes to completely dissolve it, test the properties, pH value, bacterial endotoxin, microbial limit and content of the intermediate product, after the test is qualified, filter the drug solution through a 0.22μm polyethersulfone filter for two stages, fill the filtrate, and the yield is 82.9%.

[0050] Example 2 Preparation of Octreotide Acetate Injection

[0051] The formulation of octreotide acetate injection is as follows (80,000 vials, specification: 0.1 mg / ml):

[0052] Octreotide Acetate 8g Phosphoric acid 64g Mannitol 3600g Sodium hydroxide Appropriate amount Water for Injection Add to 80L

[0053] The preparation of octreotide acetate injection includes the following steps:

[0054] (1) Add approximately 85% of the total volume of water for injection below 30°C to the mixing tank, turn on the stirrer (40±2Hz) and slowly add the required amount of phosphoric acid and mannitol. Rinse the residual phosphoric acid with approximately 2% of the total volume of water for injection to the mixing tank, stir for 5 to 10 minutes to dissolve the mannitol, adjust the pH to 4.0-4.5 with sodium hydroxide solution, and add water for injection to 99% of the total volume.

[0055] (2) Cool the mannitol phosphate buffer to below 30°C, add the required amount of octreotide acetate, rinse the container holding the active ingredient with the remaining water for injection, pour it into the mixing tank, stir (40±2Hz) for 20 minutes to completely dissolve it, test the properties, pH value, bacterial endotoxin, microbial limit and content of the intermediate product, after passing the test, filter the drug solution through a 0.22μm polyethersulfone filter for two stages, bottle the filtrate, and the yield is 85.7%.

[0056] Example 3 Preparation of Octreotide Acetate Injection

[0057] The formulation of octreotide acetate injection is as follows (80,000 vials, specification: 0.3mg / ml):

[0058] Octreotide Acetate 24.0g Phosphoric acid 64g Mannitol 3600g Sodium hydroxide Appropriate amount Water for Injection Add to 80L

[0059] The preparation of octreotide acetate injection includes the following steps:

[0060] (1) Add approximately 85% of the total volume of water for injection below 30°C to the mixing tank, turn on the stirrer (40±2Hz) and slowly add the required amount of phosphoric acid and mannitol. Rinse the residual phosphoric acid with approximately 2% of the total volume of water for injection to the mixing tank, stir for 5 to 10 minutes to dissolve the mannitol, adjust the pH to 4.0-4.5 with sodium hydroxide solution, and add water for injection to 99% of the total volume.

[0061] (2) Cool the mannitol phosphate buffer to below 30°C, add the required amount of octreotide acetate, rinse the container holding the active ingredient with the remaining water for injection, pour it into the mixing tank, stir (40±2Hz) for 20 minutes to completely dissolve it, test the properties, pH value, bacterial endotoxin, microbial limit and content of the intermediate product, after the test is qualified, filter the drug solution through a 0.22μm polyethersulfone filter for two stages, bottle the filtrate, and the yield is 83.8%.

[0062] Comparative Example 1 Preparation of Octreotide Acetate Injection

[0063] Composition of octreotide acetate injection (80,000 vials, 0.1 mg / 1 ml):

[0064]

[0065]

[0066] The preparation method of octreotide acetate injection includes the following steps:

[0067] (1) Add approximately 95% of the total volume of water for injection (temperature 80℃) to the mixing tank, turn on the stirrer (40±2Hz) and slowly add the required amount of lactic acid and mannitol. Stir for 5 to 10 minutes to dissolve the mannitol. Adjust the pH value to 4.0-4.5 with 7.5% sodium bicarbonate solution. Add water for injection to the total volume. Check the pH value of the lactate-mannitol buffer solution. It should be within the range of 4.0-4.5.

[0068] (2) Add the required amount of octreotide acetate, stir (40±2Hz) for 20 minutes to dissolve it completely, and perform intermediate product determination to detect its properties, pH value, bacterial endotoxin, microbial limit and content.

[0069] (3) After the properties and pH value are qualified, the drug solution is sterilized by filtering through a 0.22μm polyethersulfone filter and then into a drug solution receiving tank for bottling, with a yield of 77.3%.

[0070] Comparative Example 2 Preparation of Octreotide Acetate Injection of the Present Invention

[0071] The formulation of the octreotide acetate injection of this invention is as follows (80,000 vials, 0.1 mg / 1 ml):

[0072] Octreotide Acetate 8g lactic acid 272g Mannitol 3600g Sodium bicarbonate Appropriate amount (approximately 144g) Water for Injection Add to 80L

[0073] The preparation method of the octreotide acetate pharmaceutical composition of the present invention includes the following steps:

[0074] (1) Add approximately 95% of the total volume of water for injection (temperature 80℃) to the mixing tank, turn on the stirrer (40±2Hz) and slowly add the required amount of lactic acid and mannitol. Stir for 5 to 10 minutes to dissolve the mannitol. Adjust the pH value to 4.0-4.5 with 7.5% sodium bicarbonate solution. Add water for injection to the total volume. Check the pH value of the lactate-mannitol buffer solution. It should be within the range of 4.0-4.5.

[0075] (2) Add the required amount of octreotide acetate, stir (40±2Hz) for 20 minutes to dissolve it completely, and perform intermediate product determination to detect its properties, pH value, bacterial endotoxin, microbial limit and content.

[0076] (3) After the properties and pH value are qualified, the drug solution is filtered and sterilized through a 0.22μm polyethersulfone filter and a 0.45+0.22μm composite polyethersulfone filter and then transferred to a drug solution transfer receiving tank for bottling, with a yield of 80.0%.

[0077] Experimental Example 1: Study on the light stability of octreotide acetate injection

[0078] The octreotide acetate injection of Example 1 and the reference formulation (Sarvastatin, 1 ml: 0.1 mg, manufacturer: Novartis) were exposed to light at 4500 Lx to 500 Lx for 10 days. The results are shown in Table 1. The octreotide acetate injection of Example 1 showed better stability than the reference formulation.

[0079] Table 1

[0080]

[0081] Experimental Example 2: Stability Study of Octreotide Acetate Injection

[0082] The octreotide acetate injection prepared in Example 2 was placed at 25±2℃ and RH 60±10% for 6 months, and the results are shown in Table 2. The octreotide acetate injection in Example 2 has better stability than the reference preparation.

[0083] Table 2

[0084]

[0085] Experimental Example 3: Stability Study of Octreotide Acetate Injection

[0086] The octreotide acetate injection from Example 1 and the reference reagent were respectively mixed with 5% glucose injection, and the related substances were investigated. The results are shown in Table 3. The compatibility stability of the octreotide acetate injection from Example 1 with glucose injection was better than that of the reference preparation.

[0087] Table 3

[0088]

[0089] The above description of specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention, and as long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. An octreotide acetate injection solution, comprising 4g octreotide acetate, 64g phosphoric acid, 3600g mannitol, appropriate amount of sodium hydroxide, and water for injection to a volume of 80L, the preparation method comprising the following steps: (1) Add 85% of the total volume of water for injection below 30°C to the mixing tank, start stirring, slowly add the required amount of phosphoric acid and mannitol, rinse the residual phosphoric acid with 2% of the total volume of water for injection to the mixing tank, stir for 5-10 minutes to dissolve the mannitol, adjust the pH to 4.0-4.5 with sodium hydroxide solution, and add water for injection to 99% of the total volume; (2) Cool the mannitol phosphate buffer to below 30°C, add the required amount of octreotide acetate, rinse the container holding the active ingredient with the remaining water for injection, pour it into the mixing tank, stir for 20 minutes to completely dissolve it, test the properties, pH value, bacterial endotoxin, microbial limit and content of the intermediate product, after the test is qualified, filter the drug solution through a 0.22μm polyethersulfone filter for two stages, fill the filtrate, and obtain the product.

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