Terminal-sterilization-resistant stable ganirelix acetate injection and preparation method thereof

Abstract

The invention provides a stable ganirelix acetate injection capable of resisting terminal sterilization and a preparation method thereof. The injection comprises the following components in percentage by ganirelix, 0.04-0.06% of ganirelix acetate serving as a main drug, 1-3% of polyethylene glycol serving as a stabilizer, 3-6% of mannitol serving as an osmotic pressure regulator and 0.05-0.2% of succinic acid, and the pH value of liquid medicine is regulated to 4.6-5.6 by using a sodium hydroxide solution; and the balance of water for injection. According to the preparation prepared by adopting the prescription, in the long-term storage process, insoluble particles are not obviously increased, the content is stable, related substances, polymers and the like are not obviously increased, meanwhile, succinic acid and sodium hydroxide pH buffer pairs are used in the prescription, and the pH of liquid medicine can be kept unchanged. The adopted preparation process can tolerate terminal sterilization, industrial production is easy to realize, the sterile level of liquid medicine is fully ensured, and the effectiveness and safety during clinical medication are improved.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and relates to a ganirelix acetate injection resistant to terminal sterilization, its preparation process and its preparation method. Background Art

[0002] Ganirelix acetate injection was first registered and launched in the United States by Merck Sharp & Dohme Limited on July 29, 1999, with a specification of 0.5 ml: 0.25 mg (calculated as C 80 H 113 N 18 O 13 Cl); the earliest launch time and region in the European Union were May 16, 2000 (Netherlands). So far, Merck's ganirelix acetate injection has been launched and sold in many countries and regions around the world under trade names such as Orgalutran / Ganirelix Acetate Injection. Ganirelix acetate injection was first applied for import registration in China in 2011 and was successfully approved for listing in 2013 (registration number H20130386). The indication is for use in women undergoing controlled ovarian stimulation (COS) regimens in assisted reproductive technology (ART) to prevent the premature occurrence of the luteinizing hormone (LH) surge. The English trade name is "Ganirelix Injection", the Chinese trade name is "Oujiali", and the specification is 0.5 ml: 0.25 mg (calculated as C 80 H 113 N 18 O 13 Cl).

[0003] Ganirelix (INN) is a synthetic decapeptide that has high antagonistic activity against naturally occurring gonadotropin-releasing hormone (GnRH). The pulsatile release of gonadotropin-releasing hormone (GnRH) can stimulate the synthesis and secretion of LH and FSH. The LH pulse frequency in the mid and late follicular phases is approximately once per hour. These pulses are reflected in the transient increase in serum LH. In the mid-menstrual cycle, a large release of GnRH causes an LH surge. The LH surge in the mid-menstrual cycle can cause several physiological responses, including: ovulation, resumption of oocyte meiosis, and corpus luteum formation. Corpus luteum formation causes an increase in serum progesterone levels and a decrease in estradiol levels. Ganirelix acetate can competitively block the GnRH receptor on pituitary gonadotrophs and the subsequent transduction pathway. It produces a rapid and reversible inhibitory effect on gonadotropin secretion. Ganirelix acetate has a stronger inhibitory effect on pituitary LH secretion than on FSH secretion.

[0004] Ganirelix acetate injection is packaged in a prefilled syringe, which is a new form of drug packaging. It consists of a syringe barrel, a piston, and a cap, and has the advantages of convenient use, accurate dosing, good drug sealing, high stability, and reduced infection risk. It has been found that during the long-term storage of ganirelix acetate injection after sterilization, the insoluble particles in the liquid medicine increase, polymers and related substances increase, and the pH changes, thus increasing the safety risk during clinical medication.

[0005] In the patent of "A drug-loaded microsphere and its preparation method" (CN 112603892), ganirelix is prepared into a microsphere preparation, and the preparation process is complex and difficult to scale up; in the patent of "Injection containing LHRH antagonist" (CN 100404068), surfactants need to be added to reduce the aggregation tendency, improve solubility and bioavailability. However, surfactants can degrade to produce some small molecule substances during long-term storage, which may bring potential safety risks.

[0006] Therefore, it is necessary to provide a stable ganirelix acetate injection that can withstand terminal sterilization and its preparation method. Summary of the Invention

[0007] To solve the above problems, the present invention provides a stable ganirelix acetate injection that can withstand terminal sterilization and its preparation method.

[0008] The technical solution of the present invention is as follows:

[0009] The first object of the present invention is to provide a stable ganirelix acetate injection that can withstand terminal sterilization, and the injection comprises the following components:

[0010] The main drug ganirelix acetate at 0.04% - 0.06% calculated as ganirelix,

[0011] 1% - 3% of the stabilizer polyethylene glycol,

[0012] 3% - 6% of the osmotic pressure regulator mannitol,

[0013] 0.05% - 0.2% of succinic acid,

[0014] Adjust the pH of the liquid medicine to 4.6 - 5.6;

[0015] The balance is water for injection.

[0016] The percentages are all mass percentages,

[0017] Further, the polyethylene glycol is polyethylene glycol 400.

[0018] Further, 10% sodium hydroxide solution is used to adjust the pH of the liquid medicine.

[0019] The second object of the present invention is to provide the preparation method of the above-mentioned ganirelix acetate injection, and the preparation method includes the following steps:

[0020] (1) Dissolve mannitol: Add the prescribed amount of mannitol to water for injection, and stir to dissolve it;

[0021] (2) Dissolve succinic acid: Add the prescribed amount of succinic acid to the liquid medicine (1), and stir to dissolve it;

[0022] (3) Adjust the pH: Use 10% sodium hydroxide solution to adjust the pH of the solution to 4.6 - 5.6;

[0023] (4) Preparation of the polyethylene glycol mixture containing the drug: Pass the raw material drug ganirelix acetate through a 200 - mesh sieve, weigh the prescribed amount of sieved ganirelix acetate, add it to ethanol, and stir to dissolve it; Weigh the prescribed amount of polyethylene glycol, add it to ethanol at 40 - 50 °C, and stir to dissolve it; Slowly add the drug - containing solution to the polyethylene glycol solution, and continuously stir until a homogeneous mixture is formed; Vacuum - dry the mixture until the solvent completely evaporates to prepare a polyethylene glycol mixture containing the drug, and pass this mixture through an 80 - mesh sieve;

[0024] (5) Dissolve the mixture: Add the prepared polyethylene glycol mixture containing the drug to the adjusted solution (3), dissolve it and stir evenly;

[0025] (6) Make up the volume: Add water for injection to make up the volume, and stir evenly;

[0026] (7) Filter: Filter the prepared liquid medicine to prepare the above - mentioned ganirelix acetate injection.

[0027] Further, in step (4), the raw material drug: ethanol = 1:3 w / v, and polyethylene glycol: ethanol = 1:5 w / v.

[0028] Further, the stirring until a homogeneous mixture is formed in step (4) is carried out under homogenizing mixing at 1000 rpm.

[0029] Further, the vacuum drying in step (4) is carried out at 25 °C under a vacuum degree of ≤0.1 MPa.

[0030] Further, the method also includes filling and sterilizing the filtered injection.

[0031] The parameters of the sterilization are 121 °C and 15 min, and it is moist heat sterilization.

[0032] The beneficial effects of the technical solution of the present invention are as follows:

[0033] (1) By adopting the prescription and preparation method of the present invention, the problem that polypeptide drugs are unstable at high temperatures and cannot withstand the high-temperature conditions of terminal sterilization can be effectively solved, and the prepared preparation can withstand terminal sterilization.

[0034] (2) For the preparation prepared by adopting the prescription and preparation method of the present invention, during the long-term storage process, the insoluble particles do not increase significantly, the content is stable, and the related substances, polymers, etc. do not increase significantly.

[0035] (3) During the research process of the present invention, it was found that by first preparing a solution with the pH adjusted and then preparing a copolymer of polyethylene glycol containing the drug, the drug and polyethylene glycol can form a stable copolymer, avoiding the increase in related substances caused by hydrolysis, oxidation, etc. of the drug itself. At the same time, it may also be because the drug forms a copolymer with polyethylene glycol, increasing the steric hindrance of the drug, thereby reducing the drug itself or forming unstable polymers with other components, thus improving the stability of the preparation.

[0036] (4) At the same time, a pH buffer pair of succinic acid and sodium hydroxide is used in the prescription, and the pH of the liquid medicine can remain unchanged. It is easy to realize industrial production, fully ensuring the aseptic level of the liquid medicine and improving the effectiveness and safety during clinical medication. Description of the Drawings

[0037] Figure 1 It is the content determination chromatogram of Example 1;

[0038] Figure 2 It is the related substance determination chromatogram of Example 1;

[0039] Figure 3 It is the polymer determination chromatogram of Example 1;

[0040] Figure 4 It is the content determination chromatogram of Comparative Example 1;

[0041] Figure 5 It is the related substance determination chromatogram of Comparative Example 1;

[0042] Figure 6 It is the polymer determination chromatogram of Comparative Example 1. Detailed Embodiments

[0043] The following further explains the present invention in conjunction with examples, but the examples do not limit the present invention in any form.

[0044] Prescription and Preparation Process of Example 1

[0045] Prescription Information:

[0046]

[0047] Preparation Process:

[0048] (1) Dissolve mannitol: Add 235 g of mannitol to water for injection and stir to dissolve it.

[0049] (2) Dissolve succinic acid: Add 6 g of succinic acid to the liquid medicine (1) and stir to dissolve it.

[0050] (3) Adjust the pH: Use 10% sodium hydroxide solution to adjust the pH of the solution to 4.6 - 5.6.

[0051] (4) Preparation of the drug-containing polyethylene glycol mixture: Pass the raw drug ganirelix acetate through a 200-mesh sieve, weigh 2.5 g of the sieved ganirelix acetate, add it to ethanol, and stir to dissolve it. The ratio of the raw drug to ethanol is 1:3 w / v. Weigh 50 g of polyethylene glycol, add it to ethanol at 40 - 50 °C, and stir to dissolve it. The ratio of polyethylene glycol to ethanol is 1:5 w / v. Slowly add the drug-containing solution to the polyethylene glycol solution, and use a homogenizing mixer at 1000 rpm to continuously stir until a homogeneous mixture is formed. Pour the mixture into a shallow stainless steel tray, place it in a vacuum drying oven, and dry it at 25 °C under a vacuum of ≤0.1 MPa for about 6 h until the solvent completely evaporates to obtain the drug-containing polyethylene glycol mixture. Pass this mixture through an 80-mesh sieve.

[0052] (5) Dissolve the mixture: Add the prepared drug-containing polyethylene glycol mixture to the adjusted solution (3), dissolve it, and stir evenly.

[0053] (6) Make up the volume: Add water for injection to make up to 5000 g and stir evenly.

[0054] (7) Filter: Filter the prepared liquid medicine through two 0.22-μm filters into a storage tank, take samples for inspection of the intermediate product, and start filling after passing the inspection.

[0055] (8) Fill: After filtering, fill the liquid medicine into a pre-filled syringe, with a filling volume of 0.6 ml, and then add a stopper.

[0056] (9) Sterilize: Place the above filled samples in a sterilization cabinet, set the sterilization parameters at 121 °C for 15 min, and perform moist heat sterilization.

[0057] (10) Add the plunger: After sterilization, take out each sample, let it cool to room temperature, and add a plunger to the syringe to obtain the finished product.

[0058] Example 2 Prescription and Preparation Process

[0059] Prescription information:

[0060]

[0061] Preparation process:

[0062] (1) Dissolve mannitol: Add 235 g of mannitol to water for injection and stir to dissolve it.

[0063] (2) Dissolve succinic acid: Add 6 g of succinic acid to the medicinal solution (1) and stir to dissolve it.

[0064] (3) Adjust the pH: Use 10% sodium hydroxide solution to adjust the pH of the solution to 4.6 - 5.6.

[0065] (4) Preparation of the polyethylene glycol mixture containing the drug: Pass the raw drug ganirelix acetate through a 200 - mesh sieve. Weigh 2.5 g of the sieved ganirelix acetate and add it to ethanol, stirring to dissolve. The ratio of raw drug to ethanol is 1:3 w / v. Weigh 100 g of polyethylene glycol and add it to ethanol at 40 - 50 °C, stirring to dissolve. The ratio of polyethylene glycol to ethanol is 1:5 w / v. Slowly add the drug - containing solution to the polyethylene glycol solution and use a homogenizing mixer at 1000 rpm to continuously stir until a homogeneous mixture is formed. Pour the mixture into a shallow stainless - steel tray and place it in a vacuum drying oven. At 25 °C and a vacuum degree ≤ 0.1 MPa, dry for about 6 h until the solvent completely evaporates to obtain the polyethylene glycol mixture containing the drug. Pass this mixture through an 80 - mesh sieve.

[0066] (5) Dissolve the mixture: Add the prepared polyethylene glycol mixture containing the drug to the adjusted solution (3), dissolve and stir evenly.

[0067] (6) Make up the volume: Add water for injection to make up to 5000 g and stir evenly.

[0068] (7) Filter: Filter the prepared medicinal solution through two 0.22 - μm filters into a storage tank, take samples for inspection of the intermediate. After passing the inspection, start filling.

[0069] (8) Fill: After filtering, fill the medicinal solution into pre - filled syringes. The filling volume is 0.6 ml, and then add stoppers.

[0070] (9) Sterilize: Place the above - filled samples in a sterilization cabinet, set the sterilization parameters at 121 °C for 15 min, and perform moist heat sterilization.

[0071] (10) Add the plunger: After sterilization, take out each sample, let it cool to room temperature, and add a plunger to the syringe to obtain the finished product.

[0072] Example 3 Prescription and Preparation Process

[0073] Prescription information:

[0074]

[0075] [[ID=4@]

[0076] Preparation process:

[0077] (1) Dissolve mannitol: Add 235 g of mannitol to water for injection and stir to dissolve it.

[0078] (2) Dissolve succinic acid: Add 6 g of succinic acid to the medicinal solution (1) and stir to dissolve it.

[0079] (3) Adjust the pH: Use 10% sodium hydroxide solution to adjust the pH of the solution to 4.6 - 5.6.

[0080] (4) Preparation of the drug-containing polyethylene glycol mixture: Pass the raw drug ganirelix acetate through a 200-mesh sieve. Weigh 2.5 g of the sieved ganirelix acetate and add it to ethanol, stirring to dissolve it. The ratio of the raw drug to ethanol is 1:3 w / v. Weigh 150 g of polyethylene glycol and add it to ethanol at 40 - 50 °C, stirring to dissolve it. The ratio of polyethylene glycol to ethanol is 1:5 w / v. Slowly add the drug-containing solution to the polyethylene glycol solution and use a homogenizing mixer at 1000 rpm to continuously stir until a homogeneous mixture is formed. Pour the mixture into a shallow stainless steel tray and place it in a vacuum drying oven. Dry it at 25 °C under a vacuum of ≤ 0.1 MPa for about 6 h until the solvent completely evaporates to prepare the drug-containing polyethylene glycol mixture. Pass this mixture through an 80-mesh sieve.

[0081] (5) Dissolve the mixture: Add the prepared drug-containing polyethylene glycol mixture to the adjusted solution (3), dissolve it and stir evenly.

[0082] (6) Make up the volume: Add water for injection to make up to 5000 g and stir evenly.

[0083] (7) Filtration: Filter the prepared medicinal solution through two 0.22-μm filters into a storage tank, take samples for inspection of the intermediate. After passing the inspection, start filling.

[0084] (8) Filling: Fill the filtered medicinal solution into a pre-filled syringe, with a filling volume of 0.6 ml, and then add a stopper.

[0085] (9) Sterilization: Place the above-filled samples in a sterilization cabinet, set the sterilization parameters at 121 °C for 15 min, and carry out moist heat sterilization.

[0086] (10) Add the plunger: After sterilization, take out each sample, let it cool to room temperature, and add a plunger to the syringe to obtain the finished product.

[0087] Comparison with the reference preparation in Comparative Example 1

[0088] Information of the reference preparation:

[0089] Trade name of the reference preparation:

[0090] Reference preparation specification: 0.5 ml: 0.25 mg.

[0091] Reference preparation batch number: R015090.

[0092] Reference preparation manufacturer: Merck & Co., Inc.

[0093] Comparison of preparation process sequence in Comparative Example 2. Polyethylene glycol was simply dissolved and added to the prescription without forming a copolymer with the drug.

[0094] (1) Weigh the active ingredient: Weigh 2.5 g of the active ingredient (calculated as ganirelix) according to the prescription for standby.

[0095] (2) Dissolve mannitol: Measure 4000 g of injection water and place it in the liquid preparation tank. Add 235 g of mannitol according to the prescription and stir until completely dissolved.

[0096] (3) Dissolve succinic acid: Weigh 6 g of succinic acid according to the prescription and add it to the mannitol solution in (2), and stir to mix evenly.

[0097] (4) Dissolve polyethylene glycol 400: Measure 50 g of polyethylene glycol 400 according to the prescription and add it to the excipient solution in (3), and stir to mix evenly.

[0098] (5) Adjust the pH: Adjust the pH value to 4.9 using sodium hydroxide solution.

[0099] (6) Dissolve the active ingredient: Add the weighed active ingredient to the excipient solution in (5). After stirring evenly, measure the pH value of the liquid medicine.

[0100] (7) Make up the volume: Add injection water to make up to 5000 g and stir evenly.

[0101] (8) Filtration: Filter the prepared liquid medicine through two 0.22 μm filters into the storage tank, take samples to detect the intermediate, and start filling after passing the inspection.

[0102] (9) Filling: Fill the filtered liquid medicine into pre-filled syringes, with a filling volume of 0.6 ml, and then stopper.

[0103] (10) Sterilization: Place the filled samples in the sterilization cabinet, set the sterilization parameters to 121 °C for 15 minutes, and perform moist heat sterilization.

[0104] (11) Add the plunger: After sterilization, take out each sample, cool it to room temperature, and add a plunger to the syringe to obtain the finished product. Comparative Example 3 Comparison of the reduction of polyethylene glycol 400

[0105] Prescription information:

[0106]

[0107] Preparation process:

[0108] (1) Dissolve mannitol: Add 235 g of mannitol to water for injection and stir to dissolve it;

[0109] (2) Dissolve succinic acid: Add 6 g of succinic acid to the liquid medicine (1) and stir to dissolve it;

[0110] (3) Adjust the pH: Use 10% sodium hydroxide solution to adjust the pH of the solution to 4.6 - 5.6;

[0111] (4) Preparation of the polyethylene glycol mixture containing the drug: Pass the raw drug ganirelix acetate through a 200 - mesh sieve, weigh 2.5 g of the sieved ganirelix acetate, add it to ethanol and stir to dissolve it, raw drug:ethanol = 1:3 w / v; Weigh 30 g of polyethylene glycol, add it to ethanol at 40 - 50 °C and stir to dissolve it, polyethylene glycol:ethanol = 1:5 w / v; Slowly add the drug - containing solution to the polyethylene glycol solution, and use a homogenizing mixer at 1000 rpm to continuously stir until a uniform mixture is formed; Pour the mixture into a shallow stainless - steel tray, place it in a vacuum drying oven, and dry it at 25 °C under a vacuum degree ≤ 0.1 MPa for about 6 h until the solvent completely evaporates, to prepare the polyethylene glycol mixture containing the drug, and pass this mixture through an 80 - mesh sieve;

[0112] (5) Dissolve the mixture: Add the prepared polyethylene glycol mixture containing the drug to the adjusted solution (3), dissolve it and stir evenly;

[0113] (6) Make up the volume: Add water for injection to make up to 5000 g and stir evenly;

[0114] (7) Filtration: Filter the prepared liquid medicine through two 0.22 - μm filters into a storage tank, take samples to detect the intermediate, and start filling after passing the inspection.

[0115] (8) Filling: Fill the filtered liquid medicine into a pre - filled syringe, the filling volume is 0.6 ml, and then add a stopper.

[0116] (9) Sterilization: Place the above - filled samples in a sterilization cabinet, set the sterilization parameters at 121 °C for 15 min, and carry out moist heat sterilization.

[0117] (10) Add the plunger: After sterilization, take out each sample, let it cool to room temperature, add a plunger to the syringe to obtain the finished product. Comparison of swapping the preparation process sequence in Comparative Example 4

[0118] Prescription information:

[0119]

[0120] Preparation process:

[0121] (1) Dissolve mannitol: Add 235 g of mannitol to water for injection and stir to dissolve it.

[0122] (2) Preparation of drug-containing polyethylene glycol mixture: Pass the raw drug ganirelix acetate through a 200-mesh sieve. Weigh 2.5 g of the sieved ganirelix acetate and add it to ethanol, stirring to dissolve. The ratio of raw drug to ethanol is 1:3 w / v. Weigh 50 g of polyethylene glycol and add it to ethanol at 40 - 50 °C, stirring to dissolve. The ratio of polyethylene glycol to ethanol is 1:5 w / v. Slowly add the drug-containing solution to the polyethylene glycol solution and use a homogenizing mixer at 1000 rpm to continuously stir until a homogeneous mixture is formed. Pour the mixture into a shallow stainless-steel tray and place it in a vacuum drying oven. Dry it at 25 °C under a vacuum of ≤0.1 MPa for about 6 h until the solvent completely evaporates to obtain the drug-containing polyethylene glycol mixture. Pass this mixture through an 80-mesh sieve.

[0123] (3) Dissolve the mixture: Add the prepared drug-containing polyethylene glycol mixture to the adjusted solution (1), dissolve it and stir evenly.

[0124] (4) Dissolve succinic acid: Add 6 g of succinic acid to the drug solution (3) and stir to dissolve it.

[0125] (5) Adjust the pH: Use 10% sodium hydroxide solution to adjust the pH of the solution to 4.6 - 5.6.

[0126] (6) Make up the volume: Add water for injection to make up to 5000 g and stir evenly.

[0127] (7) Filtration: Filter the prepared drug solution through two 0.22 μm filter elements into a storage tank, take samples for inspection of intermediates. After passing the inspection, start filling.

[0128] (8) Filling: After filtration, fill the drug solution into pre-filled syringes. The filling volume is 0.6 ml, and then add stoppers.

[0129] (9) Sterilization: Place the above filled samples in a sterilization cabinet, set the sterilization parameters at 121 °C for 15 min, and carry out moist heat sterilization.

[0130] (10) Add plungers: After sterilization, take out each sample, let it cool to room temperature, and add plungers to the syringes to obtain the finished products.

[0131] Place the samples prepared in Examples 1 - 3 and the samples in Comparative Examples 1 - 4 under the accelerated test conditions of 40 °C and 75% RH. Take them out at 1, 2, 3, and 6 months respectively to measure the content, polymer, related substances, insoluble particles, pH and other test items; place each sample under the long-term test conditions of 25 °C and 60% RH and take them out at 6, 12, and 24 months respectively to measure each test item.

[0132] Method for determining insoluble particles:

[0133] Take ultrapure water, filter it by suction through a 0.22 μm water-based filter membrane, and use it as the water for particle inspection, and set it aside. Set the parameters of the particle detector according to the requirements of the Chinese Pharmacopoeia, and set the channels to 10 μm and 25 μm. Among them, when detecting the water for particle inspection, the injection volume is set to 5.0 ml, and the pre-injection volume is set to 1.0 ml; when detecting the sample, the injection volume is set to 5.0 ml, and the pre-injection volume is set to 1.0 ml. The number of injection times is 3 times. Each time, 100 samples are taken, combined in the sampling cup, and then detected.

[0134] Method for content determination:

[0135] Determine according to the high performance liquid chromatography method in the Chinese Pharmacopoeia. Test solution: Take this product to obtain it. Reference solution: Take an appropriate amount of ganirelix acetate reference substance, weigh it accurately, dissolve it with the excipient solution and quantitatively dilute it to make a solution containing 0.5 mg of ganirelix per 1 ml. Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler (Inertil ODS-3 4.6×250 mm, 5 μm chromatographic column); use the solvent under the related substances item as the mobile phase, and perform isocratic elution for 30 min; the detection wavelength is 240 nm; the column temperature is 30 °C; the injection volume is 10 μl. Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, record the chromatogram, and calculate according to the external standard method with the peak area, see Figure 1 .

[0136] Method for determination of related substances:

[0137] Determine according to the high performance liquid chromatography method in the Chinese Pharmacopoeia. Solvent: Use a buffer solution (aqueous solution containing 0.2 mol / L potassium dihydrogen phosphate and 0.5 mol / L sodium acetate, adjusted to pH 3.0 with phosphoric acid)-water-acetonitrile (60:20:20). Test solution: Take an appropriate amount of this product and dilute it with the solvent to make a solution containing 0.25 mg of ganirelix per 1 ml. Control solution: Accurately measure 1 ml of the test solution, place it in a 100 ml volumetric flask, and dilute it to the mark with the diluent [solvent-water (70:30)]. Chromatographic conditions: Use octadecyl bonded silica gel as the filler (Inertil ODS-3 4.6×250 mm, 5 μm chromatographic column); use an aqueous solution containing 0.2 mol / L potassium dihydrogen phosphate and 0.5 mol / L sodium sulfate as mobile phase A, mobile phase B is water, and mobile phase C is water-acetonitrile (20:80), and perform gradient elution as follows; the detection wavelength is 230 nm; the column temperature is 30 °C; the injection volume is 20 μl. Determination method: Accurately measure the test solution and the control solution, inject them into the liquid chromatograph respectively, record the chromatogram, see Figure 2 .

[0138] Gradient elution program for determination of related substances

[0139]

[0140] Polymer determination method:

[0141] Determined by high performance liquid chromatography according to the Chinese Pharmacopoeia. Solvent: trifluoroacetic acid - water - acetonitrile (0.2:30:70). Test solution: Take an appropriate amount of this product and dilute it with the solvent to prepare a solution containing ganirelix 0.25 mg per 1 ml. Control solution: Accurately measure 1 ml of the test solution and transfer it to a 100 - ml volumetric flask, dilute it with the diluent [solvent - water (80:20)] to the scale to prepare a solution containing approximately 2.5 μg of ganirelix per 1 ml as the control solution. Chromatographic conditions: Use spherical hydrophilic modified silica gel (TSK - GEL G2000SWXL, 7.8 mm × 300 mm × 5 μm, ) as the filler; use trifluoroacetic acid - water - acetonitrile (0.2:60:40) as the mobile phase; the detection wavelength is 230 nm; the column temperature is 30 °C; the injection volume is 20 μl. Determination method: Accurately measure the test solution and the control solution, inject them into the liquid chromatograph respectively, record the chromatogram, see Figure 3 .

[0142] The results of the accelerated test and long - term test stability determination of the samples in each example and the comparative example are as follows:

[0143] Stability test results of each sample under accelerated test conditions

[0144]

[0145]

[0146]

[0147] Stability test results of each sample under long - term test conditions

[0148]

[0149]

[0150] The above research shows that, compared with the comparative example, during the 6 - month accelerated test, 24 - month long - term test and the storage process of the medicinal liquid of the present invention, the main drug content, related substances, polymers, etc. have not increased significantly, the pH of the medicinal liquid can remain unchanged, and the quality is stable, thus ensuring the effectiveness and safety during clinical medication.

[0151] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A stable ganirelix acetate injection resistant to terminal sterilization, characterized in that, The injection solution comprises the following components: The main drug ganirelix acetate at 0.04% - 0.06% calculated as ganirelix, 1% - 3% of the stabilizer polyethylene glycol, 3% - 6% of the osmotic pressure regulator mannitol, 0.05% - 0.2% of succinic acid, Adjusting the pH of the liquid medicine to 4.6 - 5.6; The balance is water for injection.

2. The ganirelix acetate injection according to claim 1, wherein, The polyethylene glycol is polyethylene glycol 400.

3. The ganirelix acetate injection according to claim 1, wherein, Adjust the pH of the liquid medicine using 10% sodium hydroxide solution.

4. The preparation method of ganirelix acetate injection according to claim 1, characterized in that, The preparation method comprises the following steps: (1) Dissolve mannitol: Add the prescribed amount of mannitol to water for injection and stir to dissolve it; (2) Dissolve succinic acid: Add the prescribed amount of succinic acid to the liquid medicine (1) and stir to dissolve it; (3) Adjust the pH: Use 10% sodium hydroxide solution to adjust the pH of the solution to 4.6 - 5.6; (4) Preparation of the polyethylene glycol mixture containing the drug: Pass the raw material drug ganirelix acetate through a 200 - mesh sieve, weigh the prescribed amount of the sieved ganirelix acetate, add it to ethanol and stir to dissolve; Weigh the prescribed amount of polyethylene glycol, add it to ethanol at 40 - 50 °C and stir to dissolve; Slowly add the drug - containing solution to the polyethylene glycol solution and continuously stir until a homogeneous mixture is formed; Vacuum - dry the mixture until the solvent completely evaporates to prepare the polyethylene glycol mixture containing the drug, and pass this mixture through an 80 - mesh sieve; (5) Dissolve the mixture: Add the prepared polyethylene glycol mixture containing the drug to the adjusted solution (3), dissolve and stir evenly; (6) Make up the volume: Add water for injection to make up the volume and stir evenly; (7) Filter: Filter the prepared liquid medicine to prepare the ganirelix acetate injection solution.

5. The preparation method according to claim 4, characterized in that, In step (4), the ratio of the raw material drug to ethanol is 1:3 w / v, and the ratio of polyethylene glycol to ethanol is 1:5 w / v.

6. The preparation method according to claim 4, characterized in that, The stirring in step (4) until a homogeneous mixture is formed is carried out under homogenizing mixing at 1000 rpm.

7. The preparation method according to claim 4, wherein The vacuum drying in step (4) is carried out at 25 °C under a vacuum degree ≤ 0.1 MPa.

8. The preparation method according to claim 4, characterized in that, The method further comprises filling and sterilizing the filtered injection solution.

9. The preparation method according to claim 8, characterized in that, The parameters of the sterilization are 121 °C and 15 min, by moist heat sterilization.

Images