Carbetocin injection and preparation method thereof

Abstract

The application provides a carbetocin injection and a preparation method thereof, and belongs to the technical field of preparations. The preparation method is as follows: a pH regulator is used to prepare an aqueous solution, 50 parts by weight of glucose, 10-15 parts by weight of polyethylene glycol 300 and 5-8 parts by weight of sodium alginate are fully dissolved, 1-3 parts by weight of an antioxidant and 0.1 part by weight of carbetocin are added to the obtained system, the system is dissolved, the volume is fixed, the system is filtered, and the system is filled and sealed to obtain the carbetocin injection. The specific dose of glucose, polyethylene glycol 300 and sodium alginate is added as an auxiliary material, the three materials are matched with each other, the viscosity, density and intermolecular gap of the carbetocin in the injection are improved, so that the carbetocin in the carbetocin injection is prevented from gathering when the carbetocin injection is shaken, and the stability of the carbetocin injection is improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the preparation technology of pharmaceutical preparation, in particular to a carbetocin injection and a preparation method thereof. BACKGROUND

[0002] Carbetocin, also known as carbetocin acetate or carbetocin, is a synthetic long-acting oxytocin nonapeptide analogue with agonist properties. Its clinical and pharmacological properties are similar to those of naturally occurring oxytocin. Like oxytocin, carbetocin binds to the oxytocin receptors of uterine smooth muscle, causing rhythmic contractions of the uterus, increasing the frequency of contractions and increasing uterine tone. In a non-pregnant state, the content of uterine oxytocin receptors is low, which increases during pregnancy and reaches a peak at the time of delivery. Carbetocin is mainly used to prevent uterine atony and postpartum hemorrhage after selective epidural or spinal anesthesia for cesarean section.

[0003] Carbetocin is a special peptide, which is uncharged, ring-shaped in structure, has high lipophilicity, and does not have a stable tertiary structure. Therefore, carbetocin is a peptide with obvious aggregation tendency, which leads to poor physical stability of carbetocin. The existing carbetocin injection needs to be stored at low temperature, and also needs to avoid shaking during transportation, storage and use.

[0004] At present, the skilled person in the art has tried to improve the stability problem of carbetocin injection by adding surfactants or antioxidants, but these methods can only improve the stability of carbetocin at room temperature. When subjected to shaking, carbetocin in carbetocin injection will still aggregate. However, the problem of being subjected to shaking cannot be completely avoided during the actual transportation, storage and use of carbetocin injection. Therefore, how to improve the stability of carbetocin injection and prevent carbetocin from aggregating in solution still needs to be studied. SUMMARY

[0005] In view of the above problems, the present application provides a preparation method of carbetocin and a preparation method of carbetocin injection.

[0006] To achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows:

[0007] A carbetocin injection, by weight, the raw materials for preparing the carbetocin injection include: carbetocin 0.1 parts, glucose 50 parts, polyethylene glycol 300 10-15 parts, sodium alginate 5-8 parts, antioxidant 1-3 parts and pH adjuster.

[0008] Further, the pH value of the carbetocin injection is 5.4-6.0.

[0009] Furthermore, the pH adjuster is a mixture of 3.99 to 6.72 parts by weight of citric acid and 20 to 23.82 parts by weight of sodium citrate.

[0010] Furthermore, the antioxidant is vitamin E.

[0011] Furthermore, the preparation method comprises preparing an aqueous solution with a pH regulator, adding glucose, polyethylene glycol 300 and sodium alginate and fully dissolving them, then adding an antioxidant and carbetocin to the resulting system, dissolving the solution, fixing the volume, filtering and encapsulating the solution to obtain the carbetocin injection.

[0012] Furthermore, the carbetocin needs to be stirred during the dissolution process; the stirring speed is 145-155 rpm and the stirring time is controlled within 10 minutes.

[0013] Furthermore, the system needs to be cooled to 10-20°C before adding the antioxidant and carbetocin for dissolution. The dissolution temperature of the antioxidant and carbetocin is 10-20°C.

[0014] Furthermore, the filtration is performed by first filtering through a 0.45 μm filter element, then by a second filtering through a 0.22 μm filter element, and then by a third filtering through a 0.22 μm filter element.

[0015] Furthermore, the pressure of the first filtration is ≤0.38 MPa, and the pressure of the second and third filtrations is ≤0.30 MPa; and the temperature of the three filtrations is 10-20°C.

[0016] Furthermore, during the potting process, nitrogen gas with a pressure of 0.2 to 0.4 MPa needs to be injected.

[0017] The beneficial effects of the preparation method of carbetocin and the preparation method of carbetocin injection of the present invention are:

[0018] The present invention adds specific doses of glucose, polyethylene glycol 300, and sodium alginate as excipients. The three cooperate with each other to improve the viscosity and density of the injection and the molecular spacing of carbetocin in the injection, thereby preventing the carbetocin contained therein from aggregating when the carbetocin injection is shaken, thereby improving the stability of the carbetocin injection.

[0019] At the same time, the glucose and polyethylene glycol 300 in the present invention also have a certain solubility-promoting effect, which can promote the dissolution of carbetocin in the injection solution and further prevent the aggregation and precipitation of carbetocin;

[0020] The present invention uses vitamin E as an antioxidant to effectively inhibit the oxidative degradation of carbetocin, thereby improving the stability of carbetocin injection;

[0021] The glucose in the present invention can also act as an isotonicity regulator, which is beneficial to improving the safety of the carbetocin injection. DETAILED DESCRIPTION

[0022] The technical solutions in the embodiments of the present invention are described clearly and completely below. Many specific details are set forth in the following description to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0023] Example 1 A method for preparing carbetocin injection

[0024] This embodiment is a method for preparing carbetocin injection, comprising the following specific steps:

[0025] 5.78 g of citric acid and 21.32 g of sodium citrate were added to 0.8 L of water for injection to prepare an aqueous solution. 50 g of glucose, 12 g of polyethylene glycol 300 and 7 g of sodium alginate were added to the obtained aqueous solution and stirred to fully dissolve. The obtained system was cooled to 15 ° C (the temperature after cooling was marked as T, that is, T = 15 ° C in this embodiment), and then 2 g of vitamin E and 100 mg of carbetocin were added. The mixture was stirred and dissolved at 15 ° C with a speed of 150 rpm, and the stirring and dissolving time was controlled within 10 min (8 min in this embodiment), and the volume was adjusted to 1 L. The mixture was filtered through a 0.45 μm filter element in sequence. The first filtration was performed at a pressure of ≤0.38 MPa (0.35 MPa in this embodiment), followed by a second filtration through a 0.22 μm filter element, and then a third filtration through a 0.22 μm filter element. The pressures of the second and third filtrations were ≤0.30 MPa; the temperature of the three filtrations was 15 ° C. After the three filtrations were completed, the filtrate was potted. During the potting process, the filtrate was filled into an ampoule and filled with nitrogen at a pressure of 0.3 MPa to remove oxygen, thereby obtaining the carbetocin injection, which was labeled K1. The pH value of the carbetocin injection was 5.6.

[0026] Preparation method of carbetocin of embodiment 2~5

[0027] Examples 2 to 5 are respectively methods for preparing carbetocin. The steps thereof are substantially the same as those of Example 1, and the only difference is the process parameters. See Table 1 for details:

[0028] Table 1 List of process parameters in Examples 2 to 5

[0029]

[0030]

[0031] The process parameters and steps of other parts of Examples 2 to 5 are the same as those of Example 1.

[0032] Experimental Example 1

[0033] Comparative Examples 1 to 9 are comparative tests for preparing carbetocin in Example 1, with the only difference being that:

[0034] 7 g of polyethylene glycol 300 and 7 g of sodium alginate were added to Comparative Example 1, and the resulting carbetocin injection was labeled DK1;

[0035] In Comparative Example 2, 17 g of polyethylene glycol 300 and 7 g of sodium alginate were added, and the resulting carbetocin injection was labeled DK2;

[0036] In Comparative Example 3, 12 g of polyethylene glycol 300 and 12 g of sodium alginate were added, and the resulting carbetocin injection was labeled DK3;

[0037] In Comparative Example 4, 17 g of polyethylene glycol 300 and 3 g of sodium alginate were added, and the resulting carbetocin injection was labeled DK4;

[0038] In Comparative Example 5, 7 g of polyethylene glycol 300 and 12 g of sodium alginate were added, and the resulting carbetocin injection was labeled DK5;

[0039] In Comparative Example 6, 12 g of polyethylene glycol 300 and 3 g of sodium alginate were added, and the resulting carbetocin injection was labeled DK6;

[0040] In Comparative Example 7, 9 g of sodium chloride was used instead of 50 g of glucose, and the resulting carbetocin injection was labeled DK7;

[0041] The pH value of the carbetocin injection in Comparative Example 8 is 4.0, and the label code of the obtained carbetocin injection is DK8;

[0042] The pH value of the carbetocin injection in Comparative Example 9 is 6.6, and the label code of the obtained carbetocin injection is DK9.

[0043] 1. Oscillation experiment

[0044] Carbetocin injections K1-K5 and DK1-DK9 prepared in Examples 1-5 and Comparative Examples 1-9 were placed in an oscillator, and continuously oscillated at a shaking speed of 200 rpm and an inclination angle of 8° for 12 h and 24 h at room temperature in the dark. The precipitates were taken out and observed (it should be noted that the amount of precipitation was less than the amount of precipitation with a small amount of precipitation, the amount of precipitation with a small amount of precipitation was less than the amount of precipitation with precipitation, and the amount of precipitation with precipitation was less than the amount of precipitation with obvious precipitation). The specific results are shown in the table below:

[0045] Table 2 Oscillation results list

[0046]

[0047] As can be seen from Table 2, the carbetocin injection prepared by the present invention can effectively inhibit the aggregation of the carbetocin contained therein when subjected to shock, and has good stability.

[0048] 2. Freezing, thawing, and shaking experiments

[0049] Carbetocin injections K1-K5 and DK1-DK9 prepared in Examples 1-5 and Comparative Examples 1-9 were frozen at -20 ° C for 24 h, taken out and thawed, placed in an oscillator, and continuously oscillated at a shaking speed of 200 rpm and an inclination angle of 8 ° at room temperature for 12 h and 24 h in the dark. The precipitation was observed (it should be noted that the amount of precipitation was less than the amount of precipitation with a small amount of particle precipitation, the amount of precipitation with a small amount of particle precipitation was less than the amount of precipitation with precipitation, and the amount of precipitation with precipitation was less than the amount of precipitation with obvious precipitation). The specific results are shown in the table below:

[0050] Table 3 Oscillation results list

[0051]

[0052] As can be seen from Table 3, the carbetocin injection prepared by the present invention can still effectively inhibit the aggregation of the carbetocin contained therein when subjected to shock even after freezing and thawing, and has good stability.

[0053] 3. Accelerated Test

[0054] Carbetocin injections K1-K5 and DK1-DK9 prepared in Examples 1-5 and Comparative Examples 1-9 were placed at 40±2°C and RH75±5% for 6 months. Samples were taken at 1, 2, 3, and 6 months, tested according to the stability test items, and compared with the 0-day data.

[0055] The clarity, color, visible foreign matter or precipitation and other indexes were observed, and the content of carbetocin in the carbetocin injection was detected according to the method in "Analysis of Carbetocin and Related Impurities by High Performance Liquid Chromatography" (Zhang Hui et al., Journal of Pharmaceutical Analysis, 2007(10)), and the specific detection results are shown in the following table:

[0056] Table 4: Detection results

[0057]

[0058]

[0059]

[0060] As shown in Table 4, the carbetocin injection prepared in Examples 1-6 of the present application has good stability even under high temperature and high humidity conditions.

[0061] Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the protection scope of the present application.

Claims

1. A carbetocin injection, characterized in that, The raw materials for making the carbetocin injection include, by weight: 0.1 parts of carbetocin, 50 parts of glucose, 10-15 parts of polyethylene glycol 300, 5-8 parts of sodium alginate, 1-3 parts of antioxidant and a pH regulator; The pH value of the carbetocin injection is 5.4-6.

0.

2. The carbetocin injection according to claim 1, characterized in that The pH regulator is a mixture of citric acid and sodium citrate.

3. The carbetocin injection according to claim 1, characterized in that The antioxidant is vitamin E.

4. The method for preparing the carbetocin injection according to any one of claims 1 to 3, characterized in that: The preparation method comprises the following steps: preparing an aqueous solution with a pH regulator, adding glucose, polyethylene glycol 300 and sodium alginate to fully dissolve the mixture, adding an antioxidant and carbetocin to the resulting system, dissolving the mixture, fixing the volume, filtering and encapsulating the mixture to obtain the carbetocin injection.

5. The method for preparing carbetocin injection according to claim 4, wherein The carbetocin needs to be stirred during the dissolution process; the stirring speed is 145-155 rpm and the time is controlled within 10 minutes.

6. The method for preparing the carbetocin injection according to claim 4 or 5, wherein: The system needs to be cooled to 10-20°C before adding the antioxidant and carbetocin for dissolution. The dissolution temperature of the antioxidant and carbetocin is 10-20°C.

7. The method for preparing the carbetocin injection according to claim 4 or 5, characterized in that: The filtration is carried out in sequence by first filtering through a 0.45 μm filter element, then second filtering through a 0.22 μm filter element, and then third filtering through a 0.22 μm filter element.

8. The method for preparing carbetocin injection according to claim 7, wherein The pressure of the first filtration is ≤0.38 MPa, and the pressure of the second and third filtrations is ≤0.30 MPa; the temperature of the three filtrations is 10-20°C.

9. The method for preparing the carbetocin injection according to claim 4, 5 or 8, wherein: During the potting process, nitrogen gas with a pressure of 0.2-0.4 MPa needs to be filled in.

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