Heparin sodium tube sealing injection and preparation method thereof

Abstract

The invention provides a heparin sodium tube-sealing injection and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, and the preparation method comprises the following steps: adding an alkaline solution into a mixed solution of heparin sodium and sodium chloride to adjust the pH to 6.5-7.5 to obtain the heparin sodium tube-sealing injection, wherein the alkaline solution is added in stages, and the addition amount of each stage is gradually reduced, according to the preparation method of the heparin sodium tube sealing injection, the alkaline solution is added in a mode that the addition amount is gradually reduced in the preparation process, the pH value of the solution is adjusted to 6.5-7.5, the stability of the product is improved, and the injection quality is improved. The alkaline solution is adopted to stabilize the heparin sodium tube sealing injection system, the solution can stabilize without introducing other substances such as buffer salt, the valence of the product and the indexes of related substances can be ensured to meet the requirements without introducing other substances, and the level of the quality standard of the product is further improved.

Description

Technical Field

[0001] The invention relates to the technical field of medical preparations, in particular to a sodium heparin tube-sealing injection and a preparation method thereof. Background Art

[0002] In the existing preparation method of sodium heparin catheter sealing injection, crude sodium heparin is usually used as a raw material, and the sodium heparin catheter sealing injection is prepared through salt hydrolysis, ion exchange, ultrafiltration, freeze drying, osmotic pressure adjustment pretreatment and terminal sterilization. The existing preparation method of sodium heparin catheter sealing injection establishes an isotonic system by adding sodium chloride, and adds components such as phenol and buffer salt to improve the stability of sodium heparin.

[0003] However, the stability of sodium heparin is affected by many factors, including environmental conditions during the raw material production process, process parameters during the preparation process, etc. In the process of raw material production and preparation, improper control of environmental process conditions will have a significant impact on the stability of sodium heparin, reduce the efficacy, and the degradation products may also produce toxic side effects. In order to improve the stability of sodium heparin tube sealing injection, the sodium heparin tube sealing injection produced by conventional process mainly improves the stability of sodium heparin by adding components such as phenol and buffer salts. However, this method is not only prone to cause local irritation, bleeding or allergic problems, but also increases the interference with the quality detection of sodium heparin tube sealing injection.

[0004] In view of this, the present invention is proposed. Summary of the invention

[0005] One of the purposes of the present invention is to provide a method for preparing a sodium heparin catheter-sealing injection, so as to at least solve one of the technical problems existing in the prior art. The present invention uses an alkaline solution to stabilize the sodium heparin catheter-sealing injection system, and in the process of preparing the sodium heparin catheter-sealing injection, the alkaline solution is added in a gradually decreasing amount, thereby improving the stability of the sodium heparin catheter-sealing injection.

[0006] The second object of the present invention is to provide a method for preparing sodium heparin tube-sealing injection and to prepare the sodium heparin tube-sealing injection. The sodium heparin tube-sealing injection prepared by the preparation method has high stability.

[0007] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted:

[0008] In a first aspect, the present invention provides a method for preparing a sodium heparin catheter sealing injection, comprising the following steps:

[0009] Adding alkaline solution to the mixed solution of sodium heparin and sodium chloride to adjust the pH to 6.5-7.5 to obtain the sodium heparin tube sealing injection;

[0010] The alkaline solution is added in stages, with the amount added in each stage decreasing.

[0011] Furthermore, the process of adding the alkaline solution includes a first stage, a second stage, a third stage and a fourth stage;

[0012] Preferably, the time of the first stage is 55-65 min, and the addition rate of the alkaline solution is 810-820 ul / min;

[0013] Preferably, the duration of the second stage is 55-65 min, and the addition rate of the alkaline solution is 620-630 ul / min;

[0014] Preferably, the duration of the third stage is 55-65 min, and the addition rate of the alkaline solution is 480-490 ul / min;

[0015] Preferably, the duration of the fourth stage is 55-65 min, and the addition rate of the alkaline solution is 310-320 ul / min.

[0016] Furthermore, there is a transition process between each stage, and the transition process reduces the flow rate at a rate of 0.5-1.5 ul per second.

[0017] Furthermore, the alkaline solution includes sodium hydroxide solution.

[0018] Furthermore, the amount of the heparin sodium raw material is 2980625.94 units / 300kg, and the amount of the sodium chloride is 2682.57 g / 300kg.

[0019] Furthermore, the concentration of the alkaline solution is 0.3 mol / ml.

[0020] Furthermore, the dissolution process further comprises: adding the heparin sodium raw material and sodium chloride into the water for injection and performing a first stirring;

[0021] Preferably, the temperature of the water for injection is 30-40°C;

[0022] Preferably, the first stirring time is 25-35 min.

[0023] Further, after adding the alkaline solution to the target pH value, stirring is performed for the second time;

[0024] Preferably, the second stirring time is 25-35 min.

[0025] Furthermore, a quantitative peristaltic pump is used to transport the alkaline solution.

[0026] In a second aspect, the present invention provides a sodium heparin catheter sealing injection prepared by a method for preparing a sodium heparin catheter sealing injection.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] The preparation method of the sodium heparin tube-sealing injection provided by the present invention adopts a method of adding an alkaline solution in a gradually decreasing amount during the preparation process, and adjusts the pH value of the solution to 6.5-7.5, thereby improving the stability of the product. The alkaline solution is used to stabilize the sodium heparin tube-sealing injection system, and the solution can be stabilized without introducing other substances such as buffer salts. Moreover, without introducing other substances, the potency of the product and the requirements of related substance indicators can be guaranteed, and the level of the quality standard of the product is further improved. DETAILED DESCRIPTION

[0029] Unless otherwise defined herein, scientific and technical terms used in conjunction with the present invention shall have the meanings commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the case of any potential ambiguity, the definitions provided herein take precedence over any dictionary or external definitions. In this application, unless otherwise stated, the use of "or" means "and / or". In addition, the use of the term "including" and other forms is non-limiting.

[0030] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0031] The first aspect of the present invention provides a method for preparing a sodium heparin catheter sealing injection, comprising the following steps:

[0032] Adding alkaline solution to the mixed solution of sodium heparin and sodium chloride to adjust the pH to 6.5-7.5 to obtain the sodium heparin tube sealing injection;

[0033] The alkaline solution is added in stages, with the amount added in each stage decreasing.

[0034] The preparation method of the sodium heparin tube-sealing injection provided by the present invention adopts a method of adding an alkaline solution in a gradually decreasing amount during the preparation process, and the pH value of the solution is adjusted to 6.5-7.5, thereby improving the stability of the injection. The improvement of the stability of the injection can effectively reduce the occurrence of degradation of the injection during storage, and reduces allergies. The present invention only adopts an alkaline solution to stabilize the sodium heparin tube-sealing injection system, and can stabilize the solution without introducing other substances such as buffer salts. Without introducing other substances, local irritation, bleeding and the like can be avoided, and at the same time, the potency of the product and the related material indicators (such as impurities such as dermatan sulfate and polysulfated chondroitin) can be guaranteed to meet the requirements, and the level of the quality standard of the product is further improved, and the local irritation, bleeding or allergy problems caused by adding components such as phenol and buffer salts in the conventional process for producing sodium heparin tube-sealing injection in the prior art are effectively solved, and the stability and safety of the product are improved.

[0035] In some preferred embodiments, the alkaline solution comprises sodium hydroxide solution.

[0036] In some preferred embodiments, the alkaline solution addition process includes a first stage, a second stage, a third stage and a fourth stage;

[0037] In the present invention, heparin sodium is a mucopolysaccharide substance containing multiple sulfate groups and amino groups. Its aqueous solution is acidic and stable in a weakly alkaline environment. If the sodium hydroxide solution required for the preparation is added at one time during the preparation process, the pH value of the prepared solution will be stabilized at pH=11, and it will slowly decrease after being stable for one month, and the solution potency will be significantly reduced. Because the aqueous solution of heparin sodium itself has the characteristic of being acidic, the pH adjustment operation is performed using the method of the present invention, and the alkaline solution is slowly dripped in, so that the prepared solution can be fully contacted with the alkaline solution, so that the buffer system of the prepared solution itself changes from acidic to weakly alkaline, and finally stabilizes at pH=6.5-7.5 (preferably 7.5) that meets the drug standards, and ensures that the potency of the prepared solution is not destroyed and can be stable in a weakly alkaline environment.

[0038] Preferably, the time of the first stage is 55-65min, for example, it can be 55min, 56min, 57min, 58min, 59min, 60min, 61min, 62min, 63min, 64min, 65min, etc., and the addition rate of the alkaline solution is 810-820ul / min, for example, it can be 810ul / min, 811ul / min, 812ul / min, 813ul / min, 814ul / min, 815ul / min, 816ul / min, 817ul / min, 818ul / min, 819ul / min, 820ul / min, etc.;

[0039] Preferably, the time of the second stage is 55-65min, for example, it can be 55min, 56min, 57min, 58min, 59min, 60min, 61min, 62min, 63min, 64min, 65min, etc., and the addition rate of the alkaline solution is 620-630ul / min, for example, it can be 620ul / min, 621ul / min, 622ul / min, 623ul / min, 624ul / min, 625ul / min, 626ul / min, 627ul / min, 628ul / min, 629ul / min, 630ul / min, etc.;

[0040] Preferably, the time of the third stage is 55-65min, for example, it can be 55min, 56min, 57min, 58min, 59min, 60min, 61min, 62min, 63min, 64min, 65min, etc., and the addition rate of the alkaline solution is 480-490ul / min, for example, it can be 480ul / min, 481ul / min, 482ul / min, 483ul / min, 484ul / min, 485ul / min, 486ul / min, 487ul / min, 488ul / min, 489ul / min, 490ul / min, etc.;

[0041] Preferably, the time of the fourth stage is 55-65min, for example, it can be 55min, 56min, 57min, 58min, 59min, 60min, 61min, 62min, 63min, 64min, 65min, etc., and the addition rate of the alkaline solution is 310-320ul / min, for example, it can be 310ul / min, 311ul / min, 312ul / min, 313ul / min, 314ul / min, 315ul / min, 316ul / min, 317ul / min, 318ul / min, 319ul / min, 320ul / min, etc.

[0042] In some preferred embodiments, there is a transition process between each stage, and the transition process reduces the flow rate at a rate of 0.5-1.5ul per second, for example, it can be 0.5ul, 0.6ul, 0.7ul, 0.8ul, 0.9ul, 1.0ul, 1.1ul, 1.2ul, 1.3ul, 1.4ul, 1.5ul, etc.

[0043] In some preferred embodiments, a quantitative peristaltic pump is used to deliver the alkaline solution.

[0044] In the present invention, the amount of alkali used in the whole process is about 134 ml, and the total time is about 240 minutes. The amount of alkali used in the process of adjusting the pH value decreases from more to less. The present invention adopts a micro-quantitative peristaltic pump to pump the sodium hydroxide solution drop by drop, preferably a 4-channel micro-quantitative peristaltic pump, which is set to a program, and the flow rate of the 4 channels is from fast to slow. The amount of alkali is set to the required flow rate, and the process of adjusting the pH can be fully automated. In addition, the preparation method of the present invention is adopted to shorten the pH adjustment time from the original 7h to about 4h, and the total preparation time is shortened from the original 8-8.5h to 5-5.5h, which greatly shortens the preparation time and improves the preparation efficiency.

[0045] In some preferred embodiments, the amount of the heparin sodium raw material is 2980625.94 units / 300kg, and the amount of the sodium chloride is 2682.57 g / 300kg.

[0046] In some preferred embodiments, the concentration of the alkaline solution is 0.3 mol / ml.

[0047] In some preferred embodiments, the dissolution process further comprises: adding heparin sodium raw material and sodium chloride into water for injection and performing a first stirring;

[0048] Preferably, the temperature of the water for injection is 30-40°C, for example, it can be 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, etc.;

[0049] Preferably, the first stirring time is 25-35 min, for example, it can be 25 min, 26 min, 27 min, 28 min, 29 min, 30 min, 31 min, 32 min, 33 min, 34 min, 35 min, etc.

[0050] In some preferred embodiments, after adding the alkaline solution to the target pH value, stirring is performed for the second time;

[0051] Preferably, the second stirring time is 25-35 min, for example, it can be 25 min, 26 min, 27 min, 28 min, 29 min, 30 min, 31 min, 32 min, 33 min, 34 min, 35 min, etc.

[0052] A second aspect of the present invention provides a sodium heparin catheter-sealing injection prepared by a method for preparing the sodium heparin catheter-sealing injection.

[0053] In the present invention, it is preferred that a micro-quantitative peristaltic pump is used to dropwise pump a sodium hydroxide solution to adjust the pH value of the solution to 7.5 during the preparation of the sodium heparin catheter-sealing injection. Only sodium hydroxide is used to stabilize the sodium heparin catheter-sealing injection system without introducing other substances such as buffer salts. Through the above parameter control, on the one hand, the pH adjustment time can be shortened from the original 7 hours to 4 hours. On the other hand, no other substances are introduced to ensure that the potency and related substance indicators of the product meet the requirements, and the level of the quality standard is further improved.

[0054] The present invention is further described below by way of examples. Unless otherwise specified, the materials in the examples are prepared according to existing methods or directly purchased from the market.

[0055] Example 1

[0056] This embodiment provides a method for preparing a sodium heparin tube sealing injection, comprising the following steps:

[0057] Step a, adding heparin sodium raw material and sodium chloride into water for injection cooled to 35° C. and stirring for 30 minutes;

[0058] Among them, the dosage of heparin sodium raw material is 2980625.94 units / 300kg, the dosage of sodium chloride is 2682.57g / 300kg, and the specific prescription dosage of heparin sodium sealing injection is:

[0059] Heparin sodium raw material: 50 units;

[0060] Sodium chloride: 0.045 g;

[0061] Add water for injection to 5 mL.

[0062] Step b, preparing a 0.3 mol / ml sodium hydroxide solution, and using a micro-quantitative peristaltic pump to pump the sodium hydroxide solution dropwise into the prepared solution;

[0063] The alkaline solution addition process is divided into four stages. The first stage lasts for 60 minutes with a flow rate of 815ul / min, the second stage lasts for 60 minutes with a flow rate of 625ul / min, the third stage lasts for 60 minutes with a flow rate of 485ul / min, and the fourth stage lasts for 60 minutes with a flow rate of 315ul / min. The transition process between each two stages is to slowly reduce the flow rate by 1ul per second.

[0064] Step c, the final pH value of the prepared solution is stabilized at about 7.5, and the change does not exceed 0.05 within 10 minutes, indicating that the preparation is completed;

[0065] Step d: After reaching the target pH value, stir for 30 minutes and then deliver the solution.

[0066] Example 2

[0067] This embodiment provides a method for preparing a sodium heparin tube sealing injection, comprising the following steps:

[0068] Step a, adding heparin sodium raw material and sodium chloride into water for injection cooled to 30° C. and stirring for 35 minutes;

[0069] Among them, the dosage of heparin sodium raw material is 2980625.94 units / 300kg, and the dosage of sodium chloride is 2682.57g / 300kg; the specific prescription dosage of heparin sodium sealing injection is:

[0070] Heparin sodium raw material: 50 units;

[0071] Sodium chloride: 0.045 g;

[0072] Add water for injection to 5 mL.

[0073] Step b, preparing a 0.3 mol / ml sodium hydroxide solution, and using a micro-quantitative peristaltic pump to pump the sodium hydroxide solution dropwise into the prepared solution;

[0074] The alkaline solution addition process is divided into four stages. The first stage lasts for 55 minutes with a flow rate of 820ul / min, the second stage lasts for 65 minutes with a flow rate of 620ul / min, the third stage lasts for 55 minutes with a flow rate of 490ul / min, and the fourth stage lasts for 65 minutes with a flow rate of 310ul / min. The transition process between each two stages is to slowly reduce the flow rate by 0.5ul per second.

[0075] Step c, the final pH value of the prepared solution is stabilized at about 6.5, and the change does not exceed 0.05 within 10 minutes, indicating that the preparation is completed;

[0076] Step d: After reaching the target pH value, stir for 25 minutes and then deliver the solution.

[0077] Example 3

[0078] This embodiment provides a method for preparing a sodium heparin tube sealing injection, comprising the following steps:

[0079] Step a, adding heparin sodium raw material and sodium chloride into water for injection cooled to 40° C. and stirring for 25 minutes;

[0080] Among them, the dosage of heparin sodium raw material is 2980625.94 units / 300kg, and the dosage of sodium chloride is 2682.57g / 300kg; the specific prescription dosage of heparin sodium sealing injection is:

[0081] Heparin sodium raw material: 50 units;

[0082] Sodium chloride: 0.045 g;

[0083] Add water for injection to 5 mL.

[0084] Step b, preparing a 0.3 mol / ml sodium hydroxide solution, and using a micro-quantitative peristaltic pump to pump the sodium hydroxide solution dropwise into the prepared solution;

[0085] The alkaline solution addition process is divided into four stages. The first stage lasts for 65 minutes with a flow rate of 810ul / min, the second stage lasts for 55 minutes with a flow rate of 630ul / min, the third stage lasts for 65 minutes with a flow rate of 480ul / min, and the fourth stage lasts for 55 minutes with a flow rate of 320ul / min. The transition process between each two stages is to slowly reduce the flow rate by 1.5ul per second.

[0086] Step c, the final pH value of the prepared solution is stabilized at about 7, and the change does not exceed 0.05 within 10 minutes, indicating that the preparation is completed;

[0087] Step d: After reaching the target pH value, stir for 35 minutes and then deliver the solution.

[0088] Example 4

[0089] This embodiment provides a method for preparing sodium heparin tube sealing injection, which is different from embodiment 1 in that:

[0090] In step b, the first stage time was 61.2 min and the flow rate was 800 ul / min;

[0091] The rest is consistent with Example 1.

[0092] Example 5

[0093] This embodiment provides a method for preparing sodium heparin tube sealing injection, which is different from embodiment 1 in that:

[0094] In step b, the first stage time is 59 min and the flow rate is 800 ul / min;

[0095] The rest is consistent with Example 1.

[0096] Example 6

[0097] This embodiment provides a method for preparing sodium heparin tube sealing injection, which is different from embodiment 1 in that:

[0098] In step b, the second stage time is 61.5 min and the flow rate is 610 ul / min;

[0099] The rest is consistent with Example 1.

[0100] Example 7

[0101] This embodiment provides a method for preparing sodium heparin tube sealing injection, which is different from embodiment 1 in that:

[0102] In step b, the second stage time was 58.6 min and the flow rate was 640 ul / min;

[0103] The rest is consistent with Example 1.

[0104] Example 8

[0105] This embodiment provides a method for preparing sodium heparin tube sealing injection, which is different from embodiment 1 in that:

[0106] In step b, the third stage time was 61.9 min and the flow rate was 470 ul / min;

[0107] The rest is consistent with Example 1.

[0108] Example 9

[0109] This embodiment provides a method for preparing sodium heparin tube sealing injection, which is different from embodiment 1 in that:

[0110] In step b, the third stage time is 58.2 min, and the flow rate is 500 ul / min;

[0111] The rest is consistent with Example 1.

[0112] Example 10

[0113] This embodiment provides a method for preparing sodium heparin tube sealing injection, which is different from embodiment 1 in that:

[0114] In step b, the fourth stage time is 63 min, and the flow rate is 300 ul / min;

[0115] The rest is consistent with Example 1.

[0116] Embodiment 11

[0117] This embodiment provides a method for preparing sodium heparin tube sealing injection, which is different from embodiment 1 in that:

[0118] In step b, the fourth stage time is 57.3 min, and the flow rate is 330 ul / min;

[0119] The rest is consistent with Example 1.

[0120] Comparative Example 1

[0121] This comparative example provides a method for preparing sodium heparin tube-sealing injection, which differs from Example 1 in that:

[0122] In step b, sodium hydroxide solution is added to the prepared solution by a micro-quantitative peristaltic pump at a flow rate of 560 ul / min for 240 min, and the final pH value of the prepared solution is 9.0.

[0123] Comparative Example 2

[0124] This comparative example provides a method for preparing sodium heparin tube-sealing injection, which differs from Example 1 in that:

[0125] In step b, the addition rate of the sodium hydroxide solution is changed to increasing, that is, the first stage time is 60min, the flow rate is 315ul / min; the second stage time is 60min, the flow rate is 485ul / min; the third stage time is 60min, the flow rate is 625ul / min; the fourth stage time is 60min, the flow rate is 815ul / min; the transition process between every two stages is to slowly increase the flow rate at a rate of 1ul per second, and the final pH value of the prepared solution is 10.0.

[0126] Comparative Example 3

[0127] This comparative example provides a method for preparing sodium heparin tube-sealing injection, which differs from Example 1 in that:

[0128] In step b, the same amount of sodium hydroxide solution as in Example 1 is added to the prepared solution at one time, and the final pH value of the prepared solution is 11.

[0129] Test Case

[0130] Test samples:

[0131] The sodium heparin tube sealing injection prepared in Example 1-11 and the sodium heparin tube sealing injection prepared in Comparative Example 1-3 were used as samples.

[0132] Test method:

[0133]

Potency determination

[0134] Anti-Xa factor: Take a sample and assay it according to the heparin bioassay method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 1208 Anti-IIa Factor / Anti-Xa Factor Potency Assay Method).

[0135] Anti-factor IIa: Take a sample and assay it according to the heparin bioassay (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 1208, Anti-Factor Ia / Anti-Factor Xa Potency Assay).

[0136] The anti-factor IIa titer should be 90% to 110% of the labeled value, and the ratio of the anti-factor Xa titer to the anti-factor IIa titer should be 0.9 to 1.1.

[0137]

Related substances

[0138] According to the high performance liquid chromatography method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0512), accurately measure 1 ml of the test solution, add 0.1 mol / L hydrochloric acid solution 0.5 ml and 2.5% sodium nitrite solution 0.1 ml, shake to mix, react for 40 minutes, and add 0.1 mol / L sodium hydroxide solution 0.4 ml to terminate the reaction.

[0139] Reference solution (1): Take 10 mg of heparin reference solution, weigh accurately, add 4 ml of water accurately, and vortex to mix until completely dissolved.

[0140] Reference solution (2): Accurately measure 1.2 ml of reference solution (1), add 0.15 ml of 0.04% dermatan sulfate reference and 0.15 ml of 0.04% chondroitin sulfate reference.

[0141] Reference solution (3): Take 0.2 ml of reference solution (2) and dilute to 2 ml with water.

[0142] Reference solution (4): Take 0.8 ml of reference solution (1), add 0.2 ml of water, mix well, add 0.5 ml of 0.1 mol / L hydrochloric acid solution and 0.1 ml of 2.5% sodium nitrite solution, shake to mix well, react for 40 minutes, and add 0.4 ml of 0.1 mol / L sodium hydroxide solution to terminate the reaction.

[0143] Reference solution (5): Accurately measure 1.0 ml of reference solution (2), add 0.5 ml of 0.1 mol / L hydrochloric acid solution and 0.1 ml of 2.5% sodium nitrite solution, shake to mix, react for 40 minutes, and add 0.4 ml of 0.1 mol / L sodium hydroxide solution to terminate the reaction.

[0144] Chromatographic conditions: ethylvinylbenzene-divinylbenzene polymer resin with quaternary ammonium as functional group was used as filler (AS11-HC anion exchange column, 2mmx250mm, with AG11-HC guard column, 2mmx50mm, or other suitable chromatographic columns); 0.04% sodium dihydrogen phosphate solution (adjust the pH value to 3.0 with phosphoric acid, filter with 0.45um filter membrane, and degas before use) was used as mobile phase A; sodium perchlorate-phosphate solution (take 140g of sodium perchlorate, dissolve and dilute to 1000ml with 0.04% sodium dihydrogen phosphate solution, adjust the pH value to 3.0 with phosphoric acid, filter with 0.45μm filter membrane, and degas before use) was used as mobile phase B; linear gradient elution was performed according to Table 1 below, with a flow rate of 0.22ml per minute; column temperature was 40°C, detection wavelength was 202nm, and injection volume was 1000μl.

[0145] Table 1

[0146] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 75 25 10 75 25 35 0 100 40 0 100 40.1 75 25 80 75 25

[0147] System suitability requirements: No heparin peak should appear in the chromatogram of the reference solution (4), and the separation degree between the dermatan sulfate and polysulfated chondroitin peaks in the chromatogram of the reference solution (5) should not be less than 3.0.

[0148] Determination method: Accurately measure the test solution, inject it into the liquid chromatograph, and record the chromatogram.

[0149] Limits: The peak area of ​​dermatan sulfate in the chromatogram of the test solution shall not be greater than the peak area of ​​dermatan sulfate in the reference solution (5) (2.0%); except for the dermatan sulfate peak, no other chromatographic peaks shall appear.

[0150]

pH detection

[0151] Take a sample to test its pH value, the acceptable range of pH value is 5.5-8.0.

[0152] The specific test results are shown in Table 2 below.

[0153] Table 2

[0154]

[0155]

[0156]

[0157] As can be seen from Table 2, Examples 1 to 3 are the preferred selection methods of the present invention. In Examples 4 to 11, due to the change of some factors, the impurity content increased during the stability placement, but it is still within the qualified range and is also suitable for the present invention. In Comparative Examples 1 to 3, due to the change of important conditions, several important indicators in the subsequent two stability experiments were unqualified.

[0158] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing sodium heparin tube-sealing injection, characterized in that: The following steps are involved: Adding alkaline solution to the mixed solution of sodium heparin and sodium chloride to adjust the pH to 6.5-7.5 to obtain the sodium heparin tube sealing injection; The alkaline solution is added in stages, with the amount added in each stage decreasing.

2. The method for preparing the sodium heparin catheter sealing injection according to claim 1, characterized in that: The process of adding the alkaline solution includes a first stage, a second stage, a third stage and a fourth stage; Preferably, the time of the first stage is 55-65 min, and the addition rate of the alkaline solution is 810-820 ul / min; Preferably, the duration of the second stage is 55-65 min, and the addition rate of the alkaline solution is 620-630 ul / min; Preferably, the duration of the third stage is 55-65 min, and the addition rate of the alkaline solution is 480-490 ul / min; Preferably, the duration of the fourth stage is 55-65 min, and the addition rate of the alkaline solution is 310-320 ul / min.

3. The method for preparing the sodium heparin catheter sealing injection according to claim 2, characterized in that: There is a transition process between each stage, which reduces the flow rate by 0.5-1.5ul per second.

4. The method for preparing the sodium heparin catheter sealing injection according to claim 1, characterized in that: The alkaline solution includes sodium hydroxide solution.

5. The method for preparing the sodium heparin catheter sealing injection according to claim 1, characterized in that: The amount of heparin sodium used is 2980625.94 units / 300kg, and the amount of sodium chloride used is 2682.57 g / 300kg.

6. The method for preparing the sodium heparin catheter sealing injection according to claim 1, characterized in that: The concentration of the alkaline solution is 0.3 mol / ml.

7. The method for preparing the sodium heparin catheter sealing injection according to claim 1, characterized in that: The dissolving process further comprises: adding the heparin sodium raw material and sodium chloride into the water for injection and performing a first stirring; Preferably, the temperature of the water for injection is 30-40°C; Preferably, the first stirring time is 25-35 min.

8. The method for preparing the sodium heparin catheter sealing injection according to claim 1, characterized in that: After adding the alkaline solution to the target pH value, stir for the second time; Preferably, the second stirring time is 25-35 min.

9. The method for preparing the sodium heparin catheter sealing injection according to claim 1, characterized in that: A quantitative peristaltic pump is used to transport the alkaline solution.

10. The sodium heparin catheter sealing injection prepared by the method for preparing the sodium heparin catheter sealing injection according to any one of claims 1 to 9.

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