Freeze-drying process of erythromycin lactobionate for injection

Abstract

The invention discloses a freeze-drying process of erythromycin lactobionate for injection, and belongs to the technical field of medicine production. The freeze-drying process comprises the following steps: (1) pre-freezing: cooling an erythromycin lactobionate solution for injection to-10 DEG C to-8 DEG C, vacuumizing and keeping for 10-20 minutes, secondarily cooling to-35 DEG C to-40 DEG C, and keeping for 0.5-1 hour to obtain a pre-frozen product; (2) drying: performing primary drying on the pre-frozen product, and keeping for 12-14 hours; and drying for the second time, and keeping for 3-5 hours to obtain erythromycin lactobionate for injection. A vacuum intervention nucleation process is introduced, so that a product channel is larger, the drying time and moisture are reduced, the product stability is improved, meanwhile, the production cost is reduced, the redissolution time of the prepared erythromycin lactobionate for injection is shorter, and the compliance of clinical medication is improved.

Description

Technical Field

[0001] The invention relates to the technical field of drug production, in particular to a freeze-drying process of erythromycin lactobionate for injection. Background Art

[0002] Erythromycin lactobionate for injection is a macrolide antibiotic combined with erythromycin and lactobionic acid. It is suitable for the following infections caused by sensitive strains: respiratory tract infections, skin and skin tissue infections, diphtheria, erythrasma, acute pelvic inflammatory disease, Legionnaires' disease. It can prevent rheumatic fever and bacterial endometritis. It is usually produced by aseptic packaging or freeze-drying process in the market.

[0003] The raw material of erythromycin lactobionate is very rigid and is prone to cracking during the freeze-drying process. The current solutions on the market include aseptic packaging, inner packaging using high borosilicate glass bottles, and direct addition of lactobionate and erythromycin raw materials. The above treatment methods have problems such as affecting product quality, high cost, and poor stability.

[0004] CN118987010A discloses erythromycin lactobionate for injection and its preparation method and use. The invention reduces the bottle breakage rate during the freeze-drying process, improves the solubility of erythromycin lactobionate for injection, reduces the moisture content of the finished product, controls the risk of over-limit caused by the increase of impurities in the preparation during the stability process, and improves the quality of erythromycin lactobionate for injection, but the freeze-drying process of the invention is long and costly, and is not suitable for industrial production.

[0005] CN104819622A discloses a freeze-drying method for erythromycin lactobionate, comprising the following steps: cooling the temperature of the erythromycin lactobionate solution sample to a first temperature, wherein the first temperature is ≤-35°C; under vacuum conditions, heating the erythromycin lactobionate solution sample from the first temperature to a second temperature at a first heating rate; continuing to heat to a third temperature at a second heating rate, wherein the second heating rate is lower than the first heating rate, the difference between the first heating rate and the second heating rate is 2°C / h to 20°C / h, and the third temperature is 40°C to 55°C; keeping warm under a fourth temperature condition, wherein the fourth temperature is not lower than the third temperature, and the difference between the fourth temperature and the third temperature is 0°C to 15°C. The invention can reduce the content of related substances and improve product quality, but the freeze-drying time of the freeze-drying method is 1324.7-1556min (about 22-26h), and there are still problems of long freeze-drying time and high cost. Summary of the invention

[0006] In view of the above problems, the present invention provides a freeze-drying process for erythromycin lactobionate for injection. The present invention introduces a vacuum intervention nucleation process without changing the equipment, which greatly shortens the freeze-drying time and reduces the production cost while ensuring the product quality and stability.

[0007] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical scheme.

[0008] A freeze-drying process for erythromycin lactobionate for injection comprises the following steps:

[0009] (1) Prefreezing: cooling the erythromycin lactobionate injection solution to -10°C to -8°C, evacuating and maintaining for 10-20 min, cooling it again to -35°C to -40°C, maintaining for 0.5-1 h, and obtaining a prefrozen product;

[0010] (2) Drying: The pre-frozen product is dried once and kept for 12-14 hours; then dried again and kept for 3-5 hours to obtain erythromycin lactobionate for injection.

[0011] In some embodiments, the vacuum degree after evacuation in step (1) is 0.6-1.0 mbar, preferably 0.7-0.8 mbar.

[0012] In some embodiments, the content of erythromycin in the erythromycin lactobionate solution for injection in step (1) is 20-80 mg / mL; preferably 40-50 mg / mL.

[0013] In some embodiments, the cooling rate in step (1) is 0.2-0.4°C / min; preferably 0.25-0.3°C / min.

[0014] In some embodiments, the secondary cooling rate in step (1) is 0.4-0.7°C / min; preferably 0.5-0.6°C / min.

[0015] In some embodiments, the primary drying temperature in step (2) is 5-10°C.

[0016] In some embodiments, the temperature of the secondary drying in step (2) is 25-30°C.

[0017] In some embodiments, the drying in step (2) is as follows: the pre-frozen product is heated to 5-10°C at 0.2-0.3 mbar for primary drying and maintained for 12-14 hours; then the pre-frozen product is heated to 25-30°C at 0.07-0.13 mbar for secondary drying and maintained for 3-5 hours.

[0018] In some embodiments, the heating rate of the primary drying in step (2) is 0.5-2°C / min; preferably 0.5-1°C / min.

[0019] In some embodiments, the heating rate of the secondary drying in step (2) is 0.5-2°C / min; preferably 0.5-1°C / min.

[0020] Beneficial effects of the present invention:

[0021] (1) Compared with the prior art, the present invention introduces a vacuum-intervention nucleation process, which makes the product channel larger, shortens the primary and secondary drying times, shortens the freeze-drying time, and saves costs.

[0022] (2) The freeze-drying process of the present invention can enlarge the product channel, and the prepared erythromycin lactobionate for injection is looser, with a shorter reconstitution time, thereby improving the compliance of clinical medication.

[0023] (3) The erythromycin lactobionate for injection prepared by the present invention has low water content and good stability.

[0024] (4) The freeze-drying process of the present invention does not require equipment replacement, has a short freeze-drying time, low production cost, and no bottle breakage problem during the freeze-drying process. The quality and stability of the obtained freeze-dried preparation are good, and it is suitable for industrial promotion and application. Specific implementation methods

[0026] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention. The following embodiments are used to illustrate the present invention but are not intended to limit the scope of the present invention. In the erythromycin lactobionate solution for injection in this embodiment, the erythromycin content in each 1ml solution is 50mg, and the erythromycin content in each bottle is 0.5g.

[0027] Basic Example

[0028] A freeze-drying process for erythromycin lactobionate for injection, comprising the following steps:

[0029] (1) Prefreezing: The erythromycin lactobionate injection solution is cooled to -10°C to -8°C at a rate of 0.2-0.4°C / min, evacuated to 0.6-1.0 mbar and maintained for 10-20 min, and cooled again to -35°C to -40°C at a rate of 0.4-0.7°C / min, maintained for 0.5-1 h, to obtain a prefrozen product.

[0030] (2) Drying: The pre-frozen product is dried once at 5-10°C at a temperature of 0.2-0.3 mbar and a temperature rate of 0.5-2°C / min for 12-14 hours. Then, the pre-frozen product is dried once at 25-30°C at a temperature of 0.5-2°C / min for 3-5 hours.

[0031] Example 1

[0032] A freeze-drying process for erythromycin lactobionate for injection, comprising the following steps:

[0033] (1) Prefreezing: The erythromycin lactobionate injection solution was cooled to -10°C at a rate of 0.4°C / min, evacuated to 0.6 mbar and maintained for 20 min, and cooled to -40°C at a rate of 0.4°C / min for a second time and maintained for 1 h to obtain a prefrozen product.

[0034] (2) Drying: The pre-frozen product is dried once at 10°C at a rate of 2°C / min under 0.2 mbar and maintained for 12 h; then, it is dried twice at 25°C at a rate of 2°C / min under 0.07 mbar and maintained for 3 h.

[0035] Example 2

[0036] A freeze-drying process for erythromycin lactobionate for injection, comprising the following steps:

[0037] (1) Prefreezing: The erythromycin lactobionate injection solution was cooled to -8°C at a rate of 0.2°C / min, evacuated to 1.0 mbar and maintained for 10 min, and then cooled to -35°C at a rate of 0.7°C / min and maintained for 0.5 h to obtain a prefrozen product.

[0038] (2) Drying: The pre-frozen product is dried once at 5°C at a rate of 0.5°C / min under 0.3 mbar and maintained for 14 h; then, it is dried twice at 30°C at a rate of 0.5°C / min under 0.13 mbar and maintained for 5 h.

[0039] Example 3

[0040] A freeze-drying process for erythromycin lactobionate for injection, comprising the following steps:

[0041] (1) Prefreezing: The erythromycin lactobionate injection solution was cooled to -9°C at a rate of 0.3°C / min, evacuated to 0.8 mbar and maintained for 15 min, and then cooled to -37°C at a rate of 0.5°C / min and maintained for 0.5 h to obtain a prefrozen product.

[0042] (2) Drying: The pre-frozen product is dried once at 7°C at a rate of 1°C / min under 0.25 mbar and maintained for 13 h. Then, the pre-frozen product is dried twice at 27°C at a rate of 1.5°C / min under 0.10 mbar and maintained for 4 h.

[0043] Comparative Example 1

[0044] The difference between this comparative example and Example 3 is that the vacuum degree and storage time of the nucleation intervention in step (1) are different, and the other parameters are basically the same.

[0045] The specific steps are as follows:

[0046] (1) Prefreezing: The erythromycin lactobionate injection solution was cooled to -9°C at a rate of 0.3°C / min, evacuated to 1.2 mbar and maintained for 5 min, and then cooled to -37°C at a rate of 0.5°C / min and maintained for 0.5 h to obtain a prefrozen product.

[0047] (2) Drying: The pre-frozen product is dried once at 7°C at a rate of 1°C / min under 0.25 mbar and maintained for 13 h. Then, the pre-frozen product is dried twice at 27°C at a rate of 1.5°C / min under 0.10 mbar and maintained for 4 h.

[0048] Comparative Example 2

[0049] The difference between this comparative example and Example 1 is that the cooling temperature for nucleation in step (1) is different, and the other parameters are basically the same.

[0050] The specific steps are as follows:

[0051] (1) Prefreezing: The erythromycin lactobionate injection solution was cooled to -5°C at a rate of 0.3°C / min, evacuated to 0.5 mbar and maintained for 25 min, and cooled to -37°C at a rate of 0.5°C / min for a second time and maintained for 0.5 h to obtain a prefrozen product.

[0052] (2) Drying: The pre-frozen product is dried once at 7°C at a rate of 1°C / min under 0.25 mbar and maintained for 13 h. Then, the pre-frozen product is dried twice at 27°C at a rate of 1.5°C / min under 0.10 mbar and maintained for 4 h.

[0053] Comparative Example 3

[0054] The difference between this comparative example and Example 1 is that the nucleation process is not adopted in step (1), and the other parameters are basically the same.

[0055] The specific steps are as follows:

[0056] (1) Prefreezing: The erythromycin lactobionate injection solution is cooled to -37°C at a rate of 0.3°C / min and maintained for 0.5 h to obtain a prefrozen product.

[0057] (2) Drying: The pre-frozen product is dried once at 7°C at a rate of 1°C / min under 0.25 mbar and maintained for 13 h. Then, the pre-frozen product is dried twice at 27°C at a rate of 1.5°C / min under 0.10 mbar and maintained for 4 h.

[0058] The quality and stability of the erythromycin lactobionate for injection prepared in Examples 1-3 and Comparative Examples 1-3 and the commercially available erythromycin lactobionate for injection produced by Hospira Inc. were tested and the results are shown in Tables 1-4.

[0059] Table 1 Summary of test results of example preparations and reference preparations

[0060]

[0061]

[0062] Table 2 Summary of test results of comparative preparations

[0063]

[0064] From the analysis of Table 1 and Table 2, it can be seen that the product properties, solution clarity and color, re-dissolution and related substances of erythromycin lactobionate for injection prepared by the freeze-drying process of Examples 1-3 of the present invention meet the requirements of the registration standards, and relative to the reference preparation, the erythromycin lactobionate for injection prepared by Examples 1-3 of the present invention has a shorter re-dissolution time, lower water content, and lower total impurity content. However, there is a problem of bottle cracking during the freeze-drying process production process of Comparative Examples 1-3, and compared with the reference preparation, the total impurity content of the prepared erythromycin lactobionate for injection is lower, but the re-dissolution time is longer and the water content is higher.

[0065] Table 3 Summary of stability results of reference preparations and examples

[0066]

[0067] Table 4 Summary of stability results of comparative examples

[0068]

[0069] From the analysis of Tables 3 and 4, it can be seen that the freeze-dried products of erythromycin lactobionate for injection prepared by the freeze-drying process of Examples 1-3 of the invention have better stability, which is equivalent to the reference preparation; while the stability of the freeze-dried products of erythromycin lactobionate for injection prepared by the freeze-drying process of Comparative Examples 1-3 is significantly deteriorated.

[0070] The above description is only a preferred example of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A freeze-drying process for erythromycin lactobionate for injection, characterized in that: The following steps are involved: (1) Prefreezing: the erythromycin lactobionate injection solution is cooled to -10°C to -8°C, vacuumed and maintained for 10-20 minutes, and then cooled again to -35°C to -40°C, maintained for 0.5-1 hour, to obtain a prefrozen product; (2) Drying: The pre-frozen product is dried once and kept for 12-14 hours; then dried again and kept for 3-5 hours to obtain erythromycin lactobionate for injection.

2. The freeze-drying process according to claim 1, characterized in that The vacuum degree after evacuation in step (1) is 0.6-1.0 mbar, preferably 0.7-0.8 mbar.

3. The freeze-drying process according to claim 1, characterized in that: The cooling rate in step (1) is 0.2-0.4°C / min; preferably 0.25-0.3°C / min.

4. The freeze-drying process according to claim 1, characterized in that: The secondary cooling rate in step (1) is 0.4-0.7°C / min, preferably 0.5-0.6°C / min.

5. The freeze-drying process according to claim 1, characterized in that: The primary drying temperature in step (2) is 5-10°C.

6. The freeze-drying process according to claim 1, characterized in that: The temperature of the secondary drying in step (2) is 25-30°C.

7. The freeze-drying process according to claim 1, characterized in that: The drying in step (2) is as follows: the pre-frozen product is heated to 5-10°C at 0.2-0.3 mbar for primary drying and maintained for 12-14 hours; then the pre-frozen product is heated to 25-30°C at 0.07-0.13 mbar for secondary drying and maintained for 3-5 hours.

8. The freeze-drying process according to claim 7, characterized in that: The heating rate of the primary drying in step (2) is 0.5-2°C / min, preferably 0.5-1°C / min.

9. The freeze-drying process according to claim 7, characterized in that: The heating rate of the secondary drying in step (2) is 0.5-2°C / min; preferably 0.5-1°C / min.

10. The freeze-drying process according to any one of claims 1 to 9, characterized in that: The content of erythromycin in the erythromycin lactobionate solution for injection in step (1) is 20-80 mg / mL, preferably 40-50 mg / mL.

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