A freeze-drying process for injectable erythromycin lactobionate

Abstract

This invention discloses a freeze-drying process for injectable erythromycin lactobionate, belonging to the field of pharmaceutical manufacturing technology. The freeze-drying process includes the following steps: (1) Pre-freezing: The injectable erythromycin lactobionate solution is cooled to -10℃ to -8℃, vacuumed and maintained for 10-20 minutes, then cooled again to -35℃ to -40℃ and maintained for 0.5-1 hours to obtain a pre-frozen product; (2) Drying: The pre-frozen product is dried once and maintained for 12-14 hours; then dried a second time and maintained for 3-5 hours to obtain injectable erythromycin lactobionate. This invention introduces a vacuum-interventional nucleation process, which increases the product channel, reduces drying time and moisture, improves product stability, and reduces production costs. The prepared injectable erythromycin lactobionate has a shorter reconstitution time, improving clinical compliance.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical manufacturing technology, and more specifically, to a freeze-drying process for injectable erythromycin lactobionate. Background Technology

[0002] Erythromycin lactobionate for injection is a macrolide antibiotic composed of erythromycin and lacturonic acid. It is indicated for infections caused by susceptible strains of the following bacteria: respiratory tract infections, skin and skin tissue infections, diphtheria, erythritis, acute pelvic inflammatory disease, Legionnaires' disease, and prevention of rheumatic fever attacks and bacterial endocarditis. It is commercially available and is typically manufactured using aseptic filling or freeze-drying processes.

[0003] Erythromycin lactobionic acid raw material is highly rigid, and bottle cracking is prone to occur during freeze-drying. Current market solutions include aseptic repackaging, using high-borosilicate tubular glass bottles for inner packaging, and directly adding lactobionic acid and erythromycin to the raw material. However, these methods have drawbacks such as affecting product quality, higher costs, and poor stability.

[0004] CN118987010A discloses an injectable erythromycin lactobionate, its preparation method, and its uses. This invention reduces the bottle breakage rate during freeze-drying by precisely controlling the cooling rate during the pre-freezing stage and the heating rate during the primary and secondary drying stages, and by setting a staged heating program for the secondary drying process. This improves the reconstitution of the injectable erythromycin lactobionate, reduces the moisture content of the finished product, controls the risk of exceeding limits due to increased impurities in the formulation during stability testing, and improves the quality of the injectable erythromycin lactobionate. However, the freeze-drying process of this invention is time-consuming and costly, making it unsuitable for industrial production.

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

[0006] To address the aforementioned issues, this invention provides a freeze-drying process for injectable erythromycin lactobionate. This invention introduces a vacuum-interventional nucleation process without changing the equipment, which significantly shortens the freeze-drying time and reduces production costs while ensuring product quality and stability.

[0007] To achieve the above-mentioned objectives, the present invention adopts the following technical solution.

[0008] A lyophilization process for injectable erythromycin lactobionate includes the following steps:

[0009] (1) Pre-freezing: The erythromycin lactobionate solution for injection is cooled to -10℃ to -8℃, vacuumed and maintained for 10-20 min, then cooled again to -35℃ to -40℃ and maintained for 0.5-1 h to obtain the pre-frozen product;

[0010] (2) Drying: Dry the pre-frozen product once and keep it for 12-14 hours; then dry it a second time and keep it for 3-5 hours to obtain erythromycin lactobionate for injection.

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

[0012] In some embodiments, the erythromycin content in the injectable lactobionic acid erythromycin solution 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℃ / min; preferably 0.25-0.3℃ / min.

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

[0015] In some embodiments, the temperature of the first drying 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 dried once at 0.2-0.3 mbar to 5-10°C and held for 12-14 hours; then dried a second time at 0.07-0.13 mbar to 25-30°C and held for 3-5 hours, thus obtaining the product.

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

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

[0020] The beneficial effects of this invention are:

[0021] (1) Compared with the prior art, the present invention introduces a vacuum-interventional nucleation process, which results in a larger product channel, shorter primary and secondary drying times, shortened freeze-drying time, and cost savings.

[0022] (2) The freeze-drying process of the present invention can increase the product channel, make the prepared injectable erythromycin lactobionate more porous, and shorten the reconstitution time, thereby improving clinical drug compliance.

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

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

[0025] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with the embodiments of this invention. The following embodiments are used to illustrate this invention, but are not intended to limit the scope of this invention. In this embodiment, the erythromycin lactobionate solution for injection contains 50 mg of erythromycin per 1 ml of solution, and 0.5 g of erythromycin per vial.

[0026] Basic Implementation

[0027] A lyophilization process for injectable erythromycin lactobionate, comprising the following steps:

[0028] (1) Pre-freezing: The erythromycin lactobionate solution for injection is cooled to -10℃ to -8℃ at a rate of 0.2-0.4℃ / min, vacuumed to 0.6-1.0mbar and held for 10-20min, then cooled again to -35℃ to -40℃ at a rate of 0.4-0.7℃ / min and held for 0.5-1h to obtain the pre-frozen product.

[0029] (2) Drying: The pre-frozen product is dried once at 0.2-0.3 mbar at a rate of 0.5-2℃ / min to 5-10℃ and held for 12-14h; then dried a second time at 0.07-0.13 mbar at a rate of 0.5-2℃ / min to 25-30℃ and held for 3-5h.

[0030] Example 1

[0031] A lyophilization process for injectable erythromycin lactobionate, comprising the following steps:

[0032] (1) Pre-freezing: The erythromycin lactobionate solution for injection was cooled to -10°C at a rate of 0.4°C / min, vacuumed to 0.6 mbar and held for 20 min, and then cooled to -40°C again at a rate of 0.4°C / min and held for 1 h to obtain the pre-frozen product.

[0033] (2) Drying: The pre-frozen product is dried once at 0.2 mbar at a rate of 2 °C / min to 10 °C and held for 12 h; then dried a second time at 0.07 mbar at a rate of 2 °C / min to 25 °C and held for 3 h to obtain the product.

[0034] Example 2

[0035] A lyophilization process for injectable erythromycin lactobionate, comprising the following steps:

[0036] (1) Pre-freezing: The erythromycin lactobionate solution for injection was cooled to -8°C at a rate of 0.2°C / min, vacuumed to 1.0 mbar and held for 10 min, then cooled to -35°C again at a rate of 0.7°C / min and held for 0.5 h to obtain the pre-frozen product.

[0037] (2) Drying: The pre-frozen product is dried once at 0.3 mbar at a rate of 0.5 °C / min to 5 °C and held for 14 h; then dried a second time at 0.13 mbar at a rate of 0.5 °C / min to 30 °C and held for 5 h to obtain the product.

[0038] Example 3

[0039] A lyophilization process for injectable erythromycin lactobionate, comprising the following steps:

[0040] (1) Pre-freezing: The erythromycin lactobionate solution for injection was cooled to -9°C at a rate of 0.3°C / min, vacuumed to 0.8 mbar and held for 15 min, then cooled to -37°C again at a rate of 0.5°C / min and held for 0.5 h to obtain the pre-frozen product.

[0041] (2) Drying: The pre-frozen product is dried once at 0.25 mbar at a rate of 1 °C / min to 7 °C and held for 13 h; then dried a second time at 0.10 mbar at a rate of 1.5 °C / min to 27 °C and held for 4 h to obtain the product.

[0042] Comparative Example 1

[0043] The difference between this comparative example and Example 3 is that the vacuum degree and storage time of the nucleation in step (1) are different, while other parameters are basically the same.

[0044] The specific steps are as follows:

[0045] (1) Pre-freezing: The erythromycin lactobionate solution for injection was cooled to -9°C at a rate of 0.3°C / min, vacuumed to 1.2 mbar and held for 5 min, then cooled to -37°C again at a rate of 0.5°C / min and held for 0.5 h to obtain the pre-frozen product.

[0046] (2) Drying: The pre-frozen product is dried once at 0.25 mbar at a rate of 1 °C / min to 7 °C and held for 13 h; then dried a second time at 0.10 mbar at a rate of 1.5 °C / min to 27 °C and held for 4 h to obtain the product.

[0047] Comparative Example 2

[0048] The difference between this comparative example and Example 1 is that the cooling temperature for nucleation in step (1) is different, while other parameters are basically the same.

[0049] The specific steps are as follows:

[0050] (1) Pre-freezing: The erythromycin lactobionate solution for injection was cooled to -5°C at a rate of 0.3°C / min, vacuumed to 0.5 mbar and held for 25 min, then cooled to -37°C again at a rate of 0.5°C / min and held for 0.5 h to obtain the pre-frozen product.

[0051] (2) Drying: The pre-frozen product is dried once at 0.25 mbar at a rate of 1 °C / min to 7 °C and held for 13 h; then dried a second time at 0.10 mbar at a rate of 1.5 °C / min to 27 °C and held for 4 h to obtain the product.

[0052] Comparative Example 3

[0053] The difference between this comparative example and Example 1 is that the nucleation process was not used in step (1), while other parameters are basically the same.

[0054] The specific steps are as follows:

[0055] (1) Pre-freezing: The erythromycin lactobionate solution for injection was cooled to -37°C at a rate of 0.3°C / min and kept for 0.5h to obtain the pre-frozen product.

[0056] (2) Drying: The pre-frozen product is dried once at 0.25 mbar at a rate of 1 °C / min to 7 °C and held for 13 h; then dried a second time at 0.10 mbar at a rate of 1.5 °C / min to 27 °C and held for 4 h to obtain the product.

[0057] The injectable erythromycin lactobionate prepared in Examples 1-3 and Comparative Examples 1-3, as well as the commercially available injectable erythromycin lactobionate manufactured by Hospira Inc., were subjected to quality testing and stability studies. The results are detailed in Tables 1-4.

[0058] Table 1 Summary of test results for the formulations and reference formulations in the examples

[0059]

[0060]

[0061] Table 2 Summary of test results for comparative formulations

[0062]

[0063] Analysis of Tables 1 and 2 shows that the injectable erythromycin lactobionate prepared by the freeze-drying process of Examples 1-3 of this invention meets the registration standard requirements in terms of product appearance, solution clarity and color, reconstitution, and related substances. Furthermore, compared to the reference formulation, the injectable erythromycin lactobionate prepared by Examples 1-3 of this invention has a shorter reconstitution time, lower moisture content, and lower total impurity content. In contrast, the freeze-drying process of Comparative Examples 1-3 resulted in bottle cracking, and while the injectable erythromycin lactobionate prepared by Comparative Examples 1-3 had a lower total impurity content compared to the reference formulation, it had a longer reconstitution time and a higher moisture content.

[0064] Table 3 Summary of stability results for reference formulation and examples

[0065]

[0066] Table 4 Summary of Comparative Stability Results

[0067]

[0068] Analysis of Tables 3 and 4 shows that the freeze-dried products of erythromycin lactobionate for injection prepared by the freeze-drying process of Examples 1-3 have better stability and are comparable to the reference preparation; while the freeze-dried products of erythromycin lactobionate for injection prepared by the freeze-drying process of Comparative Examples 1-3 have significantly worse stability.

[0069] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A lyophilization process for erythromycin lactobionate for injection, characterized in that, Includes the following steps: (1) Pre-freezing: The erythromycin lactobionate solution for injection is cooled to -10℃~-8℃, vacuumed and maintained for 10-20 min, then cooled again to -35℃ to -40℃ and maintained for 0.5-1 h to obtain the pre-frozen product; (2) Drying: The pre-frozen product is dried once and kept for 12-14 hours; then it is dried a second time and kept for 3-5 hours to obtain erythromycin lactobionate for injection. The vacuum level after evacuation in step (1) is 0.6-1.0 mbar, the cooling rate is 0.2-0.4℃ / min, and the secondary cooling rate is 0.4-0.7℃ / min.

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

3. The freeze-drying process according to claim 1, characterized in that, The cooling rate in step (1) is 0.25-0.3℃ / min.

4. The freeze-drying process according to claim 1, characterized in that, The rate of secondary cooling in step (1) is 0.5-0.6℃ / min.

5. The freeze-drying process according to claim 1, characterized in that, The temperature for the first drying step (2) is 5-10℃.

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

7. The freeze-drying process according to claim 1, characterized in that, The drying process in step (2) is as follows: the pre-frozen product is dried once at 0.2-0.3 mbar to 5-10℃ and kept for 12-14 hours; then it is dried a second time at 0.07-0.13 mbar to 25-30℃ and kept for 3-5 hours.

8. The freeze-drying process according to claim 7, characterized in that, The heating rate for the first drying step (2) is 0.5-2℃ / min.

9. The freeze-drying process according to claim 8, characterized in that, The heating rate for the first drying step (2) is 0.5-1℃ / min.

10. The freeze-drying process according to claim 7, characterized in that, The heating rate for the secondary drying in step (2) is 0.5-2℃ / min.

11. The freeze-drying process according to claim 10, characterized in that, The heating rate for the secondary drying in step (2) is 0.5-1℃ / min.

12. The freeze-drying process according to any one of claims 1-11, characterized in that, The erythromycin content in the injectable lactobionic acid erythromycin solution in step (1) is 20-80 mg / mL.

13. The freeze-drying process according to claim 12, characterized in that, The erythromycin content in the injectable lactobionic acid erythromycin solution in step (1) is 40-50 mg / mL.

Images