CN112691083B

CN112691083B - Freeze-drying process of vancomycin hydrochloride

Info

Publication number: CN112691083B
Application number: CN202011577949.XA
Authority: CN
Inventors: 杜加秋; 徐慧娟; 邵婷婷; 赵技宇; 董福霞; 钟梁; 张晓燕
Original assignee: Hanhui Pharmaceutical Co ltd
Current assignee: Hanhui Pharmaceutical Co ltd
Priority date: 2020-12-28
Filing date: 2020-12-28
Publication date: 2022-05-06
Anticipated expiration: 2040-12-28
Also published as: CN112691083A

Abstract

The invention provides a freeze-drying process of vancomycin hydrochloride. The freeze-drying process comprises the following steps: carry out freeze-drying to vancomycin hydrochloride liquid medicine, freeze-drying is including prefreezing, sublimation drying and the analytical drying that go on in proper order, and vancomycin hydrochloride liquid medicine includes vancomycin hydrochloride and auxiliary material, and the auxiliary material includes mannitol, prefreezes including the following step that goes on in proper order: cooling the vancomycin hydrochloride liquid medicine to-5 to-15 ℃ in 10-40 min and preserving the heat for 45-70 min; cooling to-45 to-35 ℃ in 1-60 min and keeping the temperature for 60-100 min; heating to-16 to-23 ℃ for 10-40 min and preserving heat for 140-180 min; cooling to-45 to-35 ℃ in 10-40 min and preserving heat for 100-130 min. The combination of the supercooling heat preservation step and the annealing step ensures that the vancomycin hydrochloride freeze-dried powder is in a loose amorphous state even if the rapid cooling is not carried out.

Description

Freeze-drying process of vancomycin hydrochloride

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a freeze-drying process of vancomycin hydrochloride.

Background

The main medicine of the vancomycin hydrochloride freeze-dried powder injection for injection is vancomycin hydrochloride, belongs to glycopeptide macromolecular antibiotics, and kills bacteria by inhibiting the growth and the reproduction of the bacteria. It interferes with cell wall synthesis by interfering with a key component in the bacterial cell wall structure, inhibiting the production of phospholipids and polypeptides in the cell wall. Vancomycin has strong potency, can be used when other antibiotics are ineffective to pathogenic bacteria, and is mainly used for systemic infection and intestinal infection caused by staphylococcus (including penicillin-resistant and penicillin-resistant strains), difficile clostridium and the like, such as endocarditis, septicemia, pseudomembranous enteritis and the like.

The common vancomycin hydrochloride freeze-dried powder injection for injection usually uses mannitol as an auxiliary material in reference to an original medicine prescription, wherein the auxiliary material mannitol is more in dosage, and the mannitol is easy to generate a crystallization state in the freeze-drying process due to the property of the mannitol. In the freeze-drying process in the prior art, the temperature needs to be directly cooled to about-40 ℃ in a short time in the pre-freezing stage, and the formed freeze-dried cake is easy to layer.

Disclosure of Invention

The invention mainly aims to provide a vancomycin hydrochloride freeze-drying process, and aims to solve the problem that a freeze-dried product obtained by the vancomycin hydrochloride freeze-drying process in the prior art is easy to crystallize or stratify.

In order to accomplish the above objects, according to one aspect of the present invention, there is provided a lyophilization process of vancomycin hydrochloride, comprising: carry out freeze-drying to vancomycin hydrochloride liquid medicine, freeze-drying is including freezing in advance, sublimation drying and the analytical drying that goes on in proper order, and vancomycin hydrochloride liquid medicine includes vancomycin hydrochloride and auxiliary material, and the auxiliary material includes mannitol, freezes in advance including the following step that goes on in proper order: cooling the vancomycin hydrochloride liquid medicine to-5 to-15 ℃ in 10-40 min and preserving the heat for 45-70 min; cooling to-45 to-35 ℃ in 1-60 min and keeping the temperature for 60-100 min; heating to-16 to-23 ℃ for 10-40 min and preserving heat for 140-180 min; cooling to-45 to-35 ℃ in 10-40 min and preserving heat for 100-130 min.

Further, the pre-freezing comprises the following steps which are carried out in sequence: cooling the vancomycin hydrochloride liquid medicine to-10 to-15 ℃ in 25-30 min and preserving heat for 50-60 min; cooling to-42 to-38 ℃ in 5-10 min and keeping the temperature for 80-90 min; heating to-18-20 ℃ for 20-30 min and preserving heat for 150-160 min; cooling to-42 to-38 ℃ for 20-30 min and preserving heat for 110-120 min.

Further, the sublimation drying comprises the following steps which are carried out in sequence: vacuumizing within 5-10 min until the gauge pressure is 0.200-0.600 mbar; heating to 0-5 ℃ for 90-120 min and keeping the temperature for 800-1000 min.

Further, the sublimation drying comprises the following steps which are carried out in sequence: vacuumizing within 5-10 min until the gauge pressure is 0.200-0.300 mbar; heating to 2-5 ℃ for 90-100 min and preserving the temperature for 900-950 min.

Further, the desorption drying includes: vacuumizing within 5-10 min until the gauge pressure is 0.010-0.030 mbar; heating to 35-50 ℃ for 80-100 min and keeping the temperature for 400-600 min.

Further, the desorption drying includes: vacuumizing within 5-10 min until the gauge pressure is 0.020-0.030 mbar; heating to 38-42 ℃ for 90-100 min and keeping the temperature for 420-450 min.

Furthermore, the weight ratio of the vancomycin hydrochloride to the mannitol in the vancomycin hydrochloride liquid medicine is 500: 100-150.

Furthermore, the ratio of the vancomycin hydrochloride to the injection water in the vancomycin hydrochloride liquid medicine is 0.5g to 4.0-6.5 mL.

Further, the auxiliary material also comprises hydrochloric acid.

Further, the pH value of the vancomycin hydrochloride liquid medicine is 2.5-4.5.

By applying the technical scheme of the invention, the temperature is slowly reduced to-5 to-15 ℃ for supercooling and heat preservation without directly and rapidly reducing the temperature to-40 ℃ in a pre-freezing stage, and the temperature is preserved for 45-70 min; then cooling to-45 to-35 ℃, and keeping for 60 to 100 min; then annealing treatment is carried out, namely the temperature is slowly increased to-16 to-23 ℃ and is kept for 140-180 min; and finally, cooling to minus 45 ℃ to minus 35 ℃ within 10-40 min and preserving the heat for 100-130 min. The supercooling heat preservation step is added for transition, so that the high requirements of the pre-freezing stage of the freeze-drying process on equipment and operation are reduced, and the industrial mass production of the vancomycin is easier to realize. In addition, the combination of the supercooling heat preservation step and the annealing step ensures that the finally obtained vancomycin hydrochloride freeze-dried powder is in a loose amorphous state even if the temperature is not quickly reduced, the appearance consistent with that of the original medicine is realized, and the redissolution property of the vancomycin hydrochloride freeze-dried powder is ensured.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:

fig. 1 shows a state diagram of a lyophilized powder obtained according to example 1 of the present invention;

fig. 2 shows a state diagram of the lyophilized powder obtained according to comparative example 1 of the present invention.

Detailed Description

It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail below with reference to the embodiments with reference to the attached drawings.

According to the description of the background art of the application, in the preparation process of the vancomycin hydrochloride freeze-dried powder, the mannitol auxiliary material is easy to crystallize, so that the problem that the freeze-dried powder is easy to crystallize or stratify is caused. The problem that the freeze-dried product obtained by the existing one-time direct cooling technology is still easy to crystallize or delaminate is solved. In order to solve the above problems, the present application provides a lyophilization process of vancomycin hydrochloride, comprising: carry out freeze-drying to vancomycin hydrochloride liquid medicine, freeze-drying is including freezing in advance, sublimation drying and the analytical drying that goes on in proper order, and vancomycin hydrochloride liquid medicine includes vancomycin hydrochloride and auxiliary material, and the auxiliary material includes mannitol, should freeze in advance including the following step that goes on in proper order: cooling the vancomycin hydrochloride liquid medicine to-5 to-15 ℃ in 10-40 min and preserving the heat for 45-70 min; cooling to-45 to-35 ℃ in 1-60 min and keeping the temperature for 60-100 min; heating to-16 to-23 ℃ for 10-40 min and preserving heat for 140-180 min; cooling to-45 to-35 ℃ in 10-40 min and preserving heat for 100-130 min.

By adopting the freeze-drying process, the temperature is not required to be directly and quickly reduced to-40 ℃ in the pre-freezing stage, but is slowly reduced to-5 to-15 ℃ for supercooling and heat preservation, and the temperature is preserved for 45-70 min; then cooling to-45 to-35 ℃, and keeping for 60 to 100 min; then annealing treatment is carried out, namely, the temperature is slowly increased to-16 to-23 ℃, and the temperature is kept for 140 to 180 min; and finally, cooling to minus 45 ℃ to minus 35 ℃ within 10-40 min and preserving the heat for 100-130 min. The supercooling and heat-preserving step is added for transition, so that the high requirements of the pre-freezing stage of the freeze-drying process on equipment and operation are reduced, and the industrial mass production of the vancomycin is easier to realize. In addition, the combination of the supercooling heat preservation step and the annealing step ensures that the finally obtained vancomycin hydrochloride freeze-dried powder is in a loose amorphous state even if the temperature is not quickly reduced, the appearance consistent with that of the original medicine is realized, and the redissolution property of the vancomycin hydrochloride freeze-dried powder is ensured.

Generally, vancomycin hydrochloride liquid medicine is filled in a penicillin bottle, half of the penicillin bottle is pressed and then is subjected to a freeze-drying process. Experimental experience shows that the bottom of the penicillin bottle is easily separated from the bottle body when the temperature is excessively high in the annealing step, and further the medicament loss is caused. It is therefore preferred that the pre-freezing comprises the following steps performed in sequence: cooling the vancomycin hydrochloride liquid medicine to-10 to-15 ℃ in 25-30 min and preserving heat for 50-60 min; cooling to-42 to-38 ℃ in 5-10 min and keeping the temperature for 80-90 min; heating to-18-20 ℃ for 20-30 min and preserving heat for 150-160 min; cooling to-42 to-38 ℃ for 20-30 min and preserving heat for 110-120 min. The parameter range reduces the highest temperature of the annealing process, ensures that the penicillin bottle bottom cannot fall off, further optimizes the target temperature range, the temperature rise and fall speed and the heat preservation time, and further optimizes the loose degree of the finally prepared vancomycin hydrochloride freeze-dried powder.

As mentioned above, after the pre-freezing treatment, a drying treatment is also required, and the above-mentioned sublimation drying and desorption drying processes of the present application can refer to the corresponding drying processes of vancomycin in the prior art.

In order to improve the drying degree, the sublimation drying method preferably comprises the following steps which are sequentially carried out: vacuumizing within 5-10 min until the gauge pressure is 0.200-0.600 mbar; heating to 0-5 ℃ for 90-120 min and keeping the temperature for 800-1000 min. In above-mentioned sublimation drying, through the evacuation operation for free solvent's sublimation rate in the prefreezing article, and in the environment of high vacuum, slowly heat up to 0 ~ 5 ℃, make solid-state solvent slowly sublimate in the vancomycin hydrochloride medicament, avoided the hole reduction that sublimation speed leads to at the excessive speed.

In order to further control the stability of the removal of the free solvent, it is preferable that the above-mentioned sublimation drying comprises the following steps performed in order: vacuumizing within 5-10 min until the gauge pressure is 0.200-0.300 mbar; heating to 2-5 ℃ for 90-100 min and preserving the temperature for 900-950 min.

Since the solvent adsorbed on the surface of vancomycin hydrochloride still exists after completion of sublimation drying, this part of the solvent is removed by resolution drying. Since the removal difficulty of the adsorption solvent is increased as compared with the removal difficulty of the free solvent, in order to achieve the removal effect as fast as possible and to ensure the loose porosity of the drug, the above-mentioned analytical drying is preferably performed by: vacuumizing within 5-10 min until the gauge pressure is 0.010-0.030 mbar; heating to 35-50 ℃ for 80-100 min and keeping the temperature for 400-600 min. Under the vacuum environment with lower pressure, the temperature is further increased to 35-50 ℃ on the basis of sublimation drying and temperature maintaining, and the temperature is kept for a long time, so that the adsorption solvent is slowly analyzed, and the aim of completely removing the solvent adsorbed on the surface of the vancomycin hydrochloride as far as possible is fulfilled.

In order to further enhance the removal of the solvent adsorbed on the surface of the vancomycin hydrochloride solvent, the desorption drying preferably includes: vacuumizing within 5-10 min until the gauge pressure is 0.020-0.030 mbar; heating to 38-42 ℃ for 90-100 min and keeping the temperature for 420-450 min.

The dosage of the vancomycin hydrochloride refers to the original medicine prescription. When the freeze-drying process is applied, in order to better match with a prescription, the obtained freeze-dried product is preferably stable in quality when the weight ratio of vancomycin hydrochloride to mannitol in the vancomycin hydrochloride liquid medicine is 500: 100-150.

The vancomycin hydrochloride liquid medicine used in the present application is a liquid medicine that is used conventionally when a freeze-dried preparation is prepared in the field, and in order to further ensure the effect of the drying treatment, the ratio of vancomycin hydrochloride to injection water in the vancomycin hydrochloride liquid medicine is preferably 0.5g: 4.0-6.5 mL.

In one embodiment, the auxiliary material further comprises hydrochloric acid. The pH value of the vancomycin hydrochloride liquid medicine is adjusted by adding hydrochloric acid auxiliary materials.

In order to further ensure the stability of the vancomycin hydrochloride liquid medicine, the pH value of the vancomycin hydrochloride liquid medicine is preferably 2.5-4.5.

The advantageous effects of the present application will be further described below with reference to examples and comparative examples.

Example 1

The lyophilization process is shown in table 1, and the state of the obtained lyophilized powder is shown in fig. 1, and it can be seen that the obtained lyophilized powder is in a uniform, loose amorphous state.

TABLE 1

The composition of the vancomycin hydrochloride stock solution is shown in table 2.

TABLE 2

Example 2

The lyophilization process is shown in table 3.

TABLE 3

The composition of the vancomycin hydrochloride stock solution was identical to that of example 1.

Example 3

The lyophilization process is shown in table 4.

TABLE 4

Example 4

The lyophilization process is shown in table 5.

TABLE 5

Example 5

The lyophilization process is shown in table 6.

TABLE 6

Example 6

The lyophilization process is shown in table 7.

TABLE 7

Example 7

The lyophilization process is shown in table 8.

TABLE 8

Example 8

The lyophilization process is shown in table 9.

TABLE 9

Example 9

The lyophilization process is shown in table 10.

Watch 10

Example 10

The lyophilization process is shown in table 11.

TABLE 11

Example 11

The lyophilization process is shown in table 12.

TABLE 12

Example 12

The lyophilization process is shown in table 13.

Watch 13

Example 13

The lyophilization process is shown in table 14.

TABLE 14

Example 14

The lyophilization process is shown in table 15.

Watch 15

Comparative example 1

The freeze-drying process is shown in table 16, and the state of the obtained freeze-dried powder is shown in fig. 2, and the obtained freeze-dried powder is in a layered state, and a distinct characteristic peak can be detected by XRD detection, which indicates that the crystal exists.

TABLE 16

Comparative example 2

The lyophilization process is shown in table 17.

TABLE 17

Comparative example 3

The lyophilization process is shown in table 18 below,

watch 18

Comparative example 4

The lyophilization process is shown in table 19.

Watch 19

The state of the products obtained in each example is scored, the loose state of the product obtained in the example 1 is best 10 points, the crystalline state of the product obtained in the comparative example 1 is 0 point, layering, namely 5 points, is carried out, and other products are deducted according to the loose degree visible to the naked eye; the reconstitution time of the freeze-dried powder obtained in each example is tested, and the reconstitution time detection method comprises the following steps: samples of each example and comparative example were taken in 5 bottles, 10mL of water for injection was added, the solution was dissolved by gentle shaking, the dissolution time was recorded, and the average value was calculated. The results of the resolubility test and the product conditions of examples 1 to 16 and comparative examples 1 to 4 are shown in Table 20.

Watch 20

From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:

by adopting the freeze-drying process, the temperature is not required to be directly and quickly reduced to-40 ℃ in the pre-freezing stage, but is slowly reduced to-5 to-15 ℃ for supercooling and heat preservation, and the temperature is preserved for 45-70 min; then cooling to-45 to-35 ℃, and keeping for 60 to 100 min; then annealing treatment is carried out, namely the temperature is slowly increased to-16-23 ℃ and the temperature is kept for 140-180 min; and finally, cooling to minus 45 ℃ to minus 35 ℃ within 10-40 min and preserving the heat for 100-130 min. The supercooling heat preservation step is added for transition, so that the high requirements of the pre-freezing stage of the freeze-drying process on equipment and operation are reduced, and the industrial mass production of the vancomycin is easier to realize. In addition, the combination of the supercooling heat preservation step and the annealing step ensures that the finally obtained vancomycin hydrochloride freeze-dried powder is in a loose amorphous state even if the temperature is not quickly reduced, the appearance consistent with that of the original medicine is realized, and the redissolution property of the vancomycin hydrochloride freeze-dried powder is ensured.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, 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 of vancomycin hydrochloride comprises the following steps: the method comprises the steps of carrying out freeze drying on vancomycin hydrochloride liquid medicine, wherein the freeze drying comprises prefreezing, sublimation drying and desorption drying which are sequentially carried out, the vancomycin hydrochloride liquid medicine comprises vancomycin hydrochloride and auxiliary materials, the auxiliary materials comprise mannitol, and the method is characterized in that,

the pre-freezing comprises the following steps in sequence:

cooling the vancomycin hydrochloride liquid medicine to-5 to-15 ℃ in 10-40 min and preserving heat for 45-70 min;

cooling to-45 to-35 ℃ in 1-60 min and keeping the temperature for 60-100 min;

heating to-16 to-23 ℃ in 10-40 min and preserving the temperature for 140-180 min;

cooling to-45 to-35 ℃ in 10-40 min, and keeping the temperature for 100-130 min,

the sublimation drying comprises the following steps which are carried out in sequence:

vacuumizing within 5-10 min until the gauge pressure is 0.200-0.600 mbar;

heating to 0-5 ℃ for 90-120 min, and keeping the temperature for 800-1000 min,

the desorption drying comprises the following steps:

vacuumizing within 5-10 min until the gauge pressure is 0.010-0.030 mbar;

heating to 35-50 ℃ for 80-100 min and keeping the temperature for 400-600 min.

2. Lyophilization process according to claim 1, wherein the prefreezing comprises the following steps carried out in sequence:

cooling the vancomycin hydrochloride liquid medicine to-10 to-15 ℃ in 25-30 min and preserving heat for 50-60 min;

cooling to-42 to-38 ℃ in 5-10 min and keeping the temperature for 80-90 min;

heating to-18-20 ℃ for 20-30 min and preserving heat for 150-160 min;

cooling to-42 to-38 ℃ for 20-30 min and preserving heat for 110-120 min.

3. Lyophilization process according to claim 1, characterized in that said sublimation drying comprises the following steps carried out in sequence:

vacuumizing within 5-10 min until the gauge pressure is 0.200-0.300 mbar;

heating to 2-5 ℃ for 90-100 min and preserving the temperature for 900-950 min.

4. The lyophilization process of claim 1, wherein the resolution drying comprises:

vacuumizing within 5-10 min until the gauge pressure is 0.020-0.030 mbar;

heating to 38-42 ℃ for 90-100 min and keeping the temperature for 420-450 min.

5. The freeze-drying process according to claim 1, wherein the weight ratio of the vancomycin hydrochloride to the mannitol in the vancomycin hydrochloride liquid medicine is 500: 100-150.

6. The freeze-drying process according to claim 1, wherein the ratio of vancomycin hydrochloride to injection water in the vancomycin hydrochloride liquid medicine is 0.5g: 4.0-6.5 mL.

7. The lyophilization process of claim 1, wherein the excipient further comprises hydrochloric acid.

8. The freeze-drying process according to claim 7, wherein the pH value of the vancomycin hydrochloride liquid medicine is 2.5-4.5.