CN110577567A

CN110577567A - method for preparing active polypeptide or protein with high specific surface area

Info

Publication number: CN110577567A
Application number: CN201910827587.6A
Authority: CN
Inventors: 赵呈青; 谷海涛; 高鲁
Original assignee: Hangzhou Nortel O Sano Pharmaceutical Technology Development Co Ltd
Current assignee: Hangzhou Nortel O Sano Pharmaceutical Technology Development Co Ltd
Priority date: 2019-09-03
Filing date: 2019-09-03
Publication date: 2019-12-17

Abstract

The invention belongs to the field of medicine preparation, relates to a method for preparing active polypeptide or protein with high specific surface area, and particularly relates to a nano sustained-release technology for controlling the surface area of a polypeptide or protein medicine.

Description

Method for preparing active polypeptide or protein with high specific surface area

Technical Field

The invention belongs to the field of medicine preparation, relates to a nano slow-release technology of specific surface area of polypeptide or protein medicine, and particularly relates to a rapid and efficient preparation technology of active polypeptide or protein with high specific surface area.

Background

the nanometer polymer particle is used as carrier for medicine transmission and controlled release and is one new kind of medicine controlled release system. The main difference between it and microparticle carriers is the ultra-small volume, which penetrates the interstitial space of tissues and is taken up by cells, and can pass through the smallest capillaries of the human body, thus being widely studied as a new drug delivery system. Especially in the fields of target and positioning administration, mucosa absorption administration, gene therapy, protein polypeptide controlled release and the like, the nano particles have unique superiority. The nano controlled release system for carrying the polypeptide and protein medicaments can help the polypeptide medicaments to release effective medicament components quantitatively and at a constant speed, thereby better exerting the curative effect. The patent CN 1494900a mentions a sustained release composition and a preparation method thereof, and the patent mainly aims at the sustained release composition and the preparation method thereof, and does not describe the control conditions of high specific surface area and mass production of active peptides. The company is one of the unique domestic and global pharmaceutical commercial production enterprises which can use the nanocrystallization technology for controlling the specific surface area of the polypeptide medicament and for research and development and mass production.

Disclosure of Invention

In view of this, the invention discloses a preparation technology of active polypeptide or protein raw material with high specific surface area, which is more beneficial to large-scale industrial production.

In order to achieve the purpose, the invention provides the following technical scheme:

The invention provides a preparation method of active polypeptide or protein with high specific surface area, which comprises the following steps:

(1) The active polypeptide or protein solution is subjected to salt exchange and concentration by a chromatographic column to obtain an active polypeptide or protein solution;

(2) Filtering the active polypeptide or protein solution through a 0.22 micron filter membrane under the clean environment condition;

(3) putting the filtrate into a high-pressure tank, and connecting the high-pressure tank to automatic numerical control mechanical arm material spraying quick-freezing equipment through a high-pressure resistant clean pipeline;

(4) starting automatic numerical control mechanical arm material spraying quick-freezing equipment, uniformly spraying the material liquid into a low-temperature freeze drying tray, and uniformly quick-freezing the active polypeptide or protein solution into a solid layer with uniform thickness;

(5) putting the sprayed freeze-drying plate into a freeze dryer for freeze drying;

(6) Packaging the solid active components in the freeze dryer under the condition that the humidity is less than 40.0% to obtain high-activity polypeptide or protein raw materials;

(7) the industrial preparation of the active polypeptide or protein with specific surface area can be realized by automatic numerical control mechanical arm material spraying quick-freezing equipment.

TABLE 1 relationship of control Point temperature to specific surface area of active

Controlling temperature point	obtaining the specific surface area of the active matter
		-5℃	13.1m²/g
-10℃	20.6m²/g
		-20℃	27.2m²/g
-25℃	28.5m²/g
		-30℃	31.9m²/g
-35℃	41.3m²/g

The active polypeptide or protein solution has a concentration of about 10-300 mg/mL.

the active polypeptide comprises: lanreotide, triptyline rayls, goserelin, gonadorelin, GLP-1 and its analogs, octreotide, thymalfasin, etc.

the refrigerant used by the manipulator material spraying quick-freezing equipment is liquid nitrogen, liquid oxygen or non-toxic liquid refrigerant.

The refrigerant temperature is less than-100 ℃;

preferably, the refrigerant temperature is less than-150 ℃.

The temperature of the freeze drying plate is controlled to be lower than-20 ℃ all the time;

preferably, the temperature of the freeze drying plate is always controlled to be-35 to-150 DEG C

the freeze-drying includes a prefreezing stage, a sublimation stage, and a resolution stage.

preferably, the pre-freezing stage conditions are a temperature of 0-45 ℃, a holding time of more than 1 hour and a normal pressure.

Preferably, the sublimation stage is carried out under the conditions that the temperature is 0-45 ℃, the holding time is more than 3 hours, the ultimate vacuum or 0.01-0.9 mbar is adopted, and phenomena of drying shrinkage, foaming and material spraying are avoided in a boring state.

preferably, the analysis stage conditions are that the temperature is 0-45 ℃, the holding time is more than 3 hours, the ultimate vacuum or 0.01-0.9 mbar, and the phenomena of drying shrinkage, foaming and material spraying are avoided in a boring state.

The automatic numerical control mechanical arm material spraying quick-freezing equipment has the following functional characteristics:

A. Numerical control manipulator: the control system converts the track into an electric signal according to the edited track parameter and transmits the electric signal to the driver, the driver converts the signal into a pulse signal to drive the stepping motor to run, a gear on the shaft of the stepping motor drives the synchronous belt to run, and a moving sliding block (mechanical arm) fixed on the synchronous belt moves together.

B. The material spraying system comprises: the material spraying device comprises a feeding tank and a numerical control manipulator, wherein the material of the feeding tank is 316L, the volume of the feeding tank is 10L, an upper port adopts clean sterile nitrogen for pressurization, an electromagnetic valve is arranged at the bottom of the feeding tank and is controlled by a control system, when the system runs, the nitrogen pressurizes the pressure in the feeding tank to be more than 0.2Mpa, then the electromagnetic valve at the bottom can be opened for material spraying operation, and when a temperature detector detects that the temperature of the sprayed material is higher than a set value, the electromagnetic valve is closed, and the;

C. Liquid nitrogen insulation can and heat conductor: the heat insulation box with liquid refrigerants such as liquid nitrogen, liquid oxygen and the like is made of 800L stainless steel materials and heat insulation materials, and is a flat heat conduction stainless steel plate with the thickness of 4-50 mm, and the automatic liquid refrigerant supplementing and pressure balance automatic adjusting machine.

The automatic numerical control manipulator material spraying quick-acting equipment for spray quick-freezing has the following advantages:

A. And (3) large-scale production: manual spray quick-freezing spraying needs four workers to continuously perform, the process consumes 8-16 hours generally, only two workers are needed for post operation after the manipulator is used, the time is not limited, and only the personnel need to maintain the equipment;

B. Automatic production: after the field operator finishes assembling the equipment, the equipment automatically starts to move the spray head according to a designed track to spray materials and quickly freeze by clicking a starting button; automatic temperature control: the liquid nitrogen heat insulation box is filled with low-temperature liquid nitrogen, the freeze-drying tray is placed in the heat insulation box for pre-freezing, infrared detection temperature detection is carried out at the position where the spray head sprays materials, and material conveying and mechanical arm movement are stopped when the material temperature exceeds a set temperature.

the invention also provides an active polypeptide.

Preferably, the active polypeptide is lanreotide.

Preferably, the specific surface area of the lanreotide is 20-60m²/g。

Drawings

FIGS. 1 to 6 are electron micrographs of lanreotide;

FIG. 7 is a sectional view of a powder quick-freezing system in the apparatus for producing nano-sized sustained-release granular powder according to example 7;

FIG. 8 is a schematic view showing the construction of a powder quick-freezing system in the apparatus for producing a nano-sized sustained-release granular powder according to example 9;

FIG. 9 is a graph of control point temperature versus specific surface area of active obtained;

fig. 10 is a specific surface area test report.

Detailed Description

The present invention is further described below in conjunction with specific examples to enable those skilled in the art to better understand the present invention and to practice it, which are not intended to limit the present invention.

Example 1

1. dissolving: 1.5Kg of lanreotide acetate is taken and dissolved in a proper amount of purified water, and the solution is diluted to about 30 g per liter by adding the purified water.

2. Filtering and filter-pressing 0.22 micron into a high-pressure clean tank body, and connecting pipelines;

3. The automatic numerical control mechanical arm material spraying quick-freezing equipment is arranged, and the control parameters are set as follows: the refrigerant is liquid nitrogen, and the temperature of the freeze drying plate is always controlled to be lower than minus 45 ℃; spraying at the temperature control threshold of the spraying surface lower than-5 ℃, and stopping spraying when the height threshold value of the sprayed ice layer is set to be 1.5 cm; starting the device, namely, starting the device to form a group every 2 disks until the spraying is complete, putting the sprayed sample disks into a freeze dryer in time, and starting the freeze dryer in advance to pre-cool the sample disks until the temperature of the plate layer is lower than minus 45 ℃;

4. The freeze dryer was turned on. Lyophilization was performed according to the following lyophilization procedure:

5. and (3) opening the dehumidifier in advance, after the humidity is reduced to be less than 40.0 percent, and after the procedure of the cold dryer is finished, subpackaging and weighing to obtain 1.58Kg of solid powder, wherein the yield is 98.7 percent. The specific surface area is 13.1493 +/-0.0302 m2/g after detection; see the lanreotide nanoscale particle spectrum under an electron microscope of attached figures 1-6 and the specific surface area test report of attached figure 7.

The automatic numerical control manipulator material spraying quick-freezing equipment comprises a powder quick-freezing system and a freeze-drying system, wherein the powder quick-freezing system comprises an ultralow temperature environment box, and a refrigerant chamber is arranged in the ultralow temperature environment box; the top of the ultra-low temperature environment box is provided with a quick-freezing groove, the bottom of the quick-freezing groove extends into the refrigerant chamber, and a freeze drying disc is arranged in the quick-freezing groove; the powder quick-freezing system also comprises a powder spraying module, wherein the powder spraying module comprises a longitudinal guide rail arranged at the top of the ultralow-temperature environment box and a cross beam arranged above the quick-freezing groove; the transverse beam is connected with the longitudinal guide rail, and the longitudinal guide rail is provided with a first driving device for driving the transverse beam to move; the crossbeam is connected with a spray head mounting seat and a second driving device for driving the spray head mounting seat to move.

Example 2:

1. salt transfer chromatography conditions

Mobile phase: phase A: 0.01% acetic acid aqueous solution, phase B: 100% acetonitrile;

A chromatographic column: DAC-300, a C18 reversed phase column, and the grain diameter of the filler is 10 um;

Sample loading amount: 150g of the total weight of the mixture;

Sample loading flow rate: 300 mL/min;

detection wavelength: 220 nm;

flow rate: 600 mL/min;

Elution gradient:

time min	A％	B％	flow rate mL/min
				0	95	5	400
15	95	5	400
				16	70	30	400
56	60	40	400

And (3) fraction collection: control requirements for distillate are shown in the table below

sample name	Purity of
		peak top of salt conversion	The purity is more than 99.0 percent, and the single impurity is less than 0.2 percent.

2. quantitatively obtaining 1.51kg of sample after removing acetonitrile from the peak sample after salt conversion through rotary evaporation, filtering and pressing the sample into a high-pressure clean high-pressure tank body by using 0.22 micron filter press, and connecting pipelines;

3. The automatic numerical control mechanical arm material spraying quick-freezing equipment is arranged, and the control parameters are set as follows: the refrigerant is liquid nitrogen, and the temperature of the freeze drying plate is always controlled to be lower than minus 45 ℃; spraying when the control threshold value of the temperature of the spraying surface is lower than minus 10 ℃, and stopping spraying when the height valve value of the sprayed ice layer is set to be 1.5 cm; starting the device, namely, starting the device to form a group every 2 disks until the spraying is complete, putting the sprayed sample disks into a freeze dryer in time, and starting the freeze dryer in advance to pre-cool the sample disks until the temperature of the plate layer is lower than minus 45 ℃;

5. and (3) opening the dehumidifier in advance, after the humidity is reduced to be less than 40.0 percent, and after the procedure of the cold dryer is finished, subpackaging and weighing to obtain 1.48Kg of solid powder, wherein the yield is 98.2 percent. The specific surface area after detection is 20.6108 +/-0.0477 m2 g; see the lanreotide nanoscale particle spectrum under an electron microscope of attached figures 1-6 and the specific surface area test report of attached figure 7.

example 3

1. Salt transfer chromatography conditions

Sample loading amount: 150g of the total weight of the mixture;

Sample loading flow rate: 300 mL/min;

detection wavelength: 220 nm;

flow rate: 600 mL/min;

Elution gradient:

2. Quantitatively obtaining 2.3kg of sample after removing acetonitrile from the peak sample after salt conversion through rotary evaporation, filtering and pressing the sample into a high-pressure clean high-pressure tank body by using 0.22 micron filter press, and connecting pipelines;

3. the automatic numerical control mechanical arm material spraying quick-freezing equipment is arranged, and the control parameters are set as follows: the refrigerant is liquid nitrogen, and the temperature of the freeze drying plate is always controlled to be lower than minus 45 ℃; spraying when the control threshold value of the temperature of the spraying surface is lower than minus 20 ℃, and stopping spraying when the height valve value of the sprayed ice layer is set to be 1.5 cm; starting the device, namely, starting the device to form a group every 2 disks until the spraying is complete, putting the sprayed sample disks into a freeze dryer in time, and starting the freeze dryer in advance to pre-cool the sample disks until the temperature of the plate layer is lower than minus 45 ℃;

5. and (3) opening the dehumidifier in advance, after the humidity is reduced to be less than 40.0 percent, and after the procedure of the cold dryer is finished, subpackaging and weighing to obtain 2.25Kg of solid powder, wherein the yield is 98.1 percent. The specific surface area after detection is 27.2605 +/-0.0520 m 2/g; see the lanreotide nanoscale particle spectrum under an electron microscope of attached figures 1-6 and the specific surface area test report of attached figure 7.

example 4

1. Salt transfer chromatography conditions

Sample loading amount: 150g of the total weight of the mixture;

sample loading flow rate: 300 mL/min;

Detection wavelength: 220 nm;

Flow rate: 600 mL/min;

Elution gradient:

2. quantitatively obtaining 3.1kg of sample after removing acetonitrile from the peak sample after salt conversion through rotary evaporation, filtering and press-filtering the sample into a high-pressure clean high-pressure tank body by using 0.22 micron filter, and connecting pipelines;

3. the automatic numerical control mechanical arm material spraying quick-freezing equipment is arranged, and the control parameters are set as follows: the refrigerant is liquid nitrogen, and the temperature of the freeze drying plate is always controlled to be lower than minus 45 ℃; spraying when the control threshold value of the temperature of the spraying surface is lower than minus 25 ℃, and stopping spraying when the height valve value of the sprayed ice layer is set to be 1.5 cm; starting the device, namely, starting the device to form a group every 2 disks until the spraying is complete, putting the sprayed sample disks into a freeze dryer in time, and starting the freeze dryer in advance to pre-cool the sample disks until the temperature of the plate layer is lower than minus 45 ℃;

5. And (3) opening the dehumidifier in advance, after the humidity is reduced to be less than 40.0 percent, and after the procedure of the cold dryer is finished, subpackaging and weighing to obtain 3.05Kg of solid powder, wherein the yield is 98.5 percent. The specific surface area is 28.4980 +/-0.0473 m2/g after detection; see the lanreotide nanoscale particle spectrum under an electron microscope of attached figures 1-6 and the specific surface area test report of attached figure 7.

example 5

1. salt transfer chromatography conditions

Sample loading amount: 150g of the total weight of the mixture;

Sample loading flow rate: 300 mL/min;

Detection wavelength: 220 nm;

flow rate: 600 mL/min;

Elution gradient:

2. Removing acetonitrile from the peak top sample after salt conversion through rotary evaporation, quantifying to obtain 3.0kg of sample, filtering and press-filtering the sample into a high-pressure clean high-pressure tank body by using 0.22 micron, and connecting pipelines;

3. The automatic numerical control mechanical arm material spraying quick-freezing equipment is arranged, and the control parameters are set as follows: the refrigerant is liquid nitrogen, and the temperature of the freeze drying plate is always controlled to be lower than minus 45 ℃; spraying when the control threshold value of the temperature of the spraying surface is lower than minus 30 ℃, and stopping spraying when the height threshold value of the sprayed ice layer is set to be 1.5 cm; starting the device, namely, starting the device to form a group every 2 disks until the spraying is complete, putting the sprayed sample disks into a freeze dryer in time, and starting the freeze dryer in advance to pre-cool the sample disks until the temperature of the plate layer is lower than minus 45 ℃;

5. and (3) opening the dehumidifier in advance, after the humidity is reduced to be less than 40.0 percent, and after the procedure of the cold dryer is finished, subpackaging and weighing to obtain 2.93Kg of solid powder, wherein the yield is 97.7 percent. The specific surface area is 31.8766 +/-0.0746 m2/g after detection; see the lanreotide nanoscale particle spectrum under an electron microscope of attached figures 1-6 and the specific surface area test report of attached figure 7.

example 6

1. Salt transfer chromatography conditions

sample loading amount: 150g of the total weight of the mixture;

Sample loading flow rate: 300 mL/min;

Detection wavelength: 220 nm;

Flow rate: 600 mL/min;

Elution gradient:

2. quantitatively obtaining 3.52kg of sample after removing acetonitrile from the peak sample after salt conversion through rotary evaporation, filtering and press-filtering the sample into a high-pressure clean high-pressure tank body by using 0.22 micron filter, and connecting pipelines;

3. the automatic numerical control mechanical arm material spraying quick-freezing equipment is arranged, and the control parameters are set as follows: the refrigerant is liquid nitrogen, and the temperature of the freeze drying plate is always controlled to be lower than minus 45 ℃; spraying when the control threshold value of the temperature of the spraying surface is lower than minus 35 ℃, and stopping spraying when the height threshold value of the sprayed ice layer is set to be 1.5 cm; starting the device, namely, starting the device to form a group every 2 disks until the spraying is complete, putting the sprayed sample disks into a freeze dryer in time, and starting the freeze dryer in advance to pre-cool the sample disks until the temperature of the plate layer is lower than minus 45 ℃;

5. And (3) opening the dehumidifier in advance, after the humidity is reduced to be less than 40.0 percent, and after the procedure of the cold dryer is finished, subpackaging and weighing to obtain 3.41Kg of solid powder, wherein the yield is 97.1 percent. The specific surface area after detection is 41.3566 +/-0.0498 m2/g, and is reported by a lanreotide nanometer-scale particle spectrum under an electron microscope of attached figures 1-6 and a specific surface area test of attached figure 7.

Example 7

A production device of nano-scale slow-release particle powder and a production process of the nano-scale slow-release particle powder based on the production device.

As shown in fig. 8 and 9, a production apparatus for nano-scale slow-release granule powder comprises a powder quick-freezing system and a freeze-drying system, wherein the powder quick-freezing system comprises an ultra-low temperature environment box 3, a closed refrigerant chamber 5 is arranged in the ultra-low temperature environment box 3, the refrigerant chamber 5 is provided with a refrigerant inlet and a refrigerant outlet, and the refrigerant chamber 5 is provided with an insulating layer 4. The ultra-low temperature environment box 3 is also provided with a temperature sensor for monitoring the temperature in the refrigerant chamber 5. The bottom of the refrigerant chamber 5 is provided with a discharge valve 33 for discharging the refrigerant remaining in the refrigerant chamber 5 after the process is completed.

As shown in fig. 8 and 9, a quick-freezing groove 6 is formed in the top of the ultra-low temperature environment box 3, the bottom of the quick-freezing groove 6 extends into the refrigerant chamber 5, a freeze-drying tray 8 is arranged in the quick-freezing groove 6, the freeze-drying tray 8 and the quick-freezing groove 6 are separately arranged, and the bottom of the freeze-drying tray 8 is in close contact with the bottom surface of the quick-freezing groove 6, so that the freezing efficiency is improved, and the uniformity of the temperature distribution of the freeze-drying tray 8 is ensured. The refrigerant chamber 5 is stored in the refrigerant chamber 5, an ultralow temperature environment is created, and the freeze drying plate 8 is cooled, so that conditions are created for quick freezing of materials.

As shown in fig. 8 and 9, the powder quick-freezing system further comprises a powder spraying module, the powder spraying module comprises a powder storage tank 1 and a spray head 2 connected with the powder storage tank 1 through a pipeline, and a control valve 33 for controlling the spray head 2 to work is arranged on the spray head 2. The nozzle mounting base 10 is provided with an infrared sensor, and the infrared sensor controls the opening and closing of the control valve 33 according to the temperature of the product in the freeze drying tray 8.

As shown in fig. 8 and 9, the powder spraying module further comprises a longitudinal guide rail 9 arranged at the top of the ultra-low temperature environment box 3, and a cross beam 7 arranged above the quick-freezing tank 6 and arranged along the width direction of the quick-freezing tank 6, wherein the longitudinal guide rail 9 extends along the length direction of the quick-freezing tank 6. The beam 7 is connected with the longitudinal guide rail 9, and the longitudinal guide rail 9 is provided with a first driving device 91 for driving the beam 7 to move along the length direction of the longitudinal guide rail 9. The cross beam 7 is connected with a nozzle mounting base 10 and a second driving device 71 for driving the nozzle mounting base 10 to move along the length direction of the cross beam 7. The first driving device 91 and the second driving device 71 respectively comprise a motor and a synchronous belt driven by the motor. The arrangement of the longitudinal guide rails 9 and the cross beams 7 realizes the orderly automatic movement of the spray head 2 relative to the freeze drying tray 8, improves the efficiency of spraying materials, and simultaneously improves the uniformity of material distribution in the freeze drying tray 8, thereby ensuring the product quality.

the freeze drying system comprises a vacuum drying machine, and the freeze drying machine comprises a drying box, a condenser, a freezing unit, a vacuum pump and a cooling device. Since the freeze drying system is the prior art, the present application is directed to improvements in freeze drying systems, and therefore, will not be described herein.

A production process of nano-scale slow-release particle powder based on the production equipment at least comprises the following steps:

Step one, raw material pretreatment: dissolving and diluting the raw materials to be processed, and then filter-pressing the raw materials into a powder storage tank 1 through a 0.22 micron filter membrane.

quick-freezing and spraying: a coolant with the temperature not higher than-100 ℃ is selected to be injected into the refrigerant chamber 5 to pre-cool the freeze drying plate 8, the temperature of the refrigerant is preferably not higher than-150 ℃, and liquid nitrogen is usually adopted as the refrigerant; until the temperature of the freeze-drying tray 8 is not higher than-5 ℃, the temperature of the freeze-drying tray 8 is preferably-35 to-150 ℃;

starting the first driving device 91 and the second driving device 71, then starting the control valve 33, enabling the spray head 2 and the beam 7 to respectively move relative to the freeze-drying tray 8, and in the second process, carrying out scanning type material spraying on the spray head 2 in the freeze-drying tray 8, rapidly condensing the raw material sprayed on the freeze-drying tray 8 in an ultralow temperature environment, wherein in the quick-freezing spraying process, the thickness of the frozen powder in the freeze-drying tray 8 is not more than 1.5 cm; after the material spraying is finished, the control valve 33 is closed, and the cross beam 7 and the nozzle mounting base 10 are reset.

step three, freeze drying: pre-cooling by a freeze dryer until the temperature in a vacuum drying box is not higher than minus 45 ℃, placing a freeze drying tray 8 loaded with the frozen raw materials in the vacuum drying box, and performing heat preservation and drying for at least 7 hours; packing the solid active components in the freeze dryer under the condition that the humidity is less than 40.0% to obtain the high-activity polypeptide or protein raw material.

the specific surface area of the obtained product is related to the temperature of the freeze-drying tray, and the specific surface area of the product is larger when the temperature of the freeze-drying tray is lower, and the specific correspondence is shown in table 1.

TABLE 2 comparison table of specific surface area of product and temperature of freeze drying plate

Controlling temperature point	obtaining the specific surface area of the active matter
		-5℃	13.1m2/g
-10℃	20.6m2/g
		-20℃	27.2m2/g
-25℃	28.5m²/g
		-30℃	31.9m²/g
-35℃	41.3m²/g

the product molding quality of the freeze-drying step is related to the temperature, drying time and vacuum degree, and the specific correspondence is shown in table 2.

table 3 freeze drying process test data

Claims

1. A method for preparing high specific surface area active polypeptide or protein, comprising the following steps:

(3) Putting the filtrate into a high-pressure tank, and linking the filtrate to automatic numerical control manipulator material spraying quick-freezing equipment through a high-pressure resistant cleaning pipeline;

(5) Putting the sprayed freeze drying tray into a freeze dryer for freeze drying;

(6) Packaging the solid active components in the freeze dryer under the condition that the humidity is less than 40.0% to obtain the high-activity polypeptide or protein raw material.

2. A method according to claim 1, characterized in that: the concentration of the active polypeptide or protein solution is 10-300 mg/mL.

3. the method according to claim 1, said active polypeptide comprising: lanreotide, triptyline rayls, goserelin, gonadorelin, GLP-1 and its analogs, octreotide, thymalfasin.

4. the method according to claim 1, wherein the concentration conditions of the active polypeptide or protein solution by chromatographic column salt exchange are: the mobile phase A is 0.01% acetic acid water solution, the B is 100% acetonitrile, the chromatographic column selects DAC-300, C18 reversed phase column, the filler particle diameter is 10um, the sample loading quantity is 150g, the sample loading flow rate is: 300mL/min, detection at 220nm, flow rate: 600mL/min, gradient elution was performed.

5. The method according to claim 1, wherein the adopted automatic numerical control mechanical arm material spraying quick-freezing equipment comprises: the powder quick-freezing system comprises an ultra-low temperature environment box, and a refrigerant chamber is arranged in the ultra-low temperature environment box; the top of the ultra-low temperature environment box is provided with a quick-freezing groove, the bottom of the quick-freezing groove extends into the refrigerant chamber, and a freeze drying disc is arranged in the quick-freezing groove; the powder quick-freezing system also comprises a powder spraying module, wherein the powder spraying module comprises a longitudinal guide rail arranged at the top of the ultralow-temperature environment box and a cross beam arranged above the quick-freezing groove; the transverse beam is connected with the longitudinal guide rail, and the longitudinal guide rail is provided with a first driving device for driving the transverse beam to move; the crossbeam is connected with a spray head mounting seat and a second driving device for driving the spray head mounting seat to move.

6. the method according to claim 1 or 5, wherein the refrigerant used by the mechanical arm material spraying quick-freezing equipment is liquid nitrogen, liquid oxygen or non-toxic liquid refrigerant.

7. the process according to claim 1 or 5, wherein the refrigerant temperature is below-100 ℃.

8. the process according to claim 1 or 5, the refrigerant temperature being below-150 ℃.

9. The method according to claim 1 or 5, wherein the freeze-drying tray temperature is always controlled to be below-20 ℃.

10. the method according to claim 1 or 5, wherein the temperature of the freeze-drying plate is always controlled to be-35 to-150 ℃.

11. a method according to claim 1 or 5, said freeze-drying comprising a prefreezing stage, a sublimation stage and a resolution stage.

12. a method according to claim 1 or 5, wherein the prefreezing stage conditions are a temperature of from 0 ℃ to 45 ℃, a holding time of greater than 1 hour, and atmospheric pressure.

13. A process according to claim 1 or 5, wherein the sublimation stage conditions are a temperature of from 0 ℃ to 45 ℃, a holding time of more than 3 hours, a limiting vacuum or from 0.01 to 0.9 mbar.

14. a process according to claim 1 or claim 5, wherein the desorption phase conditions are a temperature of from 0 ℃ to 45 ℃, a holding time of greater than 3 hours, an ultimate vacuum or from 0.01 to 0.9 mbar.

15. an active polypeptide produced by the method of any one of claims 1 to 14, wherein the polypeptide is lanreotide.

16. The active polypeptide of claim 15, wherein the lanreotide has a specific surface area of 20-60m²/g。