CN111578627A - Drying process of protein medicine - Google Patents
Drying process of protein medicine Download PDFInfo
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- CN111578627A CN111578627A CN202010434309.7A CN202010434309A CN111578627A CN 111578627 A CN111578627 A CN 111578627A CN 202010434309 A CN202010434309 A CN 202010434309A CN 111578627 A CN111578627 A CN 111578627A
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
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Abstract
The invention discloses a drying process of protein medicines. The drying process comprises the steps of carrying out vacuum drying treatment on protein medicines, wherein the protein medicines comprise one or more of trypsin finished products, chymotrypsin finished products and hyaluronidase finished products; the vacuum degree of vacuum drying is below 20Pa, and the temperature of vacuum drying is 35-45 ℃; the vacuum drying time is more than 6 h; the thickness of the protein medicine is below 16 mm. The drying process is simple and convenient, the drying time is short, and the industrial production efficiency is effectively improved; and the drying weight loss of the prepared dried protein medicament can be reduced to below 2.0 percent, the bioactivity is not influenced, and the stability is better.
Description
Technical Field
The invention relates to the field of chemical pharmaceutical technology, in particular to a drying technology of protein drugs.
Background
Protein drugs such as trypsin, chymotrypsin and hyaluronidase are important proteolytic enzymes extracted from animal tissues such as pigs, cows or sheep. Trypsin can hydrolyze protein into polypeptide or amino acid, has selective hydrolysis effect on peptide chain of arginine and lysine, and is endopeptidase. Chymotrypsin not only has the effect of endopeptidase to rapidly decompose proteins into peptides with small molecular weight, but also has the effect of lipase to hydrolyze ester bonds, thereby promoting the digestion and removal of blood clots, purulent secretions, necrotic tissues and the like. Hyaluronidase catalyzes the hydrolysis of acidic mucopolysaccharides such as hyaluronic acid to generate oligosaccharide mainly containing tetrose, so that the viscosity of hyaluronic acid is obviously reduced, the tissue viscosity is reduced, the permeability of capillary vessels and tissues is improved, and the diffusion of substances inside and outside cells is accelerated.
However, the finished products of trypsin, chymotrypsin and hyaluronidase after vacuum freeze drying are very easy to absorb moisture, for example, the finished products have high water content when being freeze-dried out of a box, or the storage environment has excessive humidity, so that the drying weight loss is easily unqualified, and the stability of the finished products is reduced.
At present, the conventional treatment method in the field is a phosphorus pentoxide drying method, namely, a trypsin finished product, a chymotrypsin finished product or a hyaluronidase finished product is placed in a vacuum drying box, and a drying agent phosphorus pentoxide is added for drying treatment under reduced pressure; however, this method has problems of small throughput, excessively long drying time, poor stability of the finished product, necessity of using a large amount of a drying agent such as phosphorus pentoxide, and the like, and easy generation of a drying agent residue. Therefore, in order to make the drying weight loss of trypsin finished products, chymotrypsin finished products or hyaluronidase finished products meet the limit requirements in the pharmacopoeia of the people's republic of China, and improve the stability of the products without influencing the biological activity, the drying process of a protein medicine is urgently needed to solve the problems.
Disclosure of Invention
The invention aims to solve the problems of small treatment capacity, overlong drying time, poor stability of finished products and the like of the drying process of the protein medicines in the prior art and provides the drying process of the protein medicines. Compared with the prior art, the drying process has the advantages that the vacuum drying method is adopted, so that the drying time is saved by 1-2 days, and the industrial production efficiency is effectively improved; meanwhile, the drying weight loss of the dried protein medicine prepared by the drying process can be reduced to below 2.0 percent, the bioactivity is not influenced, and the stability is good.
The invention solves the technical problems through the following technical scheme:
the invention provides a drying process of a protein medicine, which is characterized by comprising the following steps: carrying out vacuum drying treatment on the protein medicine;
wherein the protein medicine comprises one or more of trypsin finished product, chymotrypsin finished product and hyaluronidase finished product;
the vacuum degree of the vacuum drying is below 20 Pa;
the temperature of the vacuum drying is 35-45 ℃;
the vacuum drying time is more than 6 hours;
in the vacuum drying process, the thickness of the protein medicine is less than 16 mm.
In the present invention, the drying process is preferably performed without adding a drying agent.
The drying agent is generally a drying agent used for drying protein drugs, such as phosphorus pentoxide or anhydrous calcium chloride.
In the present invention, the skilled person will know that the finished trypsin, chymotrypsin or hyaluronidase product is generally referred to as a lyophilized powder.
The freeze-dried powder is generally sterile powder which is prepared by freezing liquid medicine into a solid state in a clean area, and carrying out vacuum pumping to sublimate and dry water.
In the invention, the trypsin finished product, the chymotrypsin finished product or the hyaluronidase finished product generally refers to freeze-dried powder with the drying weight loss of more than 5%, such as trypsin freeze-dried powder with the drying weight loss of 6.5%, chymotrypsin freeze-dried powder with the drying weight loss of 5.8% or hyaluronidase freeze-dried powder with the drying weight loss of 5.2%.
In the invention, the loss on drying generally refers to the mass loss after drying to constant weight, which is the mass percentage of the sampled amount of the protein drug.
In the invention, the vacuum degree of the vacuum drying can be 10-20 Pa; for example, 10 to 15 Pa; for example still 10Pa or 15 Pa.
In the invention, the temperature of the vacuum drying can be 35-40 ℃, for example 40 ℃.
In the invention, the vacuum drying time can be 6-20 h; preferably 8-15 h; for example, 8 to 12 hours; for example, 9h or 10 h.
In the present invention, in the vacuum drying process, the thickness of the protein drug may be 15mm or less, for example, 0 to 15mm but not 0, and further, for example, 10mm, 12mm, or 15 mm.
The thickness of the protein drug can be selected by those skilled in the art according to the practical conditions such as cost, sample water content and sample treatment capacity, for example, 6-10 mm. Wherein the sample is generally a proteinaceous drug as described above.
In the present invention, the vacuum drying apparatus may be a vacuum freeze dryer. When the vacuum drying apparatus is a vacuum freeze dryer, those skilled in the art will appreciate that the temperature is generally referred to as the slab temperature of the vacuum freeze dryer.
Wherein the vacuum freeze dryer may be a vacuum freeze dryer conventional in the art, such as a Lyo-1 vacuum freeze dryer.
Preferably, the thickness of the protein drug is uniform in the vacuum drying. When the vacuum drying is performed using a vacuum freeze dryer, it is known from common knowledge that the protein drug is generally spread in a freeze plate of the vacuum freeze dryer.
In the present invention, the mass of the protein drug may be 16mm or less, or may be selected according to actual needs.
In the present invention, the vacuum drying process is known to those skilled in the art to comprise the following steps:
(1) starting the vacuum drying equipment, setting the temperature and the vacuum degree of the vacuum drying equipment, and drying the protein medicine;
(2) and closing the vacuum drying equipment, setting the vacuum drying equipment to be normal pressure, and taking out the dried protein medicine.
Wherein, as will be appreciated by those skilled in the art, the atmospheric pressure in step (2) generally refers to a standard atmospheric pressure (101325 Pa).
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
(1) compared with the prior art, the drying process of the invention adopts a vacuum drying method, saves the drying time of 1-2 days and effectively improves the industrial production efficiency.
(2) By adopting the drying process, the drying weight loss of the prepared dried trypsin finished product, dried chymotrypsin finished product or dried hyaluronidase finished product can be reduced to below 2.0 percent, the bioactivity is not influenced, and the stability is better.
Drawings
FIG. 1 is a bar graph of the loss on drying of the trypsin finished products after drying in examples 1-3 and comparative examples 1-5;
FIG. 2 is a bar graph of drying weight loss of the chymotrypsin finished products after drying in examples 4-7 and comparative examples 6-9;
FIG. 3 is a bar graph of the loss on drying of the hyaluronidase finished products after drying in examples 8-10 and comparative examples 10-13.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples and comparative examples, the trypsin finished product with unqualified drying weight loss is the trypsin finished product with the drying weight loss of more than 5%. The chymotrypsin finished product with unqualified drying weight loss is a chymotrypsin finished product with the drying weight loss more than 5 percent. The finished product of the hyaluronidase with unqualified drying weight loss is a finished product of the hyaluronidase with drying weight loss more than 5 percent.
The trypsin finished product, the chymotrypsin finished product and the hyaluronidase finished product which are raw materials in the following examples and comparative examples can be prepared according to the conventional method in the field, but the drying weight loss is unqualified because the temperature and the humidity during the box discharging process are not controlled; the loss on drying and the titer of the finished trypsin, chymotrypsin and hyaluronidase products are shown in table 1.
Wherein, the drying weight loss and the wet titer of the finished trypsin are respectively measured according to the drying weight loss and the titer measurement in trypsin on page 1170 of the 'Chinese pharmacopoeia' 2015 edition (second part);
the drying weight loss and the wet titer of the finished chymotrypsin are respectively measured according to the drying weight loss and titer measurement in chymotrypsin on page 1591 of the 2015 edition (second part) of Chinese pharmacopoeia;
the wet titer of finished hyaluronidase is measured according to the method of hyaluronidase determination on page 167 of the Chinese pharmacopoeia 2015 edition (four parts); the drying weight loss of finished hyaluronidase is measured according to the drying weight loss measuring method on page 259 of the first supplementary book of the 'Chinese pharmacopoeia' 2015 edition.
Wherein, the dry product titer in table 1 can be according to the formula: wet titer is calculated as dry titer x (1-loss on drying).
TABLE 1
Note: the dried product is a sample with water being deducted; the wet product is a sample without water being subtracted.
Examples 1 to 3 and comparative examples 1 to 4
The samples in examples 1 to 3 and comparative examples 1 to 4 were trypsin products having an unacceptable loss on drying as shown in Table 1.
The drying process in examples 1 to 3 and comparative examples 1 to 4 comprises the following steps:
(1) weighing a sample (a trypsin finished product with unqualified drying weight loss), uniformly mixing, paving in a freeze-drying tray, and putting in a vacuum freeze-drying machine; wherein the sample mass and the tiling thickness are shown in table 2;
(2) starting the vacuum freeze dryer, setting the temperature of a plate layer of the vacuum freeze dryer, adjusting the vacuum degree of the vacuum freeze dryer, and drying the trypsin finished product; wherein the slab temperature and the vacuum degree are shown in table 2;
(3) after drying, closing the vacuum freeze dryer; wherein the drying time is shown in table 2;
(4) and setting the vacuum freeze dryer to be at normal pressure, and taking out the dried trypsin finished product.
In examples 1 to 3 and comparative examples 1 to 4, the process conditions or parameters were the same except for those shown in Table 2.
In comparative examples 1-2, the thickness of the flat spread of the finished trypsin product is not within the range of 16mm or less as claimed in the application; in comparative example 3, the ply temperature was not within the range of 35 to 45 ℃ as claimed in the present application; in comparative example 4, neither the degree of vacuum nor the drying time were within the range claimed in the present application.
TABLE 2
Comparative example 5
The sample in comparative example 5 was a trypsin finished product with an unacceptable loss on drying as shown in table 1.
Comparative example 5 the phosphorus pentoxide drying process of the prior art was used, with the following steps:
(1) weighing 60.0g of trypsin finished product, uniformly mixing, then flatly paving in a freeze-drying tray, wherein the thickness of the flatly paving is 12mm, and putting in a vacuum drying oven;
(2) 30.0g of phosphorus pentoxide drying agent is weighed, laid in another freeze-drying tray and put in a vacuum drying box;
(3) starting a vacuum drying oven, setting the temperature of the vacuum drying oven to be 40 ℃, adjusting the vacuum degree of the vacuum drying oven to be 400Pa, and drying the trypsin finished product;
(4) after drying for 24 hours, closing the vacuum drying oven, and adjusting the pressure of the vacuum drying oven to normal pressure;
(5) replacing the drying agent in the step (2), spreading 30.0g of phosphorus pentoxide drying agent in another freeze-drying tray, and putting the freeze-drying tray into a vacuum drying box;
(6) opening the vacuum drying oven again, setting the temperature of the vacuum drying oven to be 40 ℃, adjusting the vacuum degree of the vacuum drying oven to be 400Pa, and drying the trypsin finished product again;
(7) and (5) after drying for 24 hours, closing the vacuum drying oven, adjusting the pressure of the vacuum drying oven to normal pressure, and taking out the dried trypsin finished product.
Effect example 1
According to the determination method of the drying weight loss and the titer in trypsin on page 1170 of the 'Chinese pharmacopoeia' 2015 edition (second part), the drying weight loss and the wet titer of the dried trypsin finished products prepared in the examples 1-3 and the comparative examples 1-5 are detected; wherein, can be according to the formula: the wet titer is expressed as dry titer (1-loss on drying), and the wet titer is converted into the dry titer to be compared.
The results are shown in FIG. 1 and Table 3:
TABLE 3
| Loss on drying (%) | Dry titer (U/mg) | |
| Trypsin finished product | 6.5 | 2851 |
| Example 1 | 1.3 | 2819 |
| Example 2 | 1.4 | 2856 |
| Example 3 | 1.8 | 2839 |
| Comparative example 1 | 2.8 | 2839 |
| Comparative example 2 | 4.0 | 2859 |
| Comparative example 3 | 4.5 | 2833 |
| Comparative example 4 | 5.4 | 2819 |
| Comparative example 5 | 4.8 | 2750 |
As can be seen from Table 3, the drying process in examples 1 to 3 is adopted for the trypsin finished product with unqualified drying weight loss (the drying weight loss is 6.5%), the weight loss of drying meets the requirement of page 1170 of Chinese pharmacopoeia 2015 edition (second part), the drying weight loss of the dried trypsin finished product is reduced to below 1.8%, and compared with comparative examples 4 to 5, the drying time is saved by 1 to 2 days.
In comparative examples 1-2, the thickness of the flat spread trypsin finished product is not less than 16mm, and in comparative example 3, the temperature of the plate layer is not within the range of 35-45 ℃; although the titer of the dried trypsin finished product is not obviously changed, the drying weight loss of the dried trypsin finished product is still more than 2.8 percent, which is inferior to that of the examples 1-3.
In comparative example 4, the trypsin finished product is dried in vacuum at 40 ℃ and 400Pa for 48h, although the titer of the dried trypsin finished product is not obviously changed, the drying weight loss of the dried trypsin finished product is 5.4% (> 5%), which does not meet the requirements of the 'Chinese pharmacopoeia' 2015 edition (second part) on page 1170.
In comparative example 5, the finished product of trypsin is dried in a vacuum drying oven for 48 hours by adopting a phosphorus pentoxide drying process in the prior art, although the drying weight loss is reduced to 4.8 percent, the requirement of the 1170 page of Chinese pharmacopoeia 2015 edition (second part) is met, the upper limit of the qualified line is approached, and the titer of the dried finished product of trypsin is slightly reduced after drying, so that the bioactivity is influenced.
Examples 4 to 7 and comparative examples 6 to 8
The samples in examples 4 to 7 and comparative examples 6 to 8 are chymotrypsin finished products with unacceptable loss on drying as shown in Table 1.
The drying process in examples 4 to 7 and comparative examples 6 to 8 includes the following steps:
(1) weighing a sample (a finished chymotrypsin product with unqualified drying weight loss), uniformly mixing, paving in a freeze-drying tray, and putting in a vacuum freeze-drying machine; wherein the sample mass and the tiling thickness are shown in table 4;
(2) starting the vacuum freeze dryer, setting the temperature of a plate layer of the vacuum freeze dryer, adjusting the vacuum degree of the vacuum freeze dryer, and drying the finished chymotrypsin product; wherein the slab temperature and the vacuum degree are shown in table 4;
(3) after drying, closing the vacuum freeze dryer; wherein the drying time is shown in table 4;
(4) and setting the vacuum freeze dryer to be at normal pressure, and taking out the dried finished chymotrypsin.
In examples 4 to 7 and comparative examples 6 to 8, the same process conditions or parameters were used except for those shown in Table 4.
Wherein, in the drying process of the comparative example 6, the vacuum degree of vacuum drying is not below 20Pa claimed in the application; in the drying process of comparative example 7, the time for vacuum drying is not more than 6 hours as claimed in the present application; in the drying process of comparative example 8, neither the degree of vacuum nor the drying time was within the range claimed in the present application.
TABLE 4
Comparative example 9
The sample in comparative example 9 was the finished chymotrypsin with an unacceptable loss on drying as shown in table 1.
Comparative example 9 the prior art phosphorus pentoxide drying process was used, with the following steps:
(1) weighing 60.0g of finished chymotrypsin, uniformly mixing, then flatly paving in a freeze-drying tray, wherein the thickness of the flatly paving is 12mm, and putting in a vacuum drying oven;
(2) 30.0g of phosphorus pentoxide drying agent is weighed, laid in another freeze-drying tray and put in a vacuum drying box;
(3) starting a vacuum drying oven, setting the temperature of the vacuum drying oven to be 40 ℃, adjusting the vacuum degree of the vacuum drying oven to be 400Pa, and drying the finished product of the chymotrypsin;
(4) after drying for 24 hours, closing the vacuum drying oven, and adjusting the pressure of the vacuum drying oven to normal pressure;
(5) replacing the drying agent in the step (2), spreading 30.0g of phosphorus pentoxide drying agent in another freeze-drying tray, and putting the freeze-drying tray into a vacuum drying box;
(6) opening the vacuum drying oven again, setting the temperature of the vacuum drying oven to be 40 ℃, adjusting the vacuum degree of the vacuum drying oven to be 400Pa, and drying the finished product of the chymotrypsin;
(7) and (3) after drying for 24 hours, closing the vacuum drying oven, adjusting the pressure of the vacuum drying oven to normal pressure, and taking out the dried finished chymotrypsin.
Effect example 2
According to the determination method of the drying weight loss and the titer in chymotrypsin on page 1591 of the 'Chinese pharmacopoeia' 2015 edition (second part), the drying weight loss and the wet titer of the dried chymotrypsin finished products prepared in the examples 4-7 and the comparative examples 6-9 are detected; wherein, can be according to the formula: the wet titer is expressed as dry titer (1-loss on drying), and the wet titer is converted into the dry titer to be compared.
The results are shown in fig. 2 and table 5:
TABLE 5
| Loss on drying (%) | Dry titer (U/mg) | |
| Chymotrypsin finished product | 5.8 | 1327 |
| Example 4 | 1.3 | 1306 |
| Example 5 | 1.3 | 1289 |
| Example 6 | 1.7 | 1293 |
| Example 7 | 1.7 | 1306 |
| Comparative example 6 | 3.5 | 1295 |
| Comparative example 7 | 4.8 | 1289 |
| Comparative example 8 | 4.8 | 1260 |
| Comparative example 9 | 4.7 | 1200 |
As can be seen from Table 5, the drying process in examples 4 to 7 is adopted for the chymotrypsin finished product with unqualified drying weight loss (the drying weight loss is 5.8%), the weight loss of drying meets the requirement of page 1591 in Chinese pharmacopoeia 2015 edition (second part), the drying weight loss of the chymotrypsin finished product after drying is reduced to below 1.8%, and compared with comparative examples 8 to 9, the drying time is saved by 1 to 2 days.
In comparative example 6, the vacuum degree of vacuum drying is not within the range claimed in the present application, and although the loss on drying is reduced to 3.5%, it meets the requirement of page 1591 of the second part of the "chinese pharmacopoeia" 2015 edition, but is significantly higher than 1.7%, which is not as good as examples 4-7.
In comparative example 7, the vacuum drying time is out of the range claimed in the present application, and although the loss on drying is reduced to 5% or less, which meets the requirement of page 1591 in "chinese pharmacopoeia" 2015 edition (second part), it is close to the upper limit of the qualified line, and is not as good as examples 4 to 7.
In comparative example 8, the finished chymotrypsin is dried in vacuum at 40 ℃ and 400Pa for 48h, but the drying weight loss of the dried chymotrypsin finished product is 4.8%, although the requirement on page 1591 of Chinese pharmacopoeia 2015 edition (second part) is met, the drying time is too long, the efficiency is low, and the titer of the dried chymotrypsin finished product is slightly reduced, so that the bioactivity is influenced.
In comparative example 9, the finished chymotrypsin is dried in a vacuum drying oven for 48 hours by adopting a phosphorus pentoxide drying process in the prior art, although the drying weight loss is reduced to 4.7 percent and meets the requirement of the No. 1591 page of the second part of the Chinese pharmacopoeia (2015 edition), the dry titer of the dried finished chymotrypsin is reduced and the bioactivity is influenced.
Examples 8 to 10 and comparative examples 10 to 12
The samples in examples 8 to 10 and comparative examples 10 to 12 were finished hyaluronidase products with unacceptable loss on drying as shown in Table 1.
The drying process in examples 8 to 10 and comparative examples 10 to 12 includes the following steps:
(1) weighing a sample (finished product of hyaluronidase with unqualified drying weight loss), uniformly mixing, paving in a freeze-drying tray, and putting in a vacuum freeze-drying machine; wherein the sample mass and the tiling thickness are shown in table 6;
(2) starting the vacuum freeze dryer, setting the temperature of a plate layer of the vacuum freeze dryer, adjusting the vacuum degree of the vacuum freeze dryer, and drying a finished product of the hyaluronidase; wherein the slab temperature and the vacuum degree are shown in table 6;
(3) after drying, closing the vacuum freeze dryer; wherein the drying time is shown in table 6;
(4) and setting the vacuum freeze dryer to be at normal pressure, and taking out the dried finished product of the hyaluronidase.
In examples 8 to 10 and comparative examples 10 to 12, the same procedure was conducted except for the process conditions or parameters shown in Table 6.
Wherein, in the drying process of the comparative example 10, the vacuum degree of vacuum drying is not below 20Pa claimed in the application; in the drying process of comparative example 11, the time for vacuum drying is not more than 6 hours as claimed in the present application; in the drying process of comparative example 12, neither the degree of vacuum nor the drying time was within the range claimed in the present application.
TABLE 6
Comparative example 13
The sample in comparative example 13 was a finished hyaluronidase product with an unacceptable loss on drying as shown in table 1.
Comparative example 13 the prior art phosphorus pentoxide drying process was used, with the following steps:
(1) weighing 60.0g of finished hyaluronidase, uniformly mixing, then flatly paving in a freeze-drying tray, wherein the thickness of the flatly paving is 12mm, and putting in a vacuum drying oven;
(2) 30.0g of phosphorus pentoxide drying agent is weighed, laid in another freeze-drying tray and put in a vacuum drying box;
(3) starting a vacuum drying oven, setting the temperature of the vacuum drying oven to be 40 ℃, adjusting the vacuum degree of the vacuum drying oven to be 400Pa, and drying the finished product of the hyaluronidase;
(4) after drying for 24 hours, closing the vacuum drying oven, and adjusting the pressure of the vacuum drying oven to normal pressure;
(5) replacing the drying agent in the step (2), spreading 30.0g of phosphorus pentoxide drying agent in another freeze-drying tray, and putting the freeze-drying tray into a vacuum drying box;
(6) opening the vacuum drying oven again, setting the temperature of the vacuum drying oven to be 40 ℃, adjusting the vacuum degree of the vacuum drying oven to be 400Pa, and drying the finished product of the hyaluronidase;
(7) and (5) after drying for 24 hours, closing the vacuum drying oven, adjusting the pressure of the vacuum drying oven to normal pressure, and taking out the dried finished product of the hyaluronidase.
Effect example 3
The wet titer of the dried finished hyaluronidase products prepared in examples 8 to 10 and comparative examples 10 to 13 is detected according to the hyaluronidase determination method on page 167 in the version (four parts) of Chinese pharmacopoeia 2015; can be expressed according to the formula: the wet titer is expressed as dry titer (1-loss on drying), and the wet titer is converted into the dry titer to be compared.
The drying weight loss of the dried finished hyaluronidase products prepared in examples 8 to 10 and comparative examples 10 to 13 was measured according to the drying weight loss measurement method on page 259 of the first supplementary book of the 'Chinese pharmacopoeia' 2015 edition.
The results are shown in FIG. 3 and Table 7:
TABLE 7
As can be seen from Table 7, the drying process in examples 8 to 10 is adopted for the finished product of hyaluronidase with unqualified drying weight loss (the drying weight loss is 5.2%), the weight loss of drying meets the requirement of the first supplementary book page 259 in Chinese pharmacopoeia 2015 edition, the drying weight loss of the finished product of hyaluronidase after drying is reduced to below 1.7%, and compared with comparative examples 12 to 13, the drying time is saved by 1 to 2 days.
In comparative example 10, the degree of vacuum drying is not within the range claimed in the present application, and although the loss on drying is reduced to 3.9%, which meets the requirement of the first supplementary book page 259 in the "chinese pharmacopoeia" 2015 edition, the loss on drying value is larger, which is not as good as examples 8-10.
In comparative example 11, the vacuum drying time is out of the range claimed in the present application, and although the loss on drying is reduced to 4.3%, it meets the requirement of the first supplementary book page 259 in the "chinese pharmacopoeia" 2015 edition, but is close to the upper limit of the qualified line, which is not as good as examples 8-10.
In comparative example 12, the finished hyaluronidase is dried under vacuum at 40 ℃ and 400Pa for 48h, and the drying weight loss of the dried finished hyaluronidase is 4.6%, which meets the requirements of the first supplement of the 'Chinese pharmacopoeia' 2015 edition on page 259, but is close to the upper limit of the qualified line, which is not the same as that of examples 8-10.
In comparative example 13, the finished product of the hyaluronidase is dried in a vacuum drying oven for 48 hours by adopting a phosphorus pentoxide drying process in the prior art, although the drying weight loss is reduced to 3.8 percent, which meets the requirements of the first supplementary book page 259 in the 'Chinese pharmacopoeia' 2015 edition, the titer of the dried finished product of the hyaluronidase is slightly reduced after drying, which affects the biological activity.
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention.
Claims (10)
1. The drying process of the protein medicine is characterized by comprising the following steps: carrying out vacuum drying treatment on the protein medicine;
wherein, the protein medicine comprises one or more of trypsin finished product, chymotrypsin finished product and hyaluronidase finished product;
the vacuum degree of the vacuum drying is below 20 Pa;
the temperature of the vacuum drying is 35-45 ℃;
the vacuum drying time is more than 6 hours;
in the vacuum drying process, the thickness of the protein medicine is less than 16 mm.
2. The process for drying a proteinaceous pharmaceutical of claim 1, wherein no drying agent is added to the drying process.
3. The process for drying a protein drug according to claim 1 or 2, wherein the vacuum degree of the vacuum drying is 10 to 20 Pa; preferably 10 to 15 Pa.
4. The process for drying a protein drug as claimed in any one of claims 1 to 3, wherein the temperature of the vacuum drying is 35 to 40 ℃.
5. The drying process of the protein drug as claimed in any one of claims 1 to 3, wherein the vacuum drying time is 6 to 20 hours; preferably 8-15 h.
6. The process for drying a protein drug according to claim 5, wherein the vacuum drying time is 9 hours or 10 hours.
7. The process for drying a protein drug according to any one of claims 1 to 3, wherein the thickness of the protein drug is 15mm or less during the vacuum drying.
8. The process for drying a protein drug according to claim 7, wherein the thickness of the protein drug is 0 to 15mm but not 0.
9. The process for drying a proteinaceous drug according to claim 8, wherein the thickness of the proteinaceous drug is 10mm, 12mm, or 15 mm.
10. The process for drying a protein drug according to any one of claims 1 to 9, wherein the vacuum drying treatment comprises the following steps:
(1) starting the vacuum drying equipment, setting the temperature and the vacuum degree of the vacuum drying equipment, and drying the protein medicine;
(2) and closing the vacuum drying equipment, setting the vacuum drying equipment to be normal pressure, and taking out the dried protein medicine.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101398254A (en) * | 2007-09-30 | 2009-04-01 | 浙江医药股份有限公司新昌制药厂 | Peptide-containing antibiotic finished product drying method |
| US20120308526A1 (en) * | 2007-11-07 | 2012-12-06 | Aridis Pharmaceuticals | Sonic Low Pressure Spray Drying |
| CN104019635A (en) * | 2014-06-19 | 2014-09-03 | 上海慈瑞医药科技有限公司 | Drying process for lansoprazole bulk drug |
| CN104697298A (en) * | 2015-03-13 | 2015-06-10 | 湖南科伦制药有限公司 | Freeze-drying technology for water-soluble vitamins |
| KR101806344B1 (en) * | 2016-03-28 | 2018-01-10 | 국민대학교 산학협력단 | Method for vacuum freeze drying of polyglutamic acid |
| CN108981291A (en) * | 2018-08-16 | 2018-12-11 | 北京同仁堂（四川）健康药业有限公司 | Rhizoma Gastrodiae drying process and Rhizoma Gastrodiae powder preparation technique and its obtained freeze-drying gastrodia elata and Rhizoma Gastrodiae powder |
| CN109200175A (en) * | 2018-10-16 | 2019-01-15 | 南通御福源药业有限公司 | A kind of preparation method of vacuum freeze drying fritillaria thunbergii |
| CN109520213A (en) * | 2018-12-03 | 2019-03-26 | 九州天润（武汉）中药研究院有限公司 | A kind of lyophilized technique of vacuum freeze drying bletilla |
| CN110151705A (en) * | 2018-02-13 | 2019-08-23 | 天士力生物医药股份有限公司 | The freeze drying process of injection recombinant human urokinase zymogen |
| CN110772487A (en) * | 2019-12-09 | 2020-02-11 | 湖南科伦制药有限公司 | Freeze-drying method of ethylenediamine diaceturate |
-
2020
- 2020-05-21 CN CN202010434309.7A patent/CN111578627A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101398254A (en) * | 2007-09-30 | 2009-04-01 | 浙江医药股份有限公司新昌制药厂 | Peptide-containing antibiotic finished product drying method |
| US20120308526A1 (en) * | 2007-11-07 | 2012-12-06 | Aridis Pharmaceuticals | Sonic Low Pressure Spray Drying |
| CN104019635A (en) * | 2014-06-19 | 2014-09-03 | 上海慈瑞医药科技有限公司 | Drying process for lansoprazole bulk drug |
| CN104697298A (en) * | 2015-03-13 | 2015-06-10 | 湖南科伦制药有限公司 | Freeze-drying technology for water-soluble vitamins |
| KR101806344B1 (en) * | 2016-03-28 | 2018-01-10 | 국민대학교 산학협력단 | Method for vacuum freeze drying of polyglutamic acid |
| CN110151705A (en) * | 2018-02-13 | 2019-08-23 | 天士力生物医药股份有限公司 | The freeze drying process of injection recombinant human urokinase zymogen |
| CN108981291A (en) * | 2018-08-16 | 2018-12-11 | 北京同仁堂（四川）健康药业有限公司 | Rhizoma Gastrodiae drying process and Rhizoma Gastrodiae powder preparation technique and its obtained freeze-drying gastrodia elata and Rhizoma Gastrodiae powder |
| CN109200175A (en) * | 2018-10-16 | 2019-01-15 | 南通御福源药业有限公司 | A kind of preparation method of vacuum freeze drying fritillaria thunbergii |
| CN109520213A (en) * | 2018-12-03 | 2019-03-26 | 九州天润（武汉）中药研究院有限公司 | A kind of lyophilized technique of vacuum freeze drying bletilla |
| CN110772487A (en) * | 2019-12-09 | 2020-02-11 | 湖南科伦制药有限公司 | Freeze-drying method of ethylenediamine diaceturate |
Non-Patent Citations (1)
| Title |
|---|
| 管华诗 王曙光: "《中华海洋本草》", 30 September 2009, 上海科学技术出版社、海洋出版社 * |
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