CN117883376A - Pharmaceutical preparation containing recombinant human interleukin-2 and preparation method thereof - Google Patents
Pharmaceutical preparation containing recombinant human interleukin-2 and preparation method thereof Download PDFInfo
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- CN117883376A CN117883376A CN202410289513.2A CN202410289513A CN117883376A CN 117883376 A CN117883376 A CN 117883376A CN 202410289513 A CN202410289513 A CN 202410289513A CN 117883376 A CN117883376 A CN 117883376A
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Abstract
The application relates to the technical field of biological medicines, in particular to a pharmaceutical preparation containing recombinant human interleukin-2 and a preparation method thereof. Specifically, the application provides a pharmaceutical preparation containing recombinant human interleukin-2, which comprises the following components: recombinant human interleukin-2 solution; a container for directly storing the recombinant human interleukin-2 solution; an actuator capable of performing a discharging operation on the recombinant human interleukin-2 solution in the container according to the first discharge amount; after a predetermined time has elapsed, the actuator can perform the discharge operation at the second discharge amount on the same container. By adopting the technical scheme, the recombinant human interleukin-2 solution in the container can be discharged as required for injection and other operations, and the residual recombinant human interleukin-2 solution in the container can be reused, so that the product is ensured to be easy and convenient to operate, and the utilization rate of the product is improved.
Description
Technical Field
The application relates to the technical field of biological medicines, in particular to a pharmaceutical preparation containing recombinant human interleukin-2 and a preparation method thereof.
Background
Interleukin-2 is a lymphokine produced by leukocytes, is a multifunctional cytokine, and has antitumor, antiviral and immunoregulatory effects. Clinically applied to the treatment of advanced renal carcinoma, malignant melanoma and cancerous pleuroperitoneal cavity effusion, and can also be used for the comprehensive treatment of other malignant tumors. The low-dose interleukin-2 is also used for carrying out immunotherapy on the leprosy, mycoplasma infection, herpes and AIDS. Is one of the genetic engineering medicines with obvious clinical curative effect.
Interleukin-2 is susceptible to degradation in the presence of water and oxygen. According to previous reports, interleukin-2 may undergo chemical degradation and physical instability in solution. Although the interleukin-2 injection has appeared in the prior art, the prior injection is difficult to preserve after one use, inconvenient to use and easy to waste.
In view of this, the present application has been proposed.
Disclosure of Invention
The application aims to provide a pharmaceutical preparation containing recombinant human interleukin-2 and a preparation method thereof, which aim to solve at least one technical problem in the background art.
In particular, in a first aspect, the present application provides a pharmaceutical formulation comprising recombinant human interleukin-2, comprising:
a recombinant human interleukin-2 solution,
A container for directly storing the recombinant human interleukin-2 solution,
An actuator capable of performing a discharging operation of the recombinant human interleukin-2 solution in the container at a first discharge amount,
After a predetermined time has elapsed, the actuator can perform the discharge operation at the second discharge amount on the same container.
By adopting the technical scheme, the recombinant human interleukin-2 solution in the container can be discharged as required for injection and other operations, and the residual recombinant human interleukin-2 solution in the container can be reused, so that the product is ensured to be easy and convenient to operate, and the utilization rate of the product is improved.
Preferably, the recombinant human interleukin-2 solution comprises the following components in parts by weight:
0.05-0.3 part of recombinant human interleukin-2,
0.02-0.2 Part of a solvent,
0.1 To 0.4 part of sodium acetate,
0.2 To 0.8 part of acetic acid,
5-10 Parts of sodium chloride
500-2000 Parts of water for injection.
Preferably, the recombinant human interleukin-2 solution comprises the following components in parts by weight:
0.1 part of recombinant human interleukin-2,
0.05 Part of a solvent-promoting agent,
0.15 Part of sodium acetate, and the total weight of the sodium acetate,
0.5 Part of acetic acid, and the mixture is prepared from the following components,
Sodium chloride 8 parts
1000 Parts of water for injection.
Preferably, the cosolvent is selected from at least one of polysorbate 80 and hydroxypropyl-beta-cyclodextrin, wherein the degree of substitution of the hydroxypropyl-beta-cyclodextrin is 0.6-10.0.
Preferably, the container has a receiving cavity made of a first material, the receiving cavity having a first end and a second end in a length direction thereof;
The first end is provided with a cap body which is provided with a membrane structure made of a second material, and the membrane structure can be penetrated by the metal needle and can restore to close the first end after the metal needle is removed;
The second end is movably provided with a piston;
the cap body and the piston seal the inside of the container to form a sealing structure.
Preferably, the actuator comprises:
The accommodating bin is matched with the container, can fix the container in the accommodating cavity and expose at least part of the cap body of the container;
The push rod mechanism is provided with a third end and a fourth end in the length direction, the third end is provided with a pressing part, the fourth end is provided with a pressing plate, the push rod mechanism also comprises a push rod connected with the pressing plate, when the pressing part is pressed, the push rod is driven to drive the pressing plate to move along the length direction at the fourth end,
The pressure plate pushes the piston to move along the inner wall of the accommodating cavity so as to apply pressure to the recombinant human interleukin-2 solution in the container.
Preferably, the actuator has an adjusting mechanism for controlling the stroke of the pressing portion to achieve setting of the first discharge amount and the second discharge amount.
Further, the actuator may further comprise a puncture needle capable of penetrating the membrane structure of the container and guiding the discharge of the recombinant human interleukin-2 solution when the recombinant human interleukin-2 solution is pressurized by the piston.
Preferably, the first material is medium borosilicate glass, and the silicone oil content of the medium borosilicate glass is not higher than 0.2 mg/container. But more preferably has a silicone oil content of 0.1-0.2mg per container. Wherein the mass of the container is 15+/-2 g/branch.
Preferably, the potency of the recombinant human interleukin-2 solution is not higher than 1.5X10 6 IU/ml.
By adopting the technical scheme, when the concentration of the recombinant human interleukin-2 solution is controlled within a certain range and the container is made of a material with a specific material, the recombinant human interleukin-2 has better stability in the container and can keep better stability after multiple uses.
Preferably, the pH of the recombinant human interleukin-2 solution is 3.6-4.5.
Preferably, the second material is nitrile rubber or chlorinated butyl rubber.
Preferably, the recombinant human interleukin-2 solution further comprises the components:
Mannitol 0.01-0.04 weight portions,
Methionine 0.01-0.02 parts.
Preferably, the recombinant human interleukin-2 solution does not contain other monosaccharides, and/or amino acids. More preferably, the recombinant human interleukin-2 solution does not contain glucose, fructose or arginine.
Preferably, the surface tension of the recombinant human interleukin-2 solution is 60-70mN/m.
Preferably, in the pharmaceutical preparation, further comprising:
nitrogen and the pressure in the container is 0.2-1.0Mpa.
In a second aspect of the present application, there is provided a method for preparing a recombinant human interleukin-2 solution according to the first aspect of the present application, comprising the steps of:
Preparing a buffer solution, weighing sodium acetate according to the components in the first aspect, adding acetic acid and sodium chloride, and then supplementing water for injection to prepare the acetic acid buffer solution;
Adding a cosolvent, adding the cosolvent with corresponding proportion, and filtering after the cosolvent is completely dissolved to remove impurities in the solution;
adding recombinant human interleukin-2, proportionally adding the solution obtained in the previous step into recombinant human interleukin-2 freeze-dried stock solution, and filtering after the protein is completely dissolved to obtain the recombinant human interleukin-2 solution.
Preferably, in the step of adding a pro-solvent, filtration is performed using a 0.22 μm filter.
Preferably, in the step of adding recombinant human interleukin-2, a 0.22 μm filter membrane is used for filtration.
Preferably, said adding recombinant human interleukin-2 is separated from said adding a pro-solvent step by a time not exceeding a second predetermined value, which is not exceeding 30min.
Preferably, when the recombinant human interleukin-2 solution comprises mannitol and methionine, in the step of adding the recombinant human interleukin-2, mannitol and methionine are added first, and after the mannitol and the methionine are fully dissolved, the recombinant human interleukin-2 freeze-dried stock solution is added.
In summary, the application has the following beneficial effects:
1. the pharmaceutical preparation containing the recombinant human interleukin-2 provided by the application can discharge the recombinant human interleukin-2 solution in the container as required for injection and other operations, and the residual recombinant human interleukin-2 solution in the container can be reused, so that the product is ensured to be easy and convenient to operate, and the utilization rate of the product is improved.
2. The pharmaceutical preparation containing the recombinant human interleukin-2 provided by the application can improve the stability of the recombinant human interleukin-2 in a container and can keep better stability after multiple uses by controlling the concentration of the recombinant human interleukin-2 solution in a certain range and selecting the material with a specific material as the container.
3. The preparation method of the recombinant human interleukin-2 solution provided by the application can improve the stability of the recombinant human interleukin-2 in the solution, and is more beneficial to the repeated use of pharmaceutical preparations.
Drawings
FIG. 1 is a graph showing the activity change trend of the test cases A to D according to the present application under the stability test;
FIG. 2 is a graph showing the trend of the activity of the test cases A to D according to the present application under the acceleration test;
FIG. 3 is a graph showing the activity change trend of the patterns D-G in the stability test in the experimental example of the present application;
FIG. 4 is a graph showing the trend of the activity of the patterns D-G in the test example of the present application under the acceleration test;
FIG. 5 is a graph showing the activity change trend of the scheme AFHIJ in the stability test in the experimental example of the present application;
FIG. 6 is a graph showing the trend of the activity of the scheme AFHIJ in the accelerated test in the experimental example of the present application;
FIG. 7 is a first angular schematic view of a container in one embodiment of the application;
FIG. 8 is a second angular schematic view of a container in one embodiment of the application;
FIG. 9 is a schematic illustration of the container mated with an actuator in an embodiment of the present application;
FIG. 10 is a schematic view of an actuator push rod mechanism in a first position according to one embodiment of the present application;
FIG. 11 is a schematic illustration of an actuator push rod mechanism in a second position in accordance with an embodiment of the present application;
FIG. 12 is a schematic view of a lancet according to one embodiment of the present application;
FIG. 13 is a schematic view showing the mating relationship of the lancet and cap in another embodiment of the present application;
fig. 14 is a schematic view of a puncture needle according to yet another embodiment of the present application.
Reference numerals:
1. a container; 11. a cap body; 111. a membrane structure; 112. a second annular rib; 113. a second mark; 12. a piston; 13. a container body; 21. a receiving bin; 22. a push rod mechanism; 221. a pressing part; 23. a rod body; 24. a closing cap; 3. a puncture needle; 31. a second needle; 32. a first needle; 33. a mating cavity; 331. a first annular rib; 332. a first mark.
Detailed Description
Reference will now be made in detail to exemplary embodiments, examples of which are illustrated in the accompanying drawings. When the following description refers to the accompanying drawings, the same numbers in different drawings refer to the same or similar elements, unless otherwise indicated. The implementations described in the following exemplary examples do not represent all implementations consistent with the application. Rather, they are merely examples of apparatus and methods consistent with aspects of the application as detailed in the accompanying claims.
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in this specification and the appended claims, the singular forms "a," "an," and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It should also be understood that the term "and/or" as used herein refers to and encompasses any or all possible combinations of one or more of the associated listed items.
The present application will be described in detail by examples.
In the prior art, interleukin-2 injection is commonly used for anti-tumor, antiviral or immunomodulatory treatment, but the existing injection is difficult to preserve after one use, inconvenient to use and easy to waste.
In view of the above, the present application is directed to a pharmaceutical preparation containing recombinant human interleukin-2 and a method for preparing the same, wherein the pharmaceutical preparation containing recombinant human interleukin-2 comprises: recombinant human interleukin-2 solution; a container for directly storing the recombinant human interleukin-2 solution; an actuator capable of setting a first discharge amount to perform a discharge operation of the recombinant human interleukin-2 solution in the container at the first discharge amount; after a predetermined time has elapsed, the actuator can perform the discharge operation at the second discharge amount on the same container. By adopting the technical scheme of the application, the recombinant human interleukin-2 solution in the container can be discharged as required for injection and other operations, and the residual recombinant human interleukin-2 solution in the container can be reused, so that the product is ensured to be easy and convenient to operate, and the utilization rate of the product is improved.
In order to better understand the above technical solutions, the following will describe the above technical solutions in detail with reference to specific embodiments, and those skilled in the art should also understand that the reaction time, the drug feeding, involved in the present application cannot be absolutely accurate in the actual production process, but are all within the allowable error range. If it is desired to heat the sample for 30 minutes, it is actually possible to operate for 30 minutes over 1 second or less than 1 second; it is desirable to weigh 30g of the sample, and it is actually possible to weigh 30.001g or 29.998g.
Experimental example 1 stability test
The container containing the recombinant human interleukin-2 solution is preserved for a long time in the dark under the conditions of 25+/-2 ℃ and relative humidity of 60+/-5% RH. The needle for injection is used for penetrating through the rubber plug at 7 days intervals but not contacting the recombinant human interleukin-2 solution, and the solution is kept for 1min, and meanwhile, the illumination with Lx of 1000+/-100 Lx is irradiated, so that the multi-application scene of the product is simulated. Interleukin-2 activity was measured at month 0, month 3, month 6, month 9, and month 12.
Wherein, the container adopts a product with the maximum capacity of 3ml and the weight of 15+/-2 g.
Experimental example 2 accelerated test
The container containing the recombinant human interleukin-2 solution is preserved for a long time in the dark under the conditions of 37+/-2 ℃ and relative humidity of 60+/-5% RH. The needle for injection is used for penetrating through the rubber plug at 7 days intervals but not contacting the recombinant human interleukin-2 solution, and the solution is kept for 1min, and meanwhile, the illumination with Lx of 1000+/-100 Lx is irradiated, so that the multi-application scene of the product is simulated. Interleukin-2 activity was measured at month 0, month 1, month 3, and month 6.
Wherein, the container adopts a product with the maximum capacity of 3ml and the weight of 15+/-2 g.
Experimental example 3 illumination experiment
The container containing the recombinant human interleukin-2 solution is preserved for a long time in the dark under the illumination condition of 4+/-2 ℃ and relative humidity of 60+/-5% RH and 1000+/-100 Lx.
Experimental example 4
The experimental example tests interleukin-2 activity of each experimental scheme under the stability test and the acceleration test.
Scheme A
Preparing a buffer solution, namely weighing 0.15 part of sodium acetate, adding 0.5 part of acetic acid and 8 parts of sodium chloride, and then supplementing 1000 parts of water for injection to prepare an acetic acid buffer solution;
adding a cosolvent, adding 0.05 part of polysorbate 80, and filtering after the polysorbate 80 is completely dissolved to remove impurities in the solution;
adding recombinant human interleukin-2, adding 0.1 part of recombinant human interleukin-2 freeze-dried stock solution into the solution obtained in the previous step, and filtering after the protein is completely dissolved to obtain the recombinant human interleukin-2 solution.
The recombinant human interleukin-2 solution obtained above was poured into 0.8ml into a container made of medium borosilicate glass with a silicone oil content of 0.6 mg/container.
Scheme B
Preparing a buffer solution, namely weighing 0.15 part of sodium acetate, adding 0.5 part of acetic acid and 8 parts of sodium chloride, and then supplementing 1000 parts of water for injection to prepare an acetic acid buffer solution;
adding a cosolvent, adding 0.05 part of polysorbate 80, and filtering after the polysorbate 80 is completely dissolved to remove impurities in the solution;
adding recombinant human interleukin-2, adding 0.02 part of mannitol into the solution obtained in the previous step, adding 0.1 part of recombinant human interleukin-2 freeze-dried stock solution after the solution is fully dissolved, and filtering after the protein is fully dissolved to obtain the recombinant human interleukin-2 solution.
The recombinant human interleukin-2 solution obtained above was poured into 0.8ml into a container made of medium borosilicate glass with a silicone oil content of 0.6 mg/container.
Scheme C
Preparing a buffer solution, namely weighing 0.15 part of sodium acetate, adding 0.5 part of acetic acid and 8 parts of sodium chloride, and then supplementing 1000 parts of water for injection to prepare an acetic acid buffer solution;
adding a cosolvent, adding 0.05 part of polysorbate 80, and filtering after the polysorbate 80 is completely dissolved to remove impurities in the solution;
Adding recombinant human interleukin-2, adding 0.01 part of methionine into the solution obtained in the last step, adding 0.1 part of recombinant human interleukin-2 freeze-dried stock solution after the methionine is fully dissolved, and filtering after the protein is fully dissolved to obtain the recombinant human interleukin-2 solution.
The recombinant human interleukin-2 solution obtained above was poured into 0.8ml into a container made of medium borosilicate glass with a silicone oil content of 0.6 mg/container.
Scheme D
Preparing a buffer solution, namely weighing 0.15 part of sodium acetate, adding 0.5 part of acetic acid and 8 parts of sodium chloride, and then supplementing 1000 parts of water for injection to prepare an acetic acid buffer solution;
adding a cosolvent, adding 0.05 part of polysorbate 80, and filtering after the polysorbate 80 is completely dissolved to remove impurities in the solution;
Adding recombinant human interleukin-2, sequentially adding 0.02 part of mannitol and 0.01 part of methionine into the solution obtained in the previous step, adding 0.1 part of recombinant human interleukin-2 freeze-dried stock solution after the mannitol and the methionine are fully dissolved, and filtering after the protein is fully dissolved to obtain the recombinant human interleukin-2 solution.
The recombinant human interleukin-2 solution obtained above was poured into 0.8ml into a container made of medium borosilicate glass with a silicone oil content of 0.6 mg/container.
The interleukin-2 activity after the stability test and the acceleration test was tested according to the methods of Experimental example 1 and Experimental example 2, respectively, and the test data are shown in FIG. 1 and FIG. 2.
From the experimental results of fig. 1 and 2, it can be understood that:
firstly, the activity of the schemes A-D is fast to be reduced under a stability test and an acceleration test, which shows that the schemes A-D are easy to have adverse effect on the stability of products under a repeated multiplexing test environment;
Secondly, the activity of the solution D is reduced more slowly than that of the solutions A-C under the stability test or the acceleration test, so that the stability is better; this shows that adding a proper amount of mannitol and methionine component into the recombinant human interleukin-2 solution can improve the stability of the product in a multiple multiplexing scene to a certain extent.
Experimental example 5
The experimental example tests interleukin-2 activity of each experimental scheme under the stability test and the acceleration test.
Scheme E
Scheme E is substantially identical to scheme D, except that:
the recombinant human interleukin-2 solution obtained was poured into 0.8ml into a container made of medium borosilicate glass with a silicone oil content of 0.3mg per container.
Scheme F
Scheme F is substantially the same as scheme D, differing only in:
The recombinant human interleukin-2 solution obtained was poured into 0.8ml into a container made of medium borosilicate glass with a silicone oil content of 0.1mg per container.
Scheme G
Scheme G is substantially the same as scheme D, differing only in:
the recombinant human interleukin-2 solution obtained was poured into 0.8ml into a container made of medium borosilicate glass with a silicone oil content of 0.05mg per container.
Scheme H
Scheme H is substantially the same as scheme a, except that:
The recombinant human interleukin-2 solution obtained was poured into 0.8ml into a container made of medium borosilicate glass with a silicone oil content of 0.1mg per container.
Scheme I
Scheme I is substantially the same as scheme a, except that:
In the step of adding recombinant human interleukin-2, 0.2 parts of recombinant human interleukin-2 freeze-dried stock solution is added.
Scheme J
Scheme J is substantially identical to scheme a, except that:
Adding 0.2 parts of recombinant human interleukin-2 freeze-dried stock solution into the step of adding the recombinant human interleukin-2;
the recombinant human interleukin-2 solution obtained was poured into a 0.8ml container made of medium borosilicate glass with a silicone oil content of 0.1mg per container.
Scheme D-scheme G is tested for interleukin-2 activity after stability test and acceleration test according to the methods of experimental example 1 and experimental example 2, and test data are shown in FIG. 3 and FIG. 4;
scheme A, scheme F, scheme H-scheme I were tested for interleukin-2 activity after stability and acceleration tests, respectively, in the manner of Experimental example 1, experimental example 2, and the test data are shown in FIGS. 5 and 6.
From the experimental results of fig. 3 to 6, it can be understood that:
Firstly, referring to fig. 3-4, the solutions D-G are mainly characterized by different silicone oil contents of the container glass, and it can be found that the stability of interleukin-2 is improved when the silicone oil content is low (e.g. the solution F and the solution G in the stability experiment); however, when the silicone oil content is less than 0.1mg, the stability is not significantly improved, and the slidability of the product in use may be reduced due to the excessively low silicone oil content, so that the tightness between the container and the rubber stopper is reduced.
Secondly, referring to fig. 5-6, the stability test and acceleration test results of the scheme a and the scheme H show that the reduction of the silicone oil content has less influence on the stability of interleukin-2 under the formulation of the scheme a; the result shows that the stability improvement effect on interleukin-2 is better when the silicone oil content is reduced under the formula of the scheme D.
Thirdly, referring to fig. 5-6, the stability test and acceleration test results of the scheme I and the scheme J show that when the interleukin-2 content is high, even if mannitol and methionine are not contained in the components, the decrease of the silicone oil content can positively affect the stability of the interleukin-2, but the activity of the interleukin-2 is reduced to a higher degree, so that the waste of the product is caused, and the use efficiency is low.
Therefore, by combining the experimental results, the potency of the recombinant human interleukin-2 solution in the product is controlled to be not higher than 1.5X10 6 IU/ml, and the silicone oil content is controlled to be 0.1-0.2 mg/branch container, at this time, the recombinant human interleukin-2 preparation with better stability can be obtained.
Example 1
The present embodiments provide a container and actuator that may be used with the present application.
In particular, referring to fig. 7-8, the container 1 comprises a container body 13, having a first end provided with a cap 11, and a second end provided with a piston 12, the container body 13 being located between the cap 11 and the piston 12, the piston 12 being slidable at the second end along the length of the container 1 and closing the second end. Wherein the cap 11 is internally provided with a membrane structure 111, which may be made of nitrile rubber or chlorinated butyl rubber, which is able to be pierced and to restore the closure of the first end after removal of the piercing device, and closes the first end. Thus, the cap 11 and the piston 12 close the inside of the container 1 to form a sealing structure for storing the recombinant human interleukin-2 solution.
Further, referring to fig. 9-11, the actuator includes a housing 21, a rod body 23, a push rod mechanism 22, a closure cap 24, and has an output end, a mating end, in its length. The housing compartment 21 may be used to house the container 1 and to expose a portion of the cap 11 outside the output end after placement of the container 1 for mating with a piercing needle. The accommodating chamber 21 is connected with a rod body 23 at the matching end thereof, and the rod body 23 is provided with a cavity for accommodating the push rod mechanism 22. The push rod mechanism 22 is provided with a third end and a fourth end on the length thereof, is movably arranged at one end of the rod body 23, and penetrates through the cavity of the rod body 23 to push the piston 12; further, a pressing part 221 is provided at the third end, a pressing plate is provided at the fourth end, the push rod mechanism further comprises a push rod connected with the pressing plate, when the pressing part 221 is pressed, the push rod is driven to drive the pressing plate to move along the length direction at the fourth end, and the pressing plate pushes the piston 12 to move along the inner wall of the cavity of the container 1 so as to apply pressure to the recombinant human interleukin-2 solution in the container 1. The sealing cap 24 is used for sleeving the outside of the accommodating bin 21 so as to play roles of protection, light shielding and the like.
With continued reference to fig. 10-12, the actuator further includes a puncture needle 3, the puncture needle 3 having a mating cavity 33, the mating cavity 33 being mated with the cap 11, in some embodiments, the mating cavity 33 having threads inside and mating with threads outside the cap 11; a first needle 32 is arranged in the matching cavity 33 in an extending manner, and the first needle 32 can puncture the membrane structure 111 of the cap body when the matching cavity 33 is matched with the cap body 11; the end of the puncture needle 3 facing away from the first needle 32 is provided with a second needle 31, and the second needle 31 is used for puncturing the human body and injecting the recombinant human interleukin-2 solution.
In some embodiments, as shown in fig. 10-11, since the recombinant human interleukin-2 solution in the container 1 of the present application may be used multiple times, the membrane structure 111 inside the cap 1 may be deformed and blocked at the same position when being punctured multiple times, so that the container cannot be sealed very tightly.
Based on this, the present application proposes a puncture needle 3 as shown in fig. 13, wherein the first needle head 32 forms an included angle with the horizontal position, and the included angle is usually 5-10 °, so that when the puncture needle 3 is repeatedly used for puncturing the membrane structure 111, the puncture needle 3 can be rotated to different angles, so that the puncture of the same position of the membrane structure 111 can be prevented from being performed for multiple times, and the tightness of the product can be ensured. In this embodiment, the puncture needle and the cap 11 are engaged with each other, the puncture needle is provided with a first annular rib 331 therein, and the outer wall of the cap 11 is also provided with a second annular rib 112 engaged with the first annular rib 331, so as to achieve the engagement. In order to further avoid puncturing the same position of the membrane structure 111 for multiple times, the first mark 332 and the second mark 113 are respectively arranged on the outer walls of the puncture needle and the cap body, and the user records the mark aligned each time, so that puncturing of the same position of the membrane structure 111 can be further avoided. In this embodiment, the first needle 32 may be other alternative forms, such as a bent structure as shown in fig. 14.
In the present application, when the actuator is operated, the discharging operation can be performed on the recombinant human interleukin-2 solution in the container 1 at the first discharge amount; after the operation, the container 1 with the recombinant human interleukin-2 solution can be stored; after a certain period of time, if it is still necessary to perform the discharge operation such as injection, the container 1 may be reinstalled and the discharge operation of the second discharge amount may be performed on the same container 1 by the actuator.
Example 2
Preparing a buffer solution, namely weighing 0.1 part of sodium acetate, adding 0.2 part of acetic acid and 5 parts of sodium chloride, and supplementing 500 parts of water for injection to prepare an acetic acid buffer solution;
adding a cosolvent, adding 0.02 part of polysorbate 80, and filtering after the polysorbate 80 is completely dissolved to remove impurities in the solution;
Adding recombinant human interleukin-2, adding 0.05 part of recombinant human interleukin-2 freeze-dried stock solution into the solution obtained in the previous step, and filtering after the protein is completely dissolved to obtain the recombinant human interleukin-2 solution.
Injecting the recombinant human interleukin-2 solution obtained above into a container as shown in example 1, wherein the maximum capacity of the container is 3ml, and injecting 0.8ml into the container; the container is made of medium borosilicate glass, and the silicone oil content of the container is 0.6 mg/container. The cap body membrane structure of the container is made of chlorinated butyl rubber.
Example 3
Preparing a buffer solution, namely weighing 0.15 part of sodium acetate, adding 0.5 part of acetic acid and 8 parts of sodium chloride, and then supplementing 1000 parts of water for injection to prepare an acetic acid buffer solution;
adding a cosolvent, adding 0.05 part of polysorbate 80, and filtering after the polysorbate 80 is completely dissolved to remove impurities in the solution;
adding recombinant human interleukin-2, adding 0.1 part of recombinant human interleukin-2 freeze-dried stock solution into the solution obtained in the previous step, and filtering after the protein is completely dissolved to obtain the recombinant human interleukin-2 solution.
Injecting the recombinant human interleukin-2 solution obtained above into a container as shown in example 1, wherein the maximum capacity of the container is 3ml, and injecting 0.8ml into the container; the container is made of medium borosilicate glass, and the silicone oil content of the container is 0.6 mg/container. The cap body membrane structure of the container is made of chlorinated butyl rubber.
Example 4
Preparing a buffer solution, namely weighing 0.4 part of sodium acetate, adding 0.8 part of acetic acid and 10 parts of sodium chloride, and supplementing 2000 parts of water for injection to prepare an acetic acid buffer solution;
Adding a cosolvent, adding 0.2 part of polysorbate 80, and filtering after the polysorbate 80 is completely dissolved to remove impurities in the solution;
Adding recombinant human interleukin-2, adding 0.3 part of recombinant human interleukin-2 freeze-dried stock solution into the solution obtained in the last step, and filtering after the protein is completely dissolved to obtain the recombinant human interleukin-2 solution.
Injecting the recombinant human interleukin-2 solution obtained above into a container as shown in example 1, wherein the maximum capacity of the container is 3ml, and injecting 0.8ml into the container; the container is made of medium borosilicate glass, and the silicone oil content of the container is 0.6 mg/container. The cap body membrane structure of the container is made of chlorinated butyl rubber.
Example 5
Preparing a buffer solution, namely weighing 0.1 part of sodium acetate, adding 0.2 part of acetic acid and 5 parts of sodium chloride, and supplementing 500 parts of water for injection to prepare an acetic acid buffer solution;
adding a cosolvent, adding 0.02 part of polysorbate 80, and filtering after the polysorbate 80 is completely dissolved to remove impurities in the solution;
Adding recombinant human interleukin-2, sequentially adding 0.01 part of mannitol and 0.01 part of methionine into the solution obtained in the previous step, adding 0.05 part of recombinant human interleukin-2 freeze-dried stock solution after the mannitol and the methionine are fully dissolved, and filtering after the protein is fully dissolved to obtain the recombinant human interleukin-2 solution.
Injecting the recombinant human interleukin-2 solution obtained above into a container as shown in example 1, wherein the maximum capacity of the container is 3ml, and injecting 0.8ml into the container; the container is made of medium borosilicate glass, and the silicone oil content of the container is 0.6 mg/container. The cap body membrane structure of the container is made of chlorinated butyl rubber.
Example 6
Preparing a buffer solution, namely weighing 0.15 part of sodium acetate, adding 0.5 part of acetic acid and 8 parts of sodium chloride, and then supplementing 1000 parts of water for injection to prepare an acetic acid buffer solution;
adding a cosolvent, adding 0.05 part of polysorbate 80, and filtering after the polysorbate 80 is completely dissolved to remove impurities in the solution;
Adding recombinant human interleukin-2, sequentially adding 0.02 part of mannitol and 0.01 part of methionine into the solution obtained in the previous step, adding 0.1 part of recombinant human interleukin-2 freeze-dried stock solution after the mannitol and the methionine are fully dissolved, and filtering after the protein is fully dissolved to obtain the recombinant human interleukin-2 solution.
Injecting the recombinant human interleukin-2 solution obtained above into a container as shown in example 1, wherein the maximum capacity of the container is 3ml, and injecting 0.8ml into the container; the container is made of medium borosilicate glass, and the silicone oil content of the container is 0.6 mg/container. The cap body membrane structure of the container is made of chlorinated butyl rubber.
Example 7
Preparing a buffer solution, namely weighing 0.4 part of sodium acetate, adding 0.8 part of acetic acid and 10 parts of sodium chloride, and supplementing 2000 parts of water for injection to prepare an acetic acid buffer solution;
Adding a cosolvent, adding 0.2 part of polysorbate 80, and filtering after the polysorbate 80 is completely dissolved to remove impurities in the solution;
adding recombinant human interleukin-2, sequentially adding 0.04 part of mannitol and 0.02 part of methionine into the solution obtained in the previous step, adding 0.3 part of recombinant human interleukin-2 freeze-dried stock solution after the solution is fully dissolved, and filtering after the protein is fully dissolved to obtain the recombinant human interleukin-2 solution.
Injecting the recombinant human interleukin-2 solution obtained above into a container as shown in example 1, wherein the maximum capacity of the container is 3ml, and injecting 0.8ml into the container; the container is made of medium borosilicate glass, and the silicone oil content of the container is 0.6 mg/container. The cap body membrane structure of the container is made of chlorinated butyl rubber.
Example 8
The solution of example 8 is basically identical to that of example 6, except that:
The container is made of medium borosilicate glass, and the silicone oil content of the container is 0.2 mg/container.
Example 9
The solution of example 10 is basically identical to that of example 6, except that:
the container is made of medium borosilicate glass, and the silicone oil content of the container is 0.1 mg/container.
Example 10
The solution of example 10 is basically identical to that of example 9, except that:
nitrogen was added to the vessel, and the pressure in the vessel was set at 0.2MPa.
Example 11
The solution of example 11 is basically identical to that of example 9, except that:
Nitrogen was added to the vessel, and the pressure in the vessel was set at 1.0MPa.
Comparative example 1
The solution of comparative example 1 is basically identical to that of example 2, except that:
In the step of adding recombinant human interleukin-2, 0.5 part of recombinant human interleukin-2 freeze-dried stock solution is added.
Comparative example 2
The solution of comparative example 2 is basically identical to that of example 9, except that:
In the step of adding the recombinant human interleukin-2, 0.02 part of mannitol, 0.01 part of methionine and 0.02 part of arginine are sequentially added into the solution obtained in the previous step, after the solution is fully dissolved, 0.1 part of recombinant human interleukin-2 freeze-dried stock solution is added, and after the protein is fully dissolved, the solution is filtered to obtain the recombinant human interleukin-2 solution.
Comparative example 3
The solution of comparative example 3 is basically identical to that of example 9, except that:
In the step of adding the recombinant human interleukin-2, 0.02 part of mannitol, 0.01 part of methionine and 0.02 part of glucose are sequentially added into the solution obtained in the previous step, after the solution is fully dissolved, 0.1 part of recombinant human interleukin-2 freeze-dried stock solution is added, and after the protein is fully dissolved, the solution is filtered to obtain the recombinant human interleukin-2 solution.
Comparative example 4
The solution of comparative example 4 is substantially identical to that of example 9, except that:
In the step of adding the recombinant human interleukin-2, 0.02 part of mannitol, 0.01 part of methionine and 0.02 part of fructose are sequentially added into the solution obtained in the previous step, after the solution is fully dissolved, 0.1 part of recombinant human interleukin-2 freeze-dried stock solution is added, and after the protein is fully dissolved, the solution is filtered to obtain the recombinant human interleukin-2 solution.
Comparative example 5
Injecting a commercially available recombinant human interleukin-2 solution into a container as shown in example 1, wherein the maximum capacity of the container is 3ml, and injecting 0.8ml into the container; the container is made of medium borosilicate glass, and the silicone oil content of the container is 0.6 mg/container. The cap body membrane structure of the container is made of chlorinated butyl rubber.
Example 12
The properties and pH at day 0 in examples 2 to 11 and comparative examples 1 to 5 were measured, and the experimental results are shown in Table 1.
The interleukin-2 biological activity of examples 2-12 and comparative examples 1-5 after standing for 12 months was measured as in experimental example 1; the interleukin-2 biological activity of examples 2-12, comparative examples 1-5 after 12 months of standing was measured as in experimental example 3; the experimental results are shown in Table 2.
TABLE 1 test results 1 for examples 2-11, comparative examples 1-5
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According to the results shown in Table 1, in the examples provided by the present application, the properties and pH of the product meet the quality standards of the product, and the product has stable quality.
TABLE 2 test results two for examples 2-11, comparative examples 1-5
From the experimental results in table 2, it can be seen that for the stability test:
First, comparative example 2 and comparative example 1, when the content of recombinant human interleukin-2 in the components is too high, the activity loss is high in the use scene of the product of the present application, so that the content of recombinant human interleukin-2 should be controlled in a proper range; the product activity loss rates for the high recombinant human interleukin-2 concentrations of comparative example 4 and examples 2-3, example 7 and examples 5-6, although slightly higher, have been controlled at lower levels than comparative example 1;
second, the comparative examples 5-7 and examples 2-4, examples 5-7 showed significantly lower activity loss than examples 2-4, indicating that the addition of mannitol, methionine component, can reduce the activity loss of the product at the appropriate recombinant human interleukin-2 content;
third, comparative examples 8-11 and examples 5-7, examples 8-11 have lower activity loss rates than examples 5-7, indicating that reducing the silicone oil content of the vessel can reduce the activity loss rate of the product;
Fourth, comparative example 9 and comparative examples 2 to 4 show a significant increase in the activity loss rate of comparative examples 2 to 4, indicating that the stability of the product may be affected by the additional addition of other components to the components. Comparative examples 2 to 4 are amino acids and monosaccharides, respectively, and thus the addition of amino acids and monosaccharides to the components may affect the stability of the product.
Furthermore, according to the experimental results of table 2, for the illumination test:
firstly, the embodiment provided by the application is relatively stable under illumination test;
Second, in comparative examples 7 and 4, in the case of containing mannitol and methionine in the components, the high concentration product is more sensitive to light, and it is considered to store in a dark environment.
In summary, the pharmaceutical preparation containing recombinant human interleukin-2 provided by the application can discharge the recombinant human interleukin-2 solution in the container as required for injection and other operations, and the residual recombinant human interleukin-2 solution in the container can be reused, so that the product operation is ensured to be simple and convenient, the utilization rate of the product is improved, and the pharmaceutical preparation containing recombinant human interleukin-2 has good commercial prospect.
It is obvious to those skilled in the art that the technical features of the above embodiments may be freely combined, and the resulting technical solutions also belong to the disclosed embodiments of the present application.
Further, the present application may be subject to several improvements and modifications without departing from the principle of the present application, and these improvements and modifications are also within the scope of protection of the claims of the present application.
Claims (10)
1. A pharmaceutical formulation comprising recombinant human interleukin-2, comprising:
a recombinant human interleukin-2 solution,
A container for directly storing the recombinant human interleukin-2 solution,
An actuator capable of performing a discharging operation of the recombinant human interleukin-2 solution in the container at a first discharge amount,
After a predetermined time has elapsed, the actuator can perform the discharge operation at the second discharge amount on the same container.
2. The pharmaceutical formulation according to claim 1, wherein:
the recombinant human interleukin-2 solution comprises the following components in parts by weight:
0.05-0.3 part of recombinant human interleukin-2,
0.02-0.2 Part of a solvent,
0.1 To 0.4 part of sodium acetate,
0.2 To 0.8 part of acetic acid,
5-10 Parts of sodium chloride
500-2000 Parts of water for injection.
3. The pharmaceutical formulation according to claim 2, wherein:
the recombinant human interleukin-2 solution comprises the following components in parts by weight:
0.1 part of recombinant human interleukin-2,
0.05 Part of a solvent-promoting agent,
0.15 Part of sodium acetate, and the total weight of the sodium acetate,
0.5 Part of acetic acid, and the mixture is prepared from the following components,
Sodium chloride 8 parts
1000 Parts of water for injection.
4. The pharmaceutical formulation according to claim 2, wherein:
the recombinant human interleukin-2 solution also comprises the following components:
Mannitol 0.01-0.04 weight portions,
Methionine 0.01-0.02 parts.
5. A pharmaceutical formulation according to any one of claims 1 to 4, wherein:
The container is provided with a containing cavity made of a first material, and the containing cavity is provided with a first end and a second end in the length direction;
The first end is provided with a cap body which is provided with a membrane structure made of a second material, and the membrane structure can be penetrated by the metal needle and can restore to close the first end after the metal needle is removed;
The second end is movably provided with a piston;
the cap body and the piston seal the inside of the container to form a sealing structure.
6. The pharmaceutical formulation of claim 5, wherein:
the first material is medium borosilicate glass, and the silicon oil content is not higher than 0.2 mg/container.
7. The pharmaceutical formulation of claim 5, wherein:
The actuator includes:
The accommodating bin is matched with the container, can fix the container in the accommodating cavity and expose at least part of the cap body of the container;
The push rod mechanism is provided with a third end and a fourth end in the length direction, the third end is provided with a pressing part, the fourth end is provided with a pressing plate, the push rod mechanism also comprises a push rod connected with the pressing plate, when the pressing part is pressed, the push rod is driven to drive the pressing plate to move along the length direction at the fourth end,
The pressing plate pushes the piston to move along the inner wall of the accommodating cavity so as to apply pressure to the recombinant human interleukin-2 solution in the container;
The actuator further includes a piercing needle capable of penetrating the membrane structure of the container and directing the expulsion of the recombinant human interleukin-2 solution when the recombinant human interleukin-2 solution is subjected to the pressure of the plunger.
8. A pharmaceutical formulation according to any one of claims 1 to 4, wherein:
The pH value of the recombinant human interleukin-2 solution is 3.6-4.5.
9. A method of preparing a solution of recombinant human interleukin-2 according to any one of claims 1 to 8, comprising the steps of:
Preparing a buffer solution, weighing sodium acetate according to the components of any one of claims 1-8, adding acetic acid and sodium chloride, and then supplementing water for injection to prepare the acetic acid buffer solution;
Adding a cosolvent, adding the cosolvent with corresponding proportion, and filtering after the cosolvent is completely dissolved to remove impurities in the solution;
adding recombinant human interleukin-2, proportionally adding the solution obtained in the previous step into recombinant human interleukin-2 freeze-dried stock solution, and filtering after the protein is completely dissolved to obtain the recombinant human interleukin-2 solution.
10. The method of manufacturing according to claim 9, wherein:
the step of adding recombinant human interleukin-2 is separated from the step of adding the pro-solvent by a time not exceeding a second predetermined value, the second predetermined value not exceeding 30 minutes.
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