Application of poloxamer as irradiation protective agent in sodium carboxymethyl cellulose hydrogel sterilization

Abstract

The invention belongs to the technical field of material sterilization, and particularly relates to application of poloxamer as an irradiation protective agent in sodium carboxymethyl cellulose hydrogel sterilization. Research finds that by adding poloxamer into sodium carboxymethyl cellulose, the poloxamer can be used as an irradiation protective agent to effectively protect sodium carboxymethyl cellulose hydrogel from being damaged by high-energy rays, so that the inherent structure and performance of the sodium carboxymethyl cellulose hydrogel are maintained, introduction of new impurities is avoided, the purity and safety of the sodium carboxymethyl cellulose hydrogel are maintained, the implementation process of protection measures is reduced, and the cost is reduced. Therefore, the method is more suitable for large-scale production, and has good practical application value.

Description

Technical Field

[0001] The invention belongs to the technical field of material sterilization, and particularly relates to application of poloxamer as a radiation protectant in the sterilization of sodium carboxymethylcellulose hydrogel. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Sodium carboxymethylcellulose hydrogel (CMC) is a basic material widely used in various fields, especially in bioengineering, wound dressings, etc. However, it needs to be sterilized before use to ensure its sterility. Conventional sterilization methods include physical sterilization, chemical sterilization, and irradiation sterilization.

[0004] Physical sterilization is divided into moist heat sterilization and dry heat sterilization. Both require high-temperature treatment of sodium carboxymethyl cellulose hydrogel, which affects its structure and sample state and other properties, and the operation is complicated. Chemical sterilization usually selects reagents or gases with sterilization effects to sterilize sodium carboxymethyl cellulose hydrogel. Common reagents include ethylene oxide, lactic acid, etc. These reagents themselves are biologically toxic, and it is difficult to control their residual amount in the hydrogel when using them for sterilization. Based on the limitations of physical sterilization and chemical sterilization, people began to try to use irradiation sterilization.

[0005] The advantage of irradiation sterilization is that there is no reagent added, it is non-toxic and pollution-free, easy to operate, and has an ideal sterilization effect. However, the currently published process for producing sodium carboxymethylcellulose hydrogel does not involve the specific process of irradiation sterilization. After verification by the inventor's irradiation sterilization test, without adding protective measures, the sodium carboxymethylcellulose hydrogel will be greatly damaged, resulting in a significant decrease in product viscosity and pH value, which ultimately affects its performance. And the measures to protect the sodium carboxymethylcellulose hydrogel from being destroyed found in the prior art, or the protection is not obvious, or these protective measures may introduce new impurities, affecting its safety, or the implementation process of the protective measures is complicated and not suitable for large-scale production. Summary of the invention

[0006] In view of the problems existing in the above-mentioned prior art, after long-term technical and practical exploration, the present invention provides the use of poloxamer as a radiation protectant in the sterilization of sodium carboxymethylcellulose hydrogel. Specifically, the present invention has found through research that by adding poloxamer to sodium carboxymethylcellulose, it can be used as a radiation protectant to effectively protect the sodium carboxymethylcellulose hydrogel from being destroyed by high-energy rays, thereby maintaining its inherent structure and performance, while avoiding the introduction of new impurities, maintaining its purity and safety, reducing the implementation process of protective measures, and making it more suitable for large-scale production. Based on the above research results, the present invention is completed.

[0007] Specifically, the present invention is achieved through the following technical solutions:

[0008] The first aspect of the present invention provides the use of poloxamer as a radiation protectant in the sterilization of sodium carboxymethylcellulose hydrogel.

[0009] The poloxamer is specifically poloxamer 188 and / or poloxamer 407.

[0010] The sodium carboxymethylcellulose hydrogel is sterilized by irradiation.

[0011] The second aspect of the present invention provides a sodium carboxymethylcellulose hydrogel, which comprises, by mass percentage, 0.5% to 3% (w / w) sodium carboxymethylcellulose, 15% to 30% (w / w) radiation protection agent, and the balance water;

[0012] It should be noted that, in the present invention, the radiation protection agent is a pharmaceutical grade agent.

[0013] The third aspect of the present invention provides a method for preparing and sterilizing the above-mentioned sodium carboxymethylcellulose hydrogel, the method comprising:

[0014] S1, adding the radiation protection agent into water, and mixing by shaking to obtain an aqueous solution containing the radiation protection agent;

[0015] S2, adding the sodium carboxymethyl cellulose to the aqueous solution containing the radiation protectant, and oscillating and mixing, so that the mixed solution changes from a liquid to a gel, thereby obtaining a sodium carboxymethyl cellulose hydrogel containing a radiation protectant;

[0016] S3. sterilizing the sodium carboxymethylcellulose hydrogel by electron beam irradiation.

[0017] Beneficial technical effects achieved by one or more of the above technical solutions:

[0018] (1) The addition of poloxamer protective agents in the above technical solution reduces the damage to the inherent structure of sodium carboxymethyl cellulose hydrogel during the irradiation process, and the protective effect is obvious and the performance is stable.

[0019] (2) Poloxamer protective agent reagent is a natural extract. Poloxamer is a triblock copolymer composed of poly(ethylene oxide) and poly(propylene oxide). It is a thermosensitive synthetic polymer and is usually used to prepare injectable hydrogels. It has high safety. In addition, poloxamer can form hydrogels at human body temperature through the hydrophilic-hydrophobic interaction between ethylene oxide and propylene oxide in the polymer. Therefore, as the temperature changes, the poloxamer solution exhibits a reversible sol-gel transition. However, the single-component poloxamer will be destroyed after irradiation, which ultimately leads to a decrease in the product's thermosensitive properties and pH value. The sodium carboxymethylcellulose hydrogel with the addition of poloxamer not only maintains its inherent properties, but also increases its thermosensitive properties and increases the product's uses.

[0020] (3) Regardless of whether it is a single-component poloxamer gel or a single-component sodium carboxymethyl cellulose hydrogel, the performance will be greatly damaged after irradiation. However, the composite hydrogel of the two protects the inherent structure and properties of both through the interaction between poloxamer and sodium carboxymethyl cellulose, and significantly improves the stability of irradiation.

[0021] (4) The radiation dose of the product has been significantly expanded, and the radiation protection effect has been further enhanced. Due to the use of effective radiation protection agents, sodium carboxymethylcellulose hydrogel can maintain good performance even at higher radiation doses, thereby broadening the scope of application of the product.

[0022] (5) In the above technical solution, the radiation protection agent is a pharmaceutical grade reagent, which is non-toxic, will not damage the product or pollute the environment, and will not introduce new impurities, thereby ensuring the purity and safety of the sodium carboxymethylcellulose hydrogel.

[0023] (6) The formula is simple, the operation is easy, and it is suitable for large-scale production. During the preparation process, it is only necessary to add the radiation protectant to the purified water, adjust the shaking speed, oscillate and mix evenly, then add sodium carboxymethyl cellulose to the aqueous solution prepared above, oscillate and stir thoroughly again, and finally sterilize by electron beam irradiation. This greatly simplifies the operation process and improves production efficiency.

[0024] (7) The above technical solution also found that under the protection of the radiation protectant, electron beam irradiation sterilization has a greater protective effect on the product and a smaller impact on performance than cobalt 60 irradiation sterilization. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0026] Figure 1This is the infrared spectrum of the sample before and after electron beam irradiation (25KGy) in Example 7 of the present invention (the blue line represents the spectrum before irradiation, and the red line represents the spectrum before irradiation). DETAILED DESCRIPTION

[0027] It should be noted that the following detailed descriptions are all illustrative and intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0028] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components and / or combinations thereof. It should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the embodiments of the present invention are intended to describe specific embodiments, rather than to limit the scope of protection of the present invention.

[0029] The present invention is further described in conjunction with specific examples. The following examples are only for explaining the present invention and are not intended to limit the content thereof. If the specific experimental conditions are not specified in the examples, they are usually carried out according to conventional conditions or the conditions recommended by the reagent company; the reagents and consumables used in the following examples, unless otherwise specified, can be obtained from commercial sources.

[0030] As mentioned above, after irradiation sterilization, sodium carboxymethyl cellulose hydrogel will be greatly damaged without adding protective measures, which will eventually lead to a significant decrease in product viscosity and pH value, ultimately affecting its performance.

[0031] In view of this, in a typical embodiment of the present invention, a use of poloxamer as a radiation protectant in the sterilization of sodium carboxymethylcellulose hydrogel is provided.

[0032] Among them, the poloxamer is specifically poloxamer 188 and / or poloxamer 407, preferably a combination of poloxamer 188 and poloxamer 407, wherein the mass ratio of poloxamer 188 to poloxamer 407 is 0-5:15-25; further preferably, the mass ratio of poloxamer 188 to poloxamer 407 is 3:20.

[0033] The sodium carboxymethylcellulose hydrogel sterilization is specifically irradiation sterilization, specifically electron beam irradiation sterilization, and the irradiation dose is 15 to 25 KGy.

[0034] In another specific embodiment of the present invention, a sodium carboxymethyl cellulose hydrogel is provided, wherein the raw material composition thereof is, by mass percentage, 0.5% to 3% (w / w) of sodium carboxymethyl cellulose, 15% to 30% (w / w) of a radiation protection agent, and the balance is water;

[0035] Wherein, the radiation protectant is poloxamer 188 and / or poloxamer 407, preferably a combination of poloxamer 188 and poloxamer 407, wherein the mass ratio of poloxamer 188 to poloxamer 407 is 0-5:15-25; further preferably, the mass ratio of poloxamer 188 to poloxamer 407 is 3:20.

[0036] It should be noted that, in the present invention, the radiation protection agent is a pharmaceutical grade agent.

[0037] In another specific embodiment of the present invention, a preparation and sterilization method of the above-mentioned sodium carboxymethylcellulose hydrogel is provided, and the preparation and sterilization method comprises:

[0038] S1, adding the radiation protection agent into water, and mixing by shaking to obtain an aqueous solution containing the radiation protection agent;

[0039] S2, adding the sodium carboxymethyl cellulose to the aqueous solution containing the radiation protectant, and oscillating and mixing, so that the mixed solution changes from a liquid to a gel, thereby obtaining a sodium carboxymethyl cellulose hydrogel containing a radiation protectant;

[0040] S3. sterilizing the sodium carboxymethylcellulose hydrogel by electron beam irradiation.

[0041] Wherein, in step S1, the oscillation mixing conditions are: the temperature is controlled at 4-15°C, the rotation speed is 100-300r / min, and the oscillation treatment time is 3-12h;

[0042] In step S2, the oscillation mixing temperature and speed of step S1 are maintained, and the oscillation treatment time is controlled to be 6 to 24 hours;

[0043] In step S3, the irradiation dose is 15 to 25 KGy.

[0044] Furthermore, in step S2, the prepared sodium carboxymethyl cellulose hydrogel may be firstly filled, and specifically, 1-10 ml of the sodium carboxymethyl cellulose hydrogel may be filled into a vial and then sealed.

[0045] The present invention is further explained by the following examples, but they are not intended to limit the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0046] Example Gel Prescription Screening

[0047] 1.1 Screening of gel matrix

[0048] Sodium carboxymethyl cellulose was used as the matrix, and different mass fractions of solution ratios were selected. The optimal ratio of the matrix was selected by viscosity, fluidity and dissolution time. The specific test steps are as follows:

[0049] Weigh appropriate amounts of sodium carboxymethyl cellulose, dissolve them in purified water, place them in a reactor and stir at 250 r / min to dissolve them. When a transparent and clear liquid appears, record the time of complete dissolution. Prepare a gel solution with sodium carboxymethyl cellulose according to the proportions in Table 1.

[0050] Take 50 ml of gel and place it in a 50 ml centrifuge tube, and measure it according to the method specified in the Pharmacopoeia of the People's Republic of China (2020 edition, Volume IV) 0633 Viscosity Determination Method, Method 3, Rotational Viscometer Determination Method.

[0051] Take 5 ml of gel and add it into a vial. Tilt the vial at 180° and observe the flow of the gel.

[0052] Take 5 ml of gel and add it to a vial, and directly measure the pH of the solution with a pH meter.

[0053] Sterilize by electron beam irradiation with a dose of 25 KGy, and then measure the viscosity, flowability and pH.

[0054] Table 1 Preparation of sodium carboxymethyl cellulose solutions with different mass fractions and properties before and after irradiation (25KGy)

[0055]

[0056] From the results in Table 1, it can be concluded that before irradiation, as the content of sodium carboxymethyl cellulose increases, the viscosity increases, and the viscosity increases. Sodium carboxymethyl cellulose has a viscosity in the range of 0.5% to 3% (w / w), and the results are acceptable; however, after electron beam irradiation (25KGy), the viscosity and pH value suddenly drop, and the results are unacceptable.

[0057] 1.2 Selection of radiation protectant concentration

[0058] The mass fraction of sodium carboxymethyl cellulose is 2% (w / w), and poloxamer 407 and poloxamer 188 are used as radiation protection agents. Different mass fraction solution ratios are selected, and the optimal ratio of radiation protection agent is selected through viscosity, fluidity, pH, gelation temperature and gelation time. The specific experimental steps are as follows:

[0059] According to Table 2, weigh appropriate amounts of poloxamer 407 and poloxamer 188 powders, add to purified water, adjust the shaker temperature to 10°C and the speed to 200r / min, shake in the shaker for 12h to mix evenly, and prepare an aqueous solution containing a radiation protectant. Then add 2% (w / w) sodium carboxymethyl cellulose to the aqueous solution prepared above, shake in the shaker for 6h to stir completely, and a transparent and clear liquid is prepared to prepare a sodium carboxymethyl cellulose hydrogel containing a radiation protectant. Adjust the filling amount, fill 10ml of the obtained sodium carboxymethyl cellulose hydrogel into a cillin bottle, add a rubber stopper and a cap. Perform electron beam irradiation sterilization, and the irradiation dose is 25KGy.

[0060] Take 50 ml of gel and place it in a 50 mL centrifuge tube. Determine it at 20°C according to the method specified in the Pharmacopoeia of the People's Republic of China (2020 edition, Volume IV) 0633 Viscosity Determination Method, Method 3, Rotational Viscometer Determination Method.

[0061] Take 5 ml of gel and add it into a vial. Tilt the vial 180° at 25°C and observe the flow of the gel.

[0062] Take 5 ml of gel and add it to a vial, and place it vertically in a constant temperature water bath. After the insulation is completed, gently take out the test tube, slowly invert it at 180°C, and observe its gelation temperature (gelation is when it does not slip off the tube wall).

[0063] Take 5 ml of gel and add it to a vial, and place it vertically in a 37°C constant temperature water bath. After the insulation is completed, gently take out the test tube, slowly invert it at 180°C, and observe the time it takes for gelation (gelation occurs when it does not slip off the tube wall).

[0064] Take 5 ml of gel and add it to a vial. Use a pH meter to directly measure the pH of the solution (the required pH range is 6.5-7.5).

[0065] Table 2 Comparative Examples and Examples Settings and Performance Before and After Irradiation

[0066]

[0067]

[0068] The results of Table 2 show that, in Comparative Examples 1, 6, and 7, sodium carboxymethylcellulose was not added, and the single-component poloxamer was destroyed after irradiation, which eventually led to a decrease in product viscosity, a decrease in temperature-sensitive properties (increase in gelation time), and a decrease in pH value; in Comparative Examples 2 to 5, the amount of poloxamer added was <15%, and the protective effect on sodium carboxymethylcellulose was poor, as shown by a decrease in viscosity and a decrease in pH value after irradiation; in Comparative Example 8, the amount of poloxamer added exceeded 30%, and the viscosity increased, but the protective effect was not obvious. In Examples 1 to 12, sodium carboxymethylcellulose hydrogels with different proportions of poloxamer 407 and poloxamer 188 not only maintained inherent properties, but also significantly increased viscosity, and also increased temperature-sensitive properties, expanding product uses (different use scenarios were selected according to different gelation temperatures), and under the same proportion of poloxamer 407, as the content of poloxamer 188 increased, the gelation temperature increased, and the viscosity of the product after irradiation was significantly increased compared to the viscosity of the product before irradiation. Therefore, the composite hydrogel of the two protects the inherent properties of both through the interaction between poloxamer and sodium carboxymethyl cellulose, and significantly improves the stability of radiation.

[0069] 1.3 Identification

[0070] The unirradiated sample and the electron beam irradiated sample of the best embodiment 7 were ground and pressed into tablets in a conventional manner. The samples were analyzed by Fourier transform infrared microspectroscopy at 400-4000 (cm -1 ) range to scan the infrared spectrum. Figure 1 shown.

[0071] From the infrared spectrum scanning results, it can be seen that the positions of the main characteristic peaks of the product did not change significantly before and after irradiation, which shows that the poloxamer protective agent reduces the damage to the inherent structure of sodium carboxymethyl cellulose hydrogel during the irradiation process, and the protective effect is obvious.

[0072] 1.4 Choice of irradiation method

[0073] The samples of Examples 1 to 12 were irradiated with electron beams of 25 KGy, electron beams of 35 KGy, and cobalt-60 25 KGy, respectively. The pH of the irradiated samples was directly measured with a pH meter. The results are shown in Table 3:

[0074] Table 3 pH before and after electron beam 25Kgy, 35Kgy and cobalt-60 25KGy irradiation

[0075]

[0076]

[0077] The results in Table 3 show that, under the same irradiation dose, the pH change after electron beam irradiation in each embodiment is smaller. This shows that after adding poloxamer protective agents, the effect of electron beam irradiation sterilization on product performance is small, and the same dose of cobalt-60 irradiation sterilization has a small protective effect on the product and a large impact on performance. However, electron beam irradiation of 35KGy has an effect on the pH of the product. Therefore, when the product is irradiated with electron beams and the irradiation dose is ≤25KGy, the irradiation protective agent has a large protective effect on the product and a small impact on performance.

[0078] 1.5 Accelerated stability test

[0079] The accelerated aging time is 2 years (730 days) and the accelerated aging condition is set at 45±2℃. The accelerated aging time is calculated based on the simplified accelerated aging formula:

[0080]

[0081] AAT: Accelerated aging time;

[0082] RT: real-time aging time;

[0083] Q10: Aging coefficient when the temperature rises or falls by 10°C;

[0084] TAA: accelerated aging temperature;

[0085] TRT: Temperature under normal storage conditions.

[0086] Q10 is generally selected as 2.0, TRT is selected as 25°C, and the simplified formula is obtained through accelerated aging:

[0087]

[0088] That is: put the sample into the stability test box and accelerate aging at 45±2℃ for 183 days, which is equivalent to real-time aging at 25℃ for 2 years.

[0089] Table 4 Accelerated stability test results

[0090]

[0091] From the results in Table 4, it can be seen that the difference between Example 7 and Comparative Example 8 is that the ratio of poloxamer 407 and poloxamer 188 added is different. Example 7 can be stored for 2 years at 25°C; after one month of storage, the pH of Comparative Example 8 is significantly reduced. This shows that poloxamer 407 and poloxamer 188 have a better protective effect on sodium carboxymethylcellulose hydrogel in a certain ratio combination, and a composite hydrogel is successfully prepared, which improves stability and breaks the limitation of low-temperature storage of gel.

[0092] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for those skilled in the art to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on parts thereof. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention. Although the above describes the specific implementation modes of the present invention in conjunction with the accompanying drawings, it is not intended to limit the protection scope of the present invention. Those skilled in the art should understand that, based on the technical solution of the present invention, various modifications or deformations that can be made by those skilled in the art without creative labor are still within the protection scope of the present invention.

Claims

1. Application of poloxamer as radiation protectant in sterilization of sodium carboxymethylcellulose hydrogel.

2. The use according to claim 1, characterized in that: The poloxamer is specifically poloxamer 188 and / or poloxamer 407, preferably a combination of poloxamer 188 and poloxamer 407, wherein the mass ratio of poloxamer 188 to poloxamer 407 is 0-5:15-25; further preferably, the mass ratio of poloxamer 188 to poloxamer 407 is 3:

20.

3. The use according to claim 1, characterized in that: The sodium carboxymethylcellulose hydrogel sterilization is specifically irradiation sterilization, and further is electron beam irradiation sterilization, and the irradiation dose is 15 to 25 KGy.

4. A sodium carboxymethylcellulose hydrogel, characterized in that The raw material composition is as follows by mass percentage: 0.5% to 3% (w / w) of sodium carboxymethyl cellulose, 15% to 30% (w / w) of radiation protection agent, and the balance is water.

5. The sodium carboxymethylcellulose hydrogel according to claim 4, characterized in that The radiation protectant is poloxamer 188 and / or poloxamer 407, preferably a combination of poloxamer 188 and poloxamer 407, wherein the mass ratio of poloxamer 188 to poloxamer 407 is 0-5:15-25; further preferably, the mass ratio of poloxamer 188 to poloxamer 407 is 3:

20.

6. The method for preparing and sterilizing the sodium carboxymethylcellulose hydrogel according to claim 4 or 5, characterized in that: The preparation and sterilization method comprises: S1, adding the radiation protection agent into water, and mixing by shaking to obtain an aqueous solution containing the radiation protection agent; S2, adding the sodium carboxymethyl cellulose to the aqueous solution containing the radiation protectant, and oscillating and mixing, so that the mixed solution changes from a liquid to a gel, thereby obtaining a sodium carboxymethyl cellulose hydrogel containing a radiation protectant; S3. sterilizing the sodium carboxymethylcellulose hydrogel by electron beam irradiation.

7. The preparation and sterilization method according to claim 6, characterized in that: In step S1, the oscillation mixing conditions are: the temperature is controlled at 4-15° C., the rotation speed is 100-300 r / min, and the oscillation treatment time is 3-12 h.

8. The preparation and sterilization method according to claim 6, characterized in that: In step S2, the oscillation mixing temperature and rotation speed of step S1 are maintained, and the oscillation treatment time is controlled to be 6 to 24 hours.

9. The preparation and sterilization method according to claim 6, characterized in that: In step S3, the irradiation dose is 15 to 25 KGy.

10. The preparation and sterilization method according to claim 6, characterized in that: In the step S2, the prepared sodium carboxymethyl cellulose hydrogel is firstly filled, and specifically, 1-10 ml of the sodium carboxymethyl cellulose hydrogel is filled into a vial and then sealed.

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